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Clinical practice guidelines: Type 1 diabetes in children and adolescents Prepared by the Australasian Paediatric Endocrine Group for the Department of Health and Ageing APPROVED BY THE NHMRC ON 9 MARCH 2005 © Commonwealth of Australia 2005 ISBN Online: 0 642 82630 7 Electronic publications This work is copyright. You may download, display, print and reproduce this material in unaltered form only (retaining this notice) for your personal, non-commercial use or use within your organisation. Apart from any use as permitted under the Copyright Act 1968, all other rights are reserved. Requests for further authorisation should be directed to the Commonwealth Copyright Administration, Attorney-General’s Department, Robert Garran Offices, National Circuit, Canberra ACT 2600 or posted at http://www.ag.gov.au/cca These guidelines were approved by the National Health and Medical Research Council (NHMRC) at its 156th Session on 9 March 2005, under Section 14A of the National Health and Medical Research Council Act 1992. Approval for the guidelines by NHMRC is granted for a period not exceeding five years, at which date the approval expires. The NHMRC expects that all guidelines will be reviewed no less than once every five years. Readers should check with the Department of Health and Ageing for any reviews or updates of these guidelines. Disclaimer This document is a general guide to appropriate practice, to be followed subject to the clinician’s judgement and the patient’s preference in each individual case. The guidelines are designed to provide information to assist decision-making and are based on the best evidence available at the time of compilation. These guidelines can be downloaded from the National Health and Medical Research Council website: www.nhmrc.gov.au/publications. i Table of Contents Table of Contents .............................................................................................................. i Tables ............................................................................................................................... x Figures .............................................................................................................................. x Introduction ....................................................................................................................... 1 Background....................................................................................................................... 1 Rationale for the Guidelines .............................................................................................. 1 Scope of the Guidelines..................................................................................................... 1 Areas beyond the remit of the guidelines........................................................................ 1 Target Audience................................................................................................................ 2 Guidelines Development Process ...................................................................................... 2 Guidelines writing committee ........................................................................................ 2 Review of existing guidelines ......................................................................................... 2 Formulation of Clinical Questions..................................................................................... 2 Locating the Evidence ....................................................................................................... 2 Levels of Evidence and Critical Appraisal ......................................................................... 3 Economic Considerations.................................................................................................. 6 Guidelines Review Date .................................................................................................... 6 Structure of the Guidelines ................................................................................................ 6 Overview of the Guidelines ............................................................................................... 6 Consultation and Peer-review Process ............................................................................... 7 Dissemination ................................................................................................................... 7 Legal Considerations......................................................................................................... 7 Reference List ................................................................................................................... 7 List of Abbreviations ....................................................................................................... 8 Acknowledgements .......................................................................................................... 9 Executive Summary of Recommendations and Principles ..................................... 10 1. Definition, Epidemiology and Classification............................................................... 10 2. Phases of Diabetes...................................................................................................... 10 3. Medical Management ................................................................................................. 11 4. Insulin Preparations and Storage................................................................................. 11 5. Insulin Regimens and Delivery................................................................................... 12 6. Glycaemic Control ..................................................................................................... 13 7. Nutrition..................................................................................................................... 13 8. Physical Activity ........................................................................................................ 14 9. Diabetic Ketoacidosis................................................................................................. 14 10. Surgery and Fasting.................................................................................................. 15 11. Sick Day Management.............................................................................................. 15 12. Hypoglycaemia ........................................................................................................ 16 13. Psychosocial Aspects................................................................................................ 17 14. Diabetes Complications ............................................................................................ 17 15. Other Complications and Associated Conditions ...................................................... 18 16. Foot Care.................................................................................................................. 18 17. Dental Health ........................................................................................................... 18 18. Adolescent Health Issues .......................................................................................... 18 19. School ...................................................................................................................... 19 20. Diabetes Camps for Children and Adolescents.......................................................... 20 21. Travelling and Holidays ........................................................................................... 20 Table of Contents Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents ii 22. Complementary and Alternative Medicine................................................................ 20 Reference List ................................................................................................................. 21 Chapter 1: Definition, Epidemiology and Classification......................................... 10 Definition........................................................................................................................ 26 Epidemiology.................................................................................................................. 26 Classification .................................................................................................................. 28 Clinical Staging of Diabetes ............................................................................................ 28 Aetiologic Classification of Diabetes............................................................................... 29 Diagnostic Criteria for Diabetes in Childhood and Adolescence ...................................... 31 Oral Glucose Tolerance Test (OGTT) ............................................................................. 32 Interpretation of OGTT ................................................................................................... 32 Intravenous Glucose Tolerance Test (IVGTT)................................................................. 33 Metabolic Syndrome ....................................................................................................... 33 Type 2 Diabetes .............................................................................................................. 34 Screening for Type 2 Diabetes......................................................................................... 35 Other Types of Diabetes.................................................................................................. 35 Maturity Onset Diabetes of the Young (MODY) ............................................................. 35 DIDMOAD Syndrome (Wolfram Syndrome) .................................................................. 36 Mitochondrial Diabetes ................................................................................................... 36 Neonatal Diabetes ........................................................................................................... 36 Cystic Fibrosis and Diabetes ........................................................................................... 37 Drug Induced Diabetes.................................................................................................... 37 Stress Hyperglycaemia .................................................................................................... 37 The Evidence .................................................................................................................. 38 Recommendations and Principles .................................................................................... 38 Reference List ................................................................................................................. 39 Chapter 2: Phases of Diabetes ...................................................................................... 41 Preclinical Diabetes......................................................................................................... 41 Risks of progression to diabetes................................................................................... 41 Presentation of Type 1 Diabetes ...................................................................................... 42 Non-emergency presentations...................................................................................... 42 Emergency presentations............................................................................................. 42 Diagnostic difficulties leading to late diagnosis........................................................... 43 Differentiating between type 1 and type 2 diabetes at diagnosis................................... 43 Partial Remission or Honeymoon Phase .......................................................................... 43 Chronic Phase of Lifelong Dependence on Insulin .......................................................... 43 Transplantation........................................................................................................... 44 The Evidence .................................................................................................................. 44 Recommendations and Principles .................................................................................... 44 Reference List ................................................................................................................. 45 Chapter 3: Medical Management................................................................................. 46 Aims of Diabetes Management........................................................................................ 46 Hospital versus Ambulatory Stabilisation ........................................................................ 46 Foundations of Diabetes Management............................................................................. 47 Diabetes Education.......................................................................................................... 47 Insulin Replacement Therapy .......................................................................................... 48 Immunisation .................................................................................................................. 48 Outreach Services ........................................................................................................... 49 Transition to Adult Services ............................................................................................ 49 Cost Issues ...................................................................................................................... 49 Table of Contents Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents iii The Evidence .................................................................................................................. 49 Recommendations and Principles .................................................................................... 50 Reference List ................................................................................................................. 51 Chapter 4: Insulin Preparations and Storage ............................................................. 53 Insulin Action ................................................................................................................. 53 Types of Insulin .............................................................................................................. 53 Rapid-acting insulin .................................................................................................... 54 Short-acting insulin ..................................................................................................... 55 Intermediate-acting insulin.......................................................................................... 55 Long-acting insulins .................................................................................................... 55 Basal insulin analogues............................................................................................... 55 Premixed insulin preparations..................................................................................... 56 Local Reactions to Insulin ............................................................................................... 56 Mixing Insulins ............................................................................................................... 56 Insulin Concentrations..................................................................................................... 57 Storage Conditions .......................................................................................................... 57 Adjunct Therapy with Oral Antidiabetic Drugs ............................................................... 57 Cost Issues ...................................................................................................................... 59 The Evidence .................................................................................................................. 59 Recommendations and Principles .................................................................................... 59 Reference List ................................................................................................................. 60 Chapter 5: Insulin Regimens and Delivery ................................................................ 62 Insulin Regimens............................................................................................................. 62 Use of Short-Acting Insulin............................................................................................. 63 Use of Intermediate and Long-Acting Insulins................................................................. 64 Regimens using Pre-mixed Insulins................................................................................. 64 Number of Injections per Day ......................................................................................... 64 Total Daily Insulin Dosage and Distribution.................................................................... 65 Insulin Administration..................................................................................................... 65 Insulin absorption ....................................................................................................... 65 Insulin Delivery Devices ................................................................................................. 67 Insulin syringes and pens ............................................................................................ 67 Automatic injection devices ......................................................................................... 68 Jet injection devices..................................................................................................... 68 Indwelling cannulas .................................................................................................... 68 Insulin pumps (CSII) ................................................................................................... 68 Practical Aspects of Insulin Administration..................................................................... 68 Insulin Adjustment .......................................................................................................... 69 Adjusting usual doses of insulin based on blood glucose patterns over several days or longer.......................................................................................................................... 69 Pro-active day to day adjustments to insulin based on activity and food intake............ 70 Adjustments to correct the current BG level when it is outside the desired range ......... 70 Insulin pump adjustments ............................................................................................ 70 Cost Issues ...................................................................................................................... 71 The Evidence .................................................................................................................. 71 Recommendations and Principles .................................................................................... 72 Reference List ................................................................................................................. 72 Chapter 6: Glycaemic Control ..................................................................................... 75 Intensive Diabetes Management ...................................................................................... 75 Risks and Side Effects of Intensive Diabetes Management .............................................. 75 Table of Contents Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents iv Indicators of Poor Glycaemic Control ............................................................................. 75 Glycaemic Goals ............................................................................................................. 76 Parameters of Glycaemic Control .................................................................................... 77 Blood Glucose Monitoring .............................................................................................. 77 Timing of blood glucose testing ................................................................................... 77 Techniques for blood glucose testing ........................................................................... 78 Devices for blood glucose testing ................................................................................ 78 Record keeping and review of records ......................................................................... 79 HbA1C ............................................................................................................................. 80 Fructosamine................................................................................................................... 81 Urine Testing for Glucose ............................................................................................... 81 Testing for Ketones ......................................................................................................... 81 Blood ketones .............................................................................................................. 81 Urine ketones .............................................................................................................. 82 The Evidence .................................................................................................................. 82 Recommendations and Principles .................................................................................... 83 Reference List ................................................................................................................. 84 Chapter 7: Nutrition ....................................................................................................... 86 Nutrition Therapy............................................................................................................ 86 Nutritional Assessment.................................................................................................... 86 Nutrition Review............................................................................................................. 86 Dietary Recommendations .............................................................................................. 87 Energy Intake.................................................................................................................. 87 Dietary Carbohydrate ...................................................................................................... 88 Glycaemic Index (GI)...................................................................................................... 88 Sugars ............................................................................................................................. 89 Artificially sweetened products.................................................................................... 89 Fibre ............................................................................................................................... 90 Dietary Fat Intake............................................................................................................ 90 Protein ............................................................................................................................ 91 Variations in Advised Meal Patterns and Insulin Regimens ............................................. 91 Age-group Specific Advice ............................................................................................. 92 Infants ......................................................................................................................... 92 Toddlers ...................................................................................................................... 92 Primary school-aged children ..................................................................................... 92 Adolescents ................................................................................................................. 92 The Evidence .................................................................................................................. 93 Recommendations and Principles .................................................................................... 93 Reference List ................................................................................................................. 96 Chapter 8: Physical Activity ......................................................................................... 98 Need for Physical Activity and General Recommendations ............................................. 98 Short-Term Effects.......................................................................................................... 98 Long-term Effects ........................................................................................................... 99 The Evidence .................................................................................................................. 99 Recommendations and Principles .................................................................................. 100 Reference List ............................................................................................................... 100 Chapter 9: Diabetic Ketoacidosis .............................................................................. 101 Definition and Aetiology............................................................................................... 101 Epidemiology................................................................................................................ 102 Management ................................................................................................................. 103 Table of Contents Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents v Steps in the Assessment and Management of Diabetic Ketoacidosis .............................. 103 Investigation ................................................................................................................. 105 Monitoring .................................................................................................................... 106 Rehydration................................................................................................................... 106 Sodium Replacement..................................................................................................... 107 Potassium Replacement................................................................................................. 107 Bicarbonate Replacement .............................................................................................. 108 Insulin........................................................................................................................... 108 Management of Cerebral Oedema ................................................................................. 109 Management of the Recovery Phase .............................................................................. 110 Oral fluids ................................................................................................................. 110 Covering snacks and meals on intravenous insulin infusion....................................... 110 Transition from intravenous to subcutaneous insulin ................................................. 110 The Evidence ................................................................................................................ 111 Recommendations and Principles .................................................................................. 113 Reference List ............................................................................................................... 114 Chapter 10: Surgery and Fasting ............................................................................... 117 Emergency Surgery....................................................................................................... 117 Elective Surgery............................................................................................................ 117 Scheduling of Surgery ................................................................................................... 117 Maintaining Metabolic Control ..................................................................................... 117 Intravenous Fluids......................................................................................................... 118 Management of Short or Minor Procedures Involving Sedation or Anaesthesia ............. 118 Patients on twice or three times daily insulin regimens.............................................. 118 Patients on basal-bolus insulin regimens................................................................... 119 Patients on insulin pumps.......................................................................................... 119 Major Surgery or Surgery where Oral Intake is not Possible for a Prolonged Period...... 120 Insulin Infusion Rates.................................................................................................... 120 The Evidence ................................................................................................................ 120 Recommendations and Principles .................................................................................. 120 Reference List ............................................................................................................... 121 Chapter 11: Sick Day Management .......................................................................... 122 Diabetes and Infectious Illnesses ................................................................................... 122 Impact of Illnesses on Diabetes ..................................................................................... 122 Infections Causing Little Effect on Blood Glucose Levels ............................................. 122 Infections Causing Low Blood Glucose levels............................................................... 123 Infections Causing High Blood Glucose Levels............................................................. 123 General Principles of Sick Day Management................................................................. 123 Insulin Regimens in Infections associated with Hyperglycaemia and Ketosis ................ 125 Management at home ................................................................................................ 125 Management in hospital ............................................................................................ 126 Insulin Regimens in Infections Associated with Persistent Hypoglycaemia ................... 127 Management at home ................................................................................................ 127 Management in hospital ............................................................................................ 127 Glucagon....................................................................................................................... 127 Minidose Glucagon ....................................................................................................... 127 Insulin Pump Sick Day Management............................................................................. 128 The Evidence ................................................................................................................ 129 Recommendations and Principles .................................................................................. 129 Reference List ............................................................................................................... 130 Table of Contents Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents vi Chapter 12: Hypoglycaemia ....................................................................................... 131 Definition...................................................................................................................... 131 Symptoms and Signs ..................................................................................................... 131 Grading ......................................................................................................................... 133 Frequency ..................................................................................................................... 133 Nocturnal Hypoglycaemia............................................................................................. 133 Consequences................................................................................................................ 134 Counter-Regulatory Responses to Hypoglycaemia and Hypoglycaemia Unawareness ... 134 Prevention..................................................................................................................... 135 Confirmation................................................................................................................. 135 Treatment...................................................................................................................... 135 Mild to moderate hypoglycaemia............................................................................... 135 Severe hypoglycaemia ............................................................................................... 136 Follow-Up of Treatment of Hypoglycaemia .................................................................. 136 Hypoglycaemia and Physical Activity ........................................................................... 137 Somogyi Phenomenon................................................................................................... 137 Hypoglycaemia in School.............................................................................................. 137 Foods for Management of Hypoglycaemia .................................................................... 138 The Evidence ................................................................................................................ 138 Recommendations and Principles .................................................................................. 139 Reference List ............................................................................................................... 139 Chapter 13: Psychosocial Aspects ............................................................................. 142 Impact on Child............................................................................................................. 142 Impact on Family .......................................................................................................... 142 Psychosocial Factors and Metabolic Control ................................................................. 143 Adherence to Therapy ................................................................................................... 144 Risk Factors .................................................................................................................. 145 Treatments and Interventions ........................................................................................ 145 The Evidence ................................................................................................................ 146 Recommendations and Principles .................................................................................. 147 Reference List ............................................................................................................... 147 Chapter 14: Diabetes Complications......................................................................... 150 Discussing Complications ............................................................................................. 150 Diabetic Retinopathy..................................................................................................... 150 Prevalence and association studies of retinopathy..................................................... 151 Screening for retinopathy .......................................................................................... 152 Interventions to prevent or delay progression of diabetic retinopathy ........................ 153 Cataracts ....................................................................................................................... 153 Refractive Errors ........................................................................................................... 153 Diabetic Nephropathy ................................................................................................... 154 Screening for nephropathy ........................................................................................ 154 Interventions to prevent or delay progression of diabetic nephropathy ...................... 155 Diabetic Neuropathy ..................................................................................................... 156 Screening for neuropathy .......................................................................................... 156 Interventions to prevent or delay diabetic neuropathy ............................................... 157 Macrovascular Disease.................................................................................................. 157 Hypertension................................................................................................................. 157 Blood pressure assessment in children and adolescents............................................. 157 Method for BP measurement ..................................................................................... 157 Paediatric reference values ....................................................................................... 158 Table of Contents Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents vii Ambulatory blood pressure monitoring...................................................................... 159 Paediatric reference values ....................................................................................... 159 Summary of blood pressure measurement methods .................................................... 159 Age of screening for hypertension.............................................................................. 160 Definition of hypertension ......................................................................................... 160 Management of hypertension..................................................................................... 160 Dyslipidaemia ............................................................................................................... 162 Interventions for dyslipidaemia ................................................................................. 162 Hypercoagulablity ......................................................................................................... 163 Cost Issues .................................................................................................................... 163 The Evidence ................................................................................................................ 163 Recommendations and Principles .................................................................................. 164 Reference List ............................................................................................................... 165 Chapter 15: Other Complications and Associated Conditions ............................. 169 Lipodystrophy (Lipoatrophy and Lipohypertrophy)....................................................... 169 Necrobiosis Lipoidica Diabeticorum ............................................................................. 169 Limited Joint Mobility .................................................................................................. 169 Osteopenia .................................................................................................................... 169 Impaired Growth and Development............................................................................... 170 Associated Autoimmune Conditions.............................................................................. 170 Hypothyroidism ......................................................................................................... 170 Hyperthyroidism........................................................................................................ 170 Coeliac disease ......................................................................................................... 171 Vitiligo ...................................................................................................................... 172 Oedema..................................................................................................................... 172 Primary adrenal insufficiency (Addison's disease)..................................................... 172 The Evidence ................................................................................................................ 172 Recommendations and Principles .................................................................................. 173 Reference List ............................................................................................................... 173 Chapter 16: Foot Care.................................................................................................. 176 Deformity...................................................................................................................... 176 Plantar Callus................................................................................................................ 177 High Plantar Pressure .................................................................................................... 177 Soft Tissue Changes ...................................................................................................... 177 Limited Joint Mobility .................................................................................................. 178 The Evidence ................................................................................................................ 178 Recommendations and Principles .................................................................................. 179 Reference List ............................................................................................................... 179 Chapter 17: Dental Health .......................................................................................... 180 Dental Caries ................................................................................................................ 180 Periodontal Disease....................................................................................................... 180 Prevention and Treatment of Dental Caries and Gingivitis............................................. 181 The Evidence ................................................................................................................ 182 Recommendations and Principles .................................................................................. 182 Reference List ............................................................................................................... 182 Chapter 18: Adolescent Health .................................................................................. 184 Introduction................................................................................................................... 184 An Approach to the Assessment of Adolescents ............................................................ 184 Transition to Adult Care................................................................................................ 184 Table of Contents Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents viii Career Options .............................................................................................................. 186 Driving.......................................................................................................................... 186 Risk Taking Behaviour.................................................................................................. 187 Smoking .................................................................................................................... 187 Alcohol...................................................................................................................... 188 Drugs ........................................................................................................................ 189 Sexuality ....................................................................................................................... 189 Impotence.................................................................................................................. 189 Contraceptives .......................................................................................................... 190 Oral contraceptive pill (OCP) ................................................................................... 190 Intrauterine devices (IUDs) ....................................................................................... 190 Barrier methods (condom, diaphragm)...................................................................... 190 Progestogen depot/implant ........................................................................................ 190 Diabetes and Pregnancy ................................................................................................ 191 Eating Disorders............................................................................................................ 191 The Evidence ................................................................................................................ 192 Recommendations and Principles .................................................................................. 192 Reference List ............................................................................................................... 193 Chapter 19: School ....................................................................................................... 196 General Considerations in the Development of the Care Plan ........................................ 197 Issues to be Considered in the Individual Care Plan....................................................... 197 Detentions..................................................................................................................... 199 Travel to and from School by Bus ................................................................................. 199 Emergencies at School .................................................................................................. 199 School Examinations..................................................................................................... 199 High School Examinations ............................................................................................ 199 School Camps ............................................................................................................... 200 Short-term Effects of Fluctuations in Glycaemia on Cognitive Function........................ 200 Long-term Effects of Fluctuations in Glycaemia on Cognitive Function ........................ 200 The Evidence ................................................................................................................ 201 Recommendations and Principles .................................................................................. 201 Reference List ............................................................................................................... 202 Chapter 20: Diabetes Camps ...................................................................................... 203 Background................................................................................................................... 203 The Need for Diabetes Camps in Australia .................................................................... 203 Benefits......................................................................................................................... 203 Goals............................................................................................................................. 204 Other Benefits ............................................................................................................... 204 Prerequisites.................................................................................................................. 204 Medical Management.................................................................................................... 205 Conclusion .................................................................................................................... 205 Information on diabetes camps ...................................................................................... 205 Recommendations and Principles .................................................................................. 206 Reference List ............................................................................................................... 206 Chapter 21: Travelling and Holidays ........................................................................ 207 Preparation.................................................................................................................... 207 Supplies ........................................................................................................................ 207 Management of Diabetes on Long Flights ..................................................................... 208 The Evidence ................................................................................................................ 208 Table of Contents Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents ix Recommendations and Principles .................................................................................. 209 Reference List ............................................................................................................... 209 Chapter 22: Complementary and Alternative Medicine ........................................ 210 Complementary and Alternative Medicine use in Diabetes ............................................ 210 Clinicians and Complementary and Alternative Medicine ............................................. 210 Management of a Patient using Complementary and Alternative Medicine.................... 211 The Evidence ................................................................................................................ 212 Recommendations and Principles .................................................................................. 212 Reference List ............................................................................................................... 213 Resources ....................................................................................................................... 214 Diabetes Australia (DA) ................................................................................................ 214 Contact Details for Diabetes Australia States & Territories............................................ 214 Juvenile Diabetes Research Foundation (JDRF) ............................................................ 214 Health Care Card........................................................................................................... 214 Carer Allowance (CA)................................................................................................... 215 International Diabetes Federation (IDF) School Information Pack ................................. 215 Other Resources ............................................................................................................ 215 Appendix 1: Guidelines Writing Committee Members and Contributors.......... 216 Writing committee members ......................................................................................... 216 Contributors .................................................................................................................. 217 Appendix 2: Evidence Tables .................................................................................... 219 Chapter 1: Definition, Epidemiology and Classification ................................................ 219 Chapter 2: Phases of Diabetes ....................................................................................... 220 Chapter 3: Medical Management................................................................................... 222 Chapter 4: Insulin Preparations and Storage .................................................................. 226 Chapter 5: Insulin Regimens and delivery ..................................................................... 230 Chapter 6: Glycaemic Control ....................................................................................... 235 Chapter 7: Nutrition ...................................................................................................... 241 Chapter 8: Physical Activity.......................................................................................... 247 Chapter 9: Diabetic Ketoacidosis................................................................................... 248 Chapter 10: Surgery and Fasting.................................................................................... 263 Chapter 11: Sick Day Management ............................................................................... 264 Chapter 12: Hypoglycaemia .......................................................................................... 265 Chapter 13: Psychosocial Aspects ................................................................................. 272 Chapter 14: Diabetes Complications.............................................................................. 280 Chapter 15: Other Complications and Associated Conditions ........................................ 283 Chapter 16: Foot Care ................................................................................................... 285 Chapter 17: Dental Health ............................................................................................. 287 Chapter 18: Adolescent Health Issues............................................................................ 289 Chapter 19: School........................................................................................................ 299 Chapter 20: Diabetes Camps ......................................................................................... 302 Chapter 21: Travelling and Holidays ............................................................................. 302 Chapter 22: Complementary and Alternative Medicine ................................................. 303 Table of Contents Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents x Tables Table I: NHMRC Levels of Evidence.................................................................................... 5 Table II: Recommendation Codes ......................................................................................... 6 Table 1.1: Aetiological Classification of Disorders of Glycaemia........................................ 29 Table 1.2: Other Specific Types of Diabetes........................................................................ 30 Table 1.3: WHO Criteria Values for Diagnosis of Diabetes Mellitus and Other Categories of Hyperglycaemia .......................................................................................................... 31 Table 4.1: Insulins Currently in Use in Australia ................................................................. 54 Table 5.1: Mean Cutis/Subcutis Thickness .......................................................................... 66 Table 7.1: The Dietary Guidelines for Children and Adolescents in Australia...................... 87 Table 7.2: The Glycaemic Index of Some Foods (Glucose = 100) ....................................... 89 Table 7.3: Summary of the Australian Dietary Guidelines for Dietary Fat Intake during Childhood ................................................................................................................... 90 Table 10.1: Maintenance Fluid Volume for Different Age Groups .................................... 118 Table 11.1: Emergency Kit For Sick Day Management at Home....................................... 124 Table 11.2: Indicators for Patient to be Transferred to Hospital ......................................... 125 Table 11.3: Sick Day Foods and Fluids ............................................................................. 125 Table 11.4: How to Calculate the Amount of Extra Insulin on Sick Day............................ 126 Table 11.5: Recommended Dose for Mini-dose Glucagon................................................. 127 Table 11.6: Management of Sick Days with Insulin Pump................................................. 128 Table 12.1: Symptoms of Hypoglycaemia in Diabetic Children and Recommendations for its Treatment.................................................................................................................. 132 Table 14.1: Blood Pressure Ranges for Height Centiles..................................................... 161 Figures Figure 1.1: Annual Incidence Rates for Type 1 Diabetes (0-14 years age group) Comparing Different Countries in the World ................................................................................. 27 Figure 4.1: Schematic Action Profiles of Insulin Preparations ............................................. 58 Figure 5.1: Recommended Injection Sites ........................................................................... 66 Figure 7.1: Body Mass Index-for-age Percentiles: Girls, 2-20 Years.................................... 94 Figure 7.2: Body Mass Index-for-age Percentiles: Boys, 2-20 Years ................................... 95 Figure 12.1: Glucagon Kit for Treatment of Hypoglycaemia ............................................. 136 Table of Contents Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 1 Introduction Background The development of the Australian Clinical Practice Guidelines for the Management of Type 1 Diabetes in Children and Adolescents arose out of a recommendation by the National Diabetes Strategy Group to update the APEG Handbook on Childhood and Adolescent Diabetes published in 1996. In updating the guidelines, the decision was made to take an evidence-based approach in order to improve the usefulness of the guidelines for practising clinicians. The project was funded by the Australian Government Department of Health and Ageing and carried out by the Australasian Paediatric Endocrine Group in collaboration with Diabetes Australia and the Juvenile Diabetes Research Foundation. Consumer input was obtained from the latter two organisations and by nationwide public consultation. The guidelines development process was coordinated by a national multidisciplinary writing committee, which met to determine the scope of the work and resolved that the new guidelines would be aimed at the practising health care professional involved in all aspects of the care of children and adolescents with type 1 diabetes. It was considered important that the guidelines were to retain the user-friendly format of the APEG handbook. The guidelines were developed in accordance with the NHMRC handbook series on preparing clinical practice guidelines.(1-7) Rationale for the Guidelines Type 1 diabetes is the one of the most common chronic diseases of childhood and adolescence. It affects approximately 10,000 children and adolescents in Australia and its incidence is rising 2-4% per year. The disease impacts heavily on their lifestyle and that of their families. Lifelong insulin replacement and monitoring of blood glucose levels are needed. Children and adolescents with type 1 diabetes are liable to acute, subacute and chronic complications of diabetes. The development and progression of the chronic microvascular complications of diabetes are influenced by diabetes control. The transition process from paediatric to adult services has been highlighted as an area of need. People with type 1 diabetes are also at greater risk of developing cardiovascular disease. These risks can be decreased by control of high blood pressure and lipid disorders. Regular review of diabetes control and of the risk factors for the development of microvascular and macrovascular complications of diabetes need to form part of the long-term management of type 1 diabetes. The economic burden of diabetes is high for the individual, the family, the health care sector and society as a whole. In addition there is a high personal and family burden in growing up and living with type 1 diabetes. Scope of the Guidelines The guidelines address the diagnosis and all relevant aspects relating to the clinical management of type 1 diabetes in children of all ages, including adolescents up to the point of transition to adult care. Areas beyond the remit of the guidelines The guidelines do not address: • The management of type 1 diabetes in adults. • The management of gestational diabetes. • The management of type 2 diabetes. Introduction Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 2 Target Audience The guidelines are aimed at all health care professionals involved in the care of children and adolescents with type 1 diabetes. Guidelines Development Process Guidelines writing committee A multidisciplinary writing committee was convened consisting of clinicians, diabetes educators, consumers, parents, and experts in guideline development. The members of the Writing Committee and other contributors are listed in Appendix 1. Review of existing guidelines Other guidelines, position papers and technical reports regarding the management of type 1 diabetes in children and adolescents were sought from the World Health Organization (WHO), International Diabetes Federation (IDF), American Diabetes Association (ADA), National Health and Medical Research Council (NHMRC), Australian Paediatric Endocrine Group (APEG) and International Society for Pediatric and Adolescent Diabetes (ISPAD). In addition, the Writing Group was privileged to have access to the UK National Health Services (NHS) National Institute of Clinical Excellence (NICE) guideline on type 1 diabetes: Diagnosis and Management of type 1 diabetes in children and young people to be released in 2004, and the findings of the Consensus Statement on Diabetic Ketoacidosis by the Lawson Wilkins Pediatric Endocrine Society (USA) and the European Society for Pediatric Endocrinology (ESPE), produced in September, 2003. The above sources were considered for their usefulness in updating the 1996 APEG Handbook. The NICE guidelines and the Consensus Statement on Diabetic Ketoacidosis (DKA), in particular, were found to be evidence-based documents which could be adapted to inform the update of the 1996 APEG guidelines. Formulation of Clinical Questions The writing committee formulated clinical questions which needed to be addressed by the updated guidelines. Questions were formulated to cover areas of controversy or of particular concern within the Australian health care context. These questions are listed in Appendix 2. Locating the Evidence The relevant literature was systematically searched with the aim of identifying the clinical, epidemiological, psychosocial, research and diagnostic data relevant to type 1 diabetes in children and adolescents. Electronic databases (Medline, Embase, the Cochrane Database of Systematic Reviews and Central Register of Controlled Trials, and, where relevant to the topic, PsychINFO and CINAHL) were searched from inception to August 31, 2003. Search strategies were devised to address the clinical questions and incorporated key words, MeSH terms (Medical Index Subject Headings) and free text terms. All searches were restricted to English language and Human studies. The only animal study cited was a classic study on CSF pH changes in diabetic ketoacidosis in dogs which was published in the Journal of Pediatrics in 1980 (Bureau MA, Begin R, Berthiaume Y, Shapcott D, Khoury K, Gagnon N: Cerebral hypoxia from bicarbonate infusion in diabetic acidosis. Journal of Pediatrics 96:968-973, 1980). Studies available only as abstracts were excluded from the main analysis. No age limit was used in the searches (ie all paediatric and adult literature was considered). In considering Introduction Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 3 the search yield, the primary focus was on childhood studies. However, the adult literature was included when considered relevant to childhood and adolescent practice. As it was anticipated that for many important areas of type 1 diabetes management and care there would be a paucity of high quality evidence, studies of all types were included. Additional references were identified from the reference lists of relevant articles and by a ‘call for information’ from colleagues and experts involved in the writing process of the guidelines. Evidence tables are listed in Appendix 2. Four additional references were added to the evidence tables as a result of the public consultation (Evidence Tables: Chapter 3, Srinivasan et al. 2004; Chapter 4, Sarnblad et al. 2003; Chapter 5, Diglas et al. 1999; Chapter 12, Schoenle et al. 2002). Additional references, provided by expert reviewers during the public consultation phase, not included in the evidence tables, but relevant to the background information of the document, were included after consideration by the writing committee (even if published after the 30th August 2003). Levels of Evidence and Critical Appraisal These guidelines searched for evidence for the following issues in detail: Chapter 1: Definition, Epidemiology and Classification Prevalence/incidence of type 1 diabetes in children in Australia/worldwide. • Chapter 2: Phases of Diabetes Intervention trials to delay or prevent the onset of type 1 diabetes. • Chapter 3: Medical Management Benefits of ambulatory care versus hospital in-patient care of patient with newly diagnosed type 1 diabetes. Differences in glycaemic control between urban and rural children and adolescents with type 1 diabetes in the Australian health care system. The effect of educational interventions on metabolic and psychological outcomes in children and adolescents with type 1 diabetes. • Chapter 4: Insulin Preparations and Storage Benefits of animal insulin over human insulin use in children and adolescents with type 1 diabetes. Treatment of children with type 1 diabetes with insulin glargine. Metformin as an adjunct therapy to insulin in the treatment of children and adolescents with type 1 diabetes. • Chapter 5: Insulin Regimens and delivery Relationship of number of daily insulin injections with glycaemic control. The length of needle for the injection for insulin therapy in the treatment of children with type 1 diabetes. Children and adolescents with type 1 diabetes and management with insulin pump therapy. • Chapter 6: Glycaemic Control Benefits of near patient testing of HbA1c at outpatient visits. Benefits of improved glycaemic control on development of microvascular and macrovascular complications. • Chapter 7: Nutrition Low glycaemic index diets in the management of type 1 diabetes in children and adolescents. Adjusting insulin dose for carbohydrate quantity in the management of type 1 diabetes in children and adolescents. • Introduction Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 4 • • • • • • • • • • • Effect of moderate use of sugars on glycaemic control in children and adolescents with type 1 diabetes. Chapter 8: Physical Activity Longterm effects of physical activity in children and adolescents with type 1 diabetes. Chapter 9: Diabetic Ketoacidosis Aetiology, epidemiology, risk factors, cerebral oedema and management of diabetic ketoacidosis. Chapter 10: Surgery and Fasting Management of surgery and fasting in children and adolescents with diabetes. Chapter 11: Sick Day Management Insulin adjustment during “sick days” /intercurrent illnesses in children and adolescents with type 1 diabetes. Management of severe hypoglycaemia with intravenous glucose or intramuscular/intravenous glucagon. Chapter 12: Hypoglycaemia Effect of intensive diabetes management on the incidence of hypoglycaemia. Management of severe hypoglycaemia with intravenous glucose or intramuscular/intravenous glucagon. Effects of hypoglycaemia on cognitive function in children and adolescents with type 1 diabetes. Chapter 13: Psychosocial Aspects The incidence and risk factors for non-adherence with treatment regimens in children and adolescents with type 1 diabetes. The effect of psychosocial interventions on metabolic and psychological outcomes in children and adolescents with type 1 diabetes. Chapter 14: Diabetes Complications Effect of intensive diabetes management on microvascular and macrovascular complications in adolescents. How frequently should children and adolescents with type 1 diabetes be screened for microvascular (retinopathy, nephropathy, neuropathy) complications? How frequently should children and adolescents with type 1 diabetes be screened for macrovascular complications? Chapter 15: Other Complications and Associated Conditions How frequently should children and adolescents with type 1 diabetes be screened for thyroid disease? How frequently should children and adolescents with Type 1 diabetes be screened for coeliac disease? Effect of a gluten free diet (GFD) in asymptomatic patients with type 1 diabetes found to have coeliac disease on routine screening. Chapter 16: Foot Care The effect of type 1 diabetes on joint mobility in the feet of young people. The management of high plantar pressure and callus in adolescents with type 1 diabetes. How frequently should children and adolescents with type 1 diabetes be screened for foot complications? Chapter 17: Dental Health How frequently should children and adolescents with type 1 diabetes have a dental review? The effect of type 1 diabetes on dental health in children and adolescents. Chapter 18: Adolescent Health Introduction Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 5 • • • • Glycaemic control in adolescents compared with adults. Current transition processes and outcomes for adolescents with type 1 diabetes moving to the adult care system The effect of type 1 diabetes on driving performance. Eating disorders in type 1 diabetes. Chapter 19: School Effects of type 1 diabetes on cognitive function in children and adolescents. Chapter 20: Diabetes Camps Benefits on glycaemic control of diabetes camps in children with type 1 diabetes. Chapter 21: Travelling and Holidays Insulin regimens during travel when crossing time zones. Chapter 22: Complementary and Alternative Medicine Do complementary and alternative medicine therapies cure or improve diabetes in children? Identified studies were assigned a level of evidence according to the NHMRC Hierarchy of Evidence (NHMRC, 2001) (Table I) and are included in the Evidence tables. Those studies which were used to formulate recommendations (and thus provided the evidence-base for those recommendations) were critically appraised for their methodological quality. Other recommendations and principles of clinical practice in the guidelines have been based on Technical Reports or when no level I-IV information existed, on Consensus Statements based on expert opinion. Apart from outlining recommendations and principles of clinical practice the guidelines provide a wealth of highly referenced information for practicing clinicians and health care professionals. Study quality was assessed on a number of parameters such as the quality of the study methodology reporting, methods of randomisation and allocation concealment (for Randomised Control Trials (RCT’s)), blinding of patients or outcomes assessors, attempts made to minimise bias, sample sizes and the ability of the study to measure ‘true effect’. The applicability of results outside the study sample was also examined as were the appropriateness of the statistical methods used to describe and evaluate the study data. As the NHMRC levels of evidence are designed for application specifically to intervention studies, the population-based studies, cohort studies and case-control studies which were identified by the literature search are allocated a relatively low level of evidence. The highest level of evidence that can be allocated to these studies based upon NHMRC criteria is Level IV. This does not reflect the high level and quality of many of the population-based studies referenced in the guidelines and used to base recommendation upon. Table I: NHMRC Levels of Evidence I II III-1 Level I Level II Level III-1 III-2 Level III-2 III-3 Level III-3 IV Level IV Evidence from a systemic review of all relevant RCT’s Evidence from at least one properly-designed RCT Evidence from well-designed pseudo-randomised controlled trials (alternate allocation or some other method). Evidence from comparative studies with concurrent controls and allocation, non-randomised (cohort studies), case-control studies, or interrupted time series with a control group Evidence from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group Evidence from case series, either post-test or pre-test and posttest Introduction Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 6 Economic Considerations A broad literature search was designed to find all economic studies relating to children and adolescents with type 1 diabetes. All studies addressing resource utilisation as well as studies comparing the costs of different alternatives (economic evaluations) were considered if they were generalisable to the Australian health care system. These were incorporated into the relevant chapters within the guidelines. It was agreed that a new economic evaluation would only be relevant if guidelines recommendations had major resource implications or represented a change in policy. Guidelines Review Date The recommendations in the guidelines incorporate the most recent published evidence, position papers, technical reports and consensus statements as of August 31, 2003. In view of the anticipated advances in diabetes research and management it is recommended that the guidelines should be reviewed after five years in 2008. Structure of the Guidelines In writing the guidelines, the writing committee aimed to retain the user-friendly format of the original 1996 APEG guidelines. For this reason it was decided to incorporate the available evidence and recommendations for care within the context of the overall discussion of the topic. At the end of each chapter the important evidence is summarised according to levels of evidence, and recommendations arising from the available evidence are made (with the corresponding level of evidence indicated using the NHMRC roman numeral system). Where no studies could be located recommendations were made based on state, national and international consensus statements, WHO technical reports, NICE technology appraisals and other relevant technical reports. Where this occurs it is clearly indicated in the text by the use of identifying codes as listed in Table II below: Table II: Recommendation Codes C Consensus T WHO technical reports Consensus statement endorsed by professional organisations Consensus statement from Government Health Departments Technical reports produced by expert panels convened by WHO Evidence tables summarising the studies which constituted the evidence-base for the recommendations can be found in Appendix 2. Overview of the Guidelines The guidelines are comprehensively referenced and incorporate up-to-date evidence-based and expert consensus management recommendations. The initial chapters contain the most recent information on diagnosis, classification and epidemiology of type 1 diabetes, the phases of diabetes, the options for the initial management of diabetes, the currently available insulin preparations and regimens, and, the methods of monitoring metabolic control. A detailed description is provided of the international consensus management guidelines of diabetic ketoacidosis as well as the management of the child with diabetes undergoing minor and major surgery. The guidelines offer practical advice on the problems of hypoglycaemia, sick day management, travelling and holidays. The psychosocial issues of diabetes are detailed as well as school and adolescent health issues. Comprehensive guidance is provided Introduction Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 7 on the screening for and the management of the chronic complications of diabetes. Other complications including thyroid disease, coeliac disease are also addressed as well as foot care and dental health. The challenges of transition from paediatric to adult care are reviewed and guidance how best to manage this difficult stage is offered. Consultation and Peer-review Process The consultation and peer-review process included a nationally advertised call for public comment, invitations for critical review by members of the Australasian Paediatric Endocrine Group, International Society for Pediatric and Adolescent Diabetes, International Diabetes Federation Consultative Section on Childhood and Adolescent Diabetes, Diabetes Australia, Australian Diabetes Society, Royal Australasian College of Physicians, Royal Australian College of General Practitioners, Dietitians Association of Australia, Australian Diabetes Educators Association and the Juvenile Diabetes Research Foundation. The comment were collated, de-identified, formally considered and addressed by the Guideline Writing Group. Dissemination The full text of the guidelines will be freely available as a pdf file on the NHMRC and APEG websites. Legal Considerations The following statement applies to the guidelines: ‘Every attempt has been made to locate the most recent evidence. Judgement is necessary when applying evidence in a clinical setting. It is important to note that weak evidence does not necessarily mean that a practice is unadvisable, but may reflect the insufficiency of evidence or the limitations of scientific investigation. The guidelines are intended to act as a guide to practice. The ultimate decision of what to do rests with the practitioner and the consumer and depends on individual circumstances and belief (NHMRC 1999)’. Reference List 1. 2. 3. 4. 5. 6. 7. National Health and Medical Research Council: How to review the evidence: systematic identification and review of the scientific literature. AusInfo, 1999 National Health and Medical Research Council: A guide to the development, implementation and evaluation of clinical practice guidelines. AusInfo, 1999 National Health and Medical Research Council: How to present the evidence for consumers: preparation of consumer publications. AusInfo, 1999 National Health and Medical Research Council: How to put the evidence into practice: implementation and dissemination strategies. AusInfo, 2000 National Health and Medical Research Council: How to use the evidence: assessment and application of scientific evidence. AusInfo, 2000 National Health and Medical Research Council: How to compare the costs and benefits: evaluation of the economic evidence. AusInfo, 2001 National Health and Medical Research Council: Using socioeconomic evidence in clinical practice guidelines. AusInfo, 2002 Introduction Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 8 List of Abbreviations ADA APEG APS BMI BP CBGM CSII DCCT DIDMOAD DKA DPT EDIC EMA ENDIT HDL HLA HNF ICA IDDM IDF IFG IGT IVGTT JDRF LDL MODY MRDM NATA NICE NIDDM OCP OGTT SDS WHO American Diabetes Association Australasian Paediatric Endocrine Group Autoimmune Polyglandular Syndrome Body Mass Index Blood pressure Continuous Blood Glucose Monitoring Continuous Subcutaneous Insulin Infusion Diabetes Control and Complications Trial Diabetes Insipidus Diabetes Mellitus Optic Atrophy Deafness Diabetic Ketoacidosis Diabetes Prevention Trial Epidemiology of Diabetes Interventions and Complications Antiendomysial Antibodies European Nicotinamide Diabetes Intervention Trial High Density Lipoprotein Human Leucocyte Antigen Hepatic Nuclear Factor Islet Cell Antigen Insulin Dependent Diabetes Mellitus International Diabetes Federation Impaired Fasting Glycaemia Impaired Glucose Tolerance Intravenous Glucose Tolerance Test Juvenile Diabetes Research Foundation Low Density Lipoprotein Maturity Onset Diabetes in the Young Malnutrition Related Diabetes Mellitus National Association of Testing Authorities National Institute for Clinical Excellence Non-insulin Dependent Diabetes Mellitus Oral Contraceptive Pill Oral Glucose Tolerance Test tandard Deviation Score World Health Organization Glossary Acanthosis nigricans Genu valgum Genu varum Hypocapnia Hypo(hyper)kalaemia dark wart-like patches on neck and in skin folds knock knee bow-leg low blood CO2 level Low(high) blood potassium List of Abbreviations Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 9 Acknowledgements The Writing Group wishes to acknowledge the outstanding contributions made by Dr Ann Maguire, APEG Fellow, to the development of the guidelines and the referencing and evidence basing the guidelines. The expert secretarial assistance of Ms Jane Haynes is most gratefully acknowledged. The Writing Group also wishes to acknowledge the critical review and advice provided by the ASERNIPS GAR experts (Ms Philippa Middleton and Dr Rebecca Tooher). Acknowledgements Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 10 Executive Summary of Recommendations and Principles 1. Definition, Epidemiology and Classification • The diagnosis of diabetes in children and adolescents should be based on the World Health Organization criteria (1999).1(T) • Worldwide the incidence of type 1 diabetes in childhood varies greatly (0.1 - 37.4 per 100,000), with the Australian incidence being 17.8 and increasing by 3.2% per year since 1990.2-5(IV) • Diabetes can be diagnosed if the characteristic symptoms and signs are present and the fasting venous plasma glucose concentration is greater than or equal to 7.0 mmol/L, and/or the random venous plasma glucose concentration taken at least 2 hours after eating is greater than or equal to 11.1 mmol/L.1(T) • The possibility of type 2 diabetes should be considered in children and adolescents with diabetes who are obese, have a strong family history of type 2 diabetes, come from an ethnic background at high risk for diabetes, produce little or no ketonuria and show evidence of insulin resistance (acanthosis nigricans or polycystic ovary syndrome).1;6(T,C) • The possibility of other types of diabetes should be considered in children and adolescents with diabetes who have any of the following: an autosomal dominant family history of diabetes, have associated conditions such as deafness, optic atrophy or syndromic features, have marked insulin resistance or require little or no insulin outside the partial remission phase or have been exposed to drugs known to be toxic to beta cells or cause insulin resistance.1;7(T,C) • An oral glucose tolerance test (OGTT) is rarely indicated in making the diagnosis of type 1 diabetes in childhood and adolescence.1;7(T,C) • The OGTT may be used in the evaluation of possible glucose intolerance in a child or adolescent suspected of having the metabolic syndrome eg an obese adolescent with acanthosis nigricans, a girl with the polycystic ovary syndrome, an obese child with a family history of type 2 diabetes or an obese child from a high risk ethnic background for type 2 diabetes.6;8(C,T,) • Targeted screening for type 2 diabetes (fasting plasma glucose or 2 hour post-prandial glucose) is recommended at the point of medical contact if high risk factors are present (obesity, strong family history of type 2 diabetes, high risk ethnic group, acanthosis nigricans, polycystic ovary syndrome) and every 2 years thereafter.8;9(T,C) 2. Phases of Diabetes • Health care professionals should be aware that there are no interventions shown to delay or prevent the onset of type 1 diabetes.10;11(II) • Neither screening of any population nor intervention in the preclinical phase should occur outside the context of defined clinical studies.12(C) • Type 1 diabetes is characterised by a preclinical, clinical, partial remission and chronic phase.7(C) • The clinical presentation of diabetes can vary from non-emergency presentations (eg polydipsia, polyuria, weight loss, enuresis) to severe dehydration, shock and diabetic ketoacidosis.1;7(T,C) • Parents and children with type 1 diabetes should be informed that the partial remission phase of diabetes is transient and does not indicate remission of diabetes.7(C) Executive Summary of Recommendations and Principles Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 11 3. Medical Management • Every child and adolescent with type 1 diabetes, including those from rural and remote areas, should have access to optimal medical management.7;13;170(C) • Health care professionals who look after children must make advocacy for the child one of their key responsibilities.13(C) • Older children and adolescents who develop diabetes but are not dehydrated or acidotic may be considered for management out of hospital if expert diabetes support teams are available.14-21(I) • Relative contraindications to ambulatory initiation of insulin therapy include very young age (under 2 years), ketoacidosis, dehydration (moderate or severe), geographic isolation, no telephone at home, language or other communication difficulties, profound grief reaction and significant psychological or psychiatric problems within the family.7;13(C) • Children and adolescents with type 1 diabetes should have access to care by a multidisciplinary team trained in childhood diabetes.7;22-24(C) • The older child and the family should be recognised as being part of the management team.(C) • Diabetes education should be part of the management of type 1 diabetes in children and adolescents. Educational interventions have beneficial effects on diabetes management outcomes.25(I) • Education should be adapted to each individual’s age, maturity, stage of diabetes, lifestyle and culture.7(C) • After the initial period of diagnosis and education (when frequent contact may be required), the child should be regularly reviewed throughout the year. This should be no less than 3-4 times per year), including one major annual review (paying particular attention to growth, blood pressure, puberty, associated conditions, nutrition and complications) with the multidisciplinary team.7;23;24(C) • Children and adolescents with type 1 diabetes should be immunised according to the Australian Standard Immunisation Schedule166 unless a contra-indication is present. Diabetes is not a contra-indication to immunisation.(C) • In rural and geographically remote areas within the Australian health care system, children with diabetes may be successfully cared for by a local paediatrician/physician with training and experience in paediatric diabetes, access to resources, support and advice from a tertiary centre diabetes team.26;27(IV) 4. Insulin Preparations and Storage • Health care professionals, parents and children and adolescents with type 1 diabetes should be informed that insulin is essential for survival. There is no alternative to treatment with insulin.1(T) • Children and adolescents with type 1 diabetes should be treated with human insulin as animal insulin has no advantage over human insulin in terms of metabolic control or hypoglycaemia.28(I) • A wide variety of human, analogue and bovine insulins are available in Australia for use in children and adolescents with type 1 diabetes.13(C) • Rapid-acting insulin should be injected at the time of a meal and short-acting insulin should be injected 15-20 minutes before a meal.29;30(C) • Rapid-acting insulin can be administered post-prandially in prepubertal children with type 1 diabetes with unpredictable eating habits (eg infants, toddlers and preschool children).29(C) Executive Summary of Recommendations and Principles Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 12 • • • • • • Insulin glargine is a long-acting basal insulin analogue which has recently been introduced as a treatment option.31(I) To avoid confusion and prescribing errors, the use of the terms ‘clear’ to describe rapidacting or short-acting insulin and ‘cloudy’ to describe intermediate- or long-acting insulin, should be discouraged as the long-acting analogues, glargine and detemir, are clear solutions.(C) The action profile of the various insulin preparations is subject to inter- and intraindividual variation. The action profile is also affected by storage conditions and the manufacturer’s storage instruction should be followed.29(C) All children should have rapid/short-acting insulin available for sick-day management.7;29(C) Families need to ensure that a small supply of spare insulin is always available so that supply is uninterrupted.7(C) As there is limited and inconsistent evidence on the use and efficacy of metformin as an adjunct therapy in type 1 diabetes, it should only be considered as an adjunct for difficult to control patients with evidence of insulin resistance. Patients should be warned of and closely monitored for hypoglycaemia during the stabilisation period and the efficacy monitored.32-34(II) 5. Insulin Regimens and Delivery 35• There is a variable effect of the number of daily injections on metabolic control. 37 • • • • • • • • • (II,IV) Intensive management (including multiple daily injections or pump therapy, education, intensive monitoring and psychosocial support) of type 1 diabetes in adolescents improves metabolic control and reduces the risk of microvascular complications.38;39(II) Many insulin regimens are used in the treatment of type 1 diabetes in children and adolescents. Any insulin regimen has to be considered in the wider context of a total diabetes management package, which must include dietary management, exercise and physical activity, blood glucose monitoring, initial and ongoing education, regular medical follow-up and psychological care.7;40(C) Insulin doses should be tailored for each patient’s individual circumstances and requirements, taking into account age, weight, stage of puberty, duration of diabetes, food intake and distribution, exercise patterns, daily routines, results of monitoring and intercurrent illness.7;13(C) It is recommended that insulin be injected in the abdomen, buttock or non-exercising thighs. The upper arm is generally not recommended because of the thin layer of subcutaneous tissue at this site and the increased risk of intramuscular injection.13;40(C) There is a significant risk of accidental intramuscular injections (and hence more rapid absorption) especially in lean individuals. This can be minimised by using a two finger pinch technique, an injection angle of 45 degrees and 8 mm needles.41(II) 5 or 6 mm needles may be appropriate in lean children or those using pens.29;40(C) Insulin pumps should be considered as a treatment option.42-44(I) Insulin pump therapy should be initiated and supervised by a specialised multidisciplinary team trained in pump therapy in children and adolescents with diabetes.42(C) Insulin syringes and pen needles need to be disposed of in a safe and hygienic way. Needles should not be recapped to avoid the risk of needle-stick injury. Approved sharps containers should be provided and disposed of according to local authority regulations.40(C) Executive Summary of Recommendations and Principles Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 13 • Health care professionals should educate and encourage children and their families to acquire skills in insulin adjustment.40(C) 6. Glycaemic Control • Diabetes Control should be optimised as much as possible as improved glycaemic control reduces the risk of development and progression of microvascular and macrovascular complications in adolescents and adults.38;39;45-48(II) • Frequent daily blood glucose monitoring as part of a package of care has been shown to be associated with improved glycaemic control.49(T) • The frequency of blood glucose monitoring should be adapted to the insulin regimen, the age of the child and the stability of the diabetes.29(C) • The use of memory-glucose meters without daily reviewing of glucose levels is not recommended as patterns of glycaemic changes may not be appreciated by the child or adolescent and the family, and appropriate changes in insulin dosage may not be made.40(C) • HbA1c is the only measure of glycaemic control that has been shown to be associated with long-term complications of diabetes and best reflects glycaemic levels over the preceding 2-3 months.49(T) • The American Diabetes Association recommends measuring the HbA1c at least twice per year in patients who are meeting treatment goals, and more frequently (quarterly) in those whose treatment has changed or who are not meeting glycaemic goals.50(C) • HbA1c results should be available at the time of the clinic visit as this may influence the outcome of the consultation.51(III-1) 7;29 • In older children and adolescents the target HbA1c should be <7.5%. (T,C) • Increased efforts to improve glycaemic control are recommended as fewer than 25% of children and adolescents in NSW had HbA1c levels <7.5%.26;36(IV) • In younger children, the HbA1c target may be set a little higher because of the dangers of hypoglycaemia to the developing brain.29(IV) • HbA1c values need to be interpreted in the context of blood glucose readings and clinical parameters (eg a child with a low HbA1c may be experiencing asymptomatic hypoglycaemia).40(C) • Children whose HbA1c is rising or is persistently elevated should have all aspects of their diabetes management reassessed.29(C) • Ketones should be tested for when the blood glucose is above 15 mmol/L and the child or adolescent is unwell.7(C) • Ketones should be tested for in the presence of abdominal pains, rapid breathing, flushed cheeks, high temperature, vomiting, diarrhoea or inappropriate drowsiness even when the blood glucose is <15 mmol/L.40(C) 7. Nutrition • Nutrition is a fundamental component in the management of type 1 diabetes in childhood and adolescence.52;53(C) • Nutritional management of children and adolescents with type 1 diabetes should be initiated by an accredited practising dietitian trained in paediatric diabetes.13(C) • Nutritional reviews should occur 2-4 weeks post-diagnosis and ongoing at least once per year by a paediatric dietitian experienced in diabetes management.13(C) • Children and adolescents with diabetes should be encouraged to follow the NHMRC Dietary Guidelines for Children and Adolescents in Australia which recommend that:54(C) Carbohydrate should provide 50-55% of total energy intake. Executive Summary of Recommendations and Principles Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 14 Dietary fat intake should provide between 25 and 40% of total energy intake depending on the child’s age. Saturated fat intake should be limited to <10% of total energy intake. Dietary protein intake should provide 15-20% of total energy intake. Children and adolescents with diabetes should be educated and encouraged to adjust their insulin dose depending upon carbohydrate quantity.55;56(II) Day to day consistency in carbohydrate intake is important for those receiving fixed doses of insulin.(C) Dietary advice should include information about low glycaemic index food as this can help to improve glycaemic control.57;167-169(I) Moderate use of sucrose in the diabetes diet should be allowed as it does not significantly influence glycaemic control in type 1 diabetes.58-62(II) • • • • 8. Physical Activity • Physical activity should be considered part of diabetes management. Children and adolescents with type 1 diabetes should be encouraged to participate in a variety of sport and physical activity and not be limited in their choice of activity.13(C) • Regular physical activity in children and adolescents with type 1 diabetes should be encouraged as it can improve aerobic capacity and muscle strength; however the reported effect of physical activity on glycaemic control (measured by HbA1c) varies.6365 • • • • • • • (II) Activities should be approached with caution if they are solo in nature, take place in water or mid-air, or limit the individual’s ability to recognise and self-treat hypoglycaemia and a ‘buddy’ is recommended.13(C) Blood glucose levels need to be measured before, during and after physical activity.29(C) Physical activity may necessitate extra carbohydrate intake and insulin reduction. Experience and blood glucose monitoring help determine the most appropriate strategies as the requirements vary for each individual.29(C) All children and adolescents participating in sport should have access to assistance from a person aware of the management of hypoglycaemia.(C) A general recommendation is that 15 gm of easily consumed and quickly absorbed carbohydrate or an extra serving should be taken for every 30 minutes of moderate to intensive sport or physical activity.(C) Extra carbohydrate should be consumed if blood glucose level is <7 mmol/L.29;40(C) Strenuous physical activity should be avoided if blood glucose levels are >15 mmol/L especially if ketones are present.40(C) 9. Diabetic Ketoacidosis • The guidelines for the management of diabetic ketoacidosis should take into account the conclusions of a consensus statement resulting from a workshop that took place in the United Kingdom in June 2003 involving the European Society for Paediatric Endocrinology (ESPE), the Lawson Wilkins Pediatric Endocrine Society (LWPES) and other societies including the Australasian Paediatric Endocrine group (APEG).66(C) • The most common precipitating factors in the development of diabetic ketoacidosis include infection, often as a result of inadequate insulin therapy during intercurrent illness and insulin omission.67-72(IV) • Diabetic ketoacidosis is the most common cause of death in newly diagnosed type 1 diabetes.68-70;73 (IV) Executive Summary of Recommendations and Principles Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 15 • The greatest risk of mortality from diabetic ketoacidosis is from cerebral oedema.6870;74;75 (IV) • • • • • • • • Although poorly understood, the risk factors for cerebral oedema in diabetic ketoacidosis include presentation with new onset type 1 diabetes,75-77 younger age,76-78 elevated serum urea nitrogen and/or severity of dehydration at presentation, severity of acidosis,74;79 greater hypocapnia at presentation (after adjusting for degree of acidosis), an attenuated rise in serum sodium during treatment for diabetic ketoacidosis;74;80-82 bicarbonate treatment to correct acidosis has also been associated with cerebral oedema.74;83(III,IV) Immediate assessment for diabetic ketoacidosis should consist of clinical history, assessment and biochemical confirmation (see algorithm in Chapter 9).7(C) ‘Low dose’ intravenous insulin is recommended for the treatment of moderate to severe diabetic ketoacidosis.66(C) A specialist/consultant paediatrician with training and expertise in the management of diabetic ketoacidosis should direct management.66(C) The child should be cared for in a unit that has experienced nursing staff trained in monitoring and management of diabetic ketoacidosis, clear written guidelines for managing diabetic ketoacidosis and access to laboratories that can provide frequent and accurate measurement of biochemical variables.66(C) Children with ketosis and hyperglycaemia, but who are not vomiting, may be managed at home or in an ambulatory care setting (such as an emergency ward).84;85(IV) Children with signs of severe diabetic ketoacidosis or those who may be at increased risk for cerebral oedema should be considered for immediate treatment in an intensive care unit (paediatric if possible) or a children’s ward specialising in diabetes care.(C) The management of cerebral oedema in diabetic ketoacidosis is a medical emergency and treatment (fluid restriction, mannitol, neurological assessment) should be initiated in an intensive care facility as soon as the condition is suspected.77;86(IV) 10. Surgery and Fasting • Surgery on children with diabetes should only be undertaken in hospitals with dedicated paediatric facilities for the care of children with diabetes and expert staff (medical, anaesthetic, surgical and nursing).7;13(C) • When fasting before an anaesthetic an intravenous glucose infusion should be commenced to prevent hypoglycaemia.7;13(C) • Children with type 1 diabetes requiring a surgical procedure should receive insulin, even if fasting, to avoid ketoacidosis. There may be increased insulin requirements peri-operatively due to physiological stress and increased counter-regulatory hormones.87(III-3) • In children and adolescents with type 1 diabetes the optimal method of maintaining metabolic control during major surgery or prolonged post-operative fasting is by an insulin infusion.87(III-3) 11. Sick Day Management • Families should be informed that intercurrent illnesses can cause high or low blood glucose levels.7;13;40(C) • All families should receive education about the management of sick days and have a sick day kit at home containing rapid-acting or short-acting insulin, glucose test strips, meters, lancets/finger pricking devices, urine test strips for glucose and ketone estimation or blood ketone meter and strips, doctor’s/hospital’s phone number, sweet cordial/fruit juice/lemonade or other soft drinks, low joule (diet drinks) or water, Executive Summary of Recommendations and Principles Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 16 • • • • • • • • • glucagon, diabetes manual or emergency guidelines, sick day foods, thermometer, paracetamol or ibuprofen (sugar-free syrup or tablets).7;13;40(C) Insulin should never be omitted even if unable to eat.7;13;40(C) Blood glucose and ketones should be monitored frequently.7;13;40(C) Any underlying illness should be treated promptly.7;13;40(C) Extra oral fluids should be encouraged especially if the blood glucose is high or ketones are present.7;13;40(C) Additional boluses of short/rapid-acting insulin equal to 10-20 per cent of the total insulin daily dosage should be given every 2-4 hours if the blood glucose is high and ketones are present.7;13;40(C) Patients/carers should seek assistance immediately if, after extra insulin boluses, the blood glucose remains high, ketones persist, or nausea, vomiting or abdominal pain develop.7;13;40(C) Severe hypoglycaemia should be treated with intravenous dextrose (in the hospital setting).88;89(II) If venous access is difficult or outside the hospital setting, intramuscular glucagon should be used to treat severe hypoglycaemia.7;13;40(C) Under the supervision of a doctor or diabetes educator, small doses of subcutaneous glucagon may be used to prevent or treat mild hypoglycaemia in an ambulatory setting.90(IV) 12. Hypoglycaemia 26;36;38;45;91 • Hypoglycaemia is the most frequent acute complication of type 1 diabetes. (II) • Hypoglycaemia is the major factor limiting intensified regimens aiming for nearnormoglycaemia.26;36;38;45;91(II) • Severe hypoglycaemia should be avoided in children, especially in those less than 5 yrs old.92-98(II, III, IV) • Blood glucose values should be maintained above 4.0 mmol/L in children and adolescents with diabetes.7;13;40(C) • Children and adolescents with diabetes should wear some form of identification or warning of their diabetes.7;13;40(C) • All children and adolescents with diabetes should carry glucose tablets or readily absorbed carbohydrate (preferably in waterproof sealed wrap) on their person and have glucagon available at home (and in boarding schools where there is a nurse on staff).7;13;40(C) • Hypoglycaemia in children is largely preventable; however there is a significant proportion of severe hypoglycaemic episodes in which no obvious cause can be determined.13;40(C) • School teachers and carers at schools should be informed of the symptoms and appropriate treatment of hypoglycaemia and should have access to advice when necessary.7;13;40(C) • In the hospital setting severe hypoglycaemia should be treated with intravenous dextrose as this is the most rapid way of treating severe hypoglycaemia.88;89(II) • The recommended dose of intravenous dextrose is 2-5ml/kg of 10% dextrose. 50% dextrose should not be used because of dangers of tissue necrosis associated with extravasation.(C) • Intramuscular or subcutaneous glucagon is an effective way of treating severe hypoglycaemia in a home-care setting or if intravenous dextrose is not possible.88;89(II) Executive Summary of Recommendations and Principles Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 17 13. Psychosocial Aspects • Type 1 diabetes in childhood imposes a number of psychological stresses on both the child and the family.7;13;29;40(C) • Non-adherence to the diabetes regimen is common in children and adolescents with type 1 diabetes.72;99-111(IV) • Non-adherence with treatment regimens is common especially during teenage years,72;104-106 when an underlying psychiatric disorder is present,99;102;109 when the parents or child have a low level of education,101;111 when self-care autonomy is promoted or impeded at an inappropriate time,112 and when there is low level of cohesion within the family.111(IV) • Health care professionals should be aware that adolescents may omit or reduce insulin doses in order to produce glycosuria as a method of weight control.113-115(IV) • Psychological interventions have been shown to improve HbA1c and psychosocial outcomes.25;116-118(I) 14. Diabetes Complications • Type 1 diabetes confers the risk of long-term diabetes microvascular complications.38;45;48;119(II) • Families with a child or adolescent with diabetes should be made aware of the potential long-term complications of diabetes as part of their diabetes education. Adolescents should be made aware at a rate appropriate to their maturity.7;13(C) • Families with a child or adolescent with diabetes should be made aware that long-term good metabolic control reduces the risk of development and progress of complications.38;45(II) • Families with a child or adolescent with diabetes should be made aware that other modifiable risk factors for diabetic microvascular complications include higher blood pressure, smoking and dyslipidaemia.38;45(II) • Screening for retinopathy should be performed annually in adolescents after 2 years of diabetes and after 5 years of diabetes in those who are prepubertal.7;13(C) • Assessment for retinopathy should be by an observer with special expertise in diabetic eye disease. If stereoscopic fundal photography is used then biennial assessment may be appropriate for those with minimal background retinopathy, diabetes duration of less than 10 years and if the HbA1c is not significantly elevated. If moderately severe retinopathy is present then more frequent review is necessary.13;120(C) • Clinical examination of the eyes for cataracts should be performed soon after diagnosis, especially if there has been slow or prolonged onset of diabetes.7;13(C) • Screening for microalbuminuria should be performed annually in adolescents after 2 years of diabetes and after 5 years of diabetes in those who are prepubertal. Assessment should be either by timed overnight urine collections or a spot urinary albumin/creatinine ratio. If microalbuminuria is found then screening should be more frequent, and other renal investigations undertaken and specific focus should be placed on blood pressure measurements.7;13(C) • In the presence of poor diabetes control, clinical evaluation of peripheral nerve function should occur annually and should as a minimum include:13(C) History (especially of numbness, pain, paraesthesia). Assessment of vibration sensation (by tuning fork or biothesiometer). Assessment of ankle reflexes. Assessment of sensation. • Type 1 diabetes frequently results in accelerated atherosclerosis. Good glycaemic control can decrease this risk.48;119(II) Executive Summary of Recommendations and Principles Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 18 • Blood pressure measurements should be recorded at diagnosis and, if normal, annually. Hypertension should be considered to be present if repeated blood pressure levels are >95th centile for age, gender and height specific normative data.13(C) • Screening for lipid disorders should begin within 6-12 months of diagnosis of diabetes, and if normal should be performed every 5 years in prepubertal children and every second year in pubertal children).22;121(C) 15. Other Complications and Associated Conditions • Monitoring of growth and development and the use of growth charts is a very important part of ongoing care of children and adolescents with type 1 diabetes.7;13(C) • Screening of thyroid function by Thyroid Stimulating Hormone (TSH) every 2 years is recommended in asymptomatic individuals without a goitre or in the absence of thyroid autoantibodies. More frequent assessment is indicated otherwise.7(C) • Screening for coeliac disease should be carried out around the time of diagnosis and every 2-3 years thereafter. More frequent assessment is indicated if the clinical situation suggests the possibility of coeliac disease.7;13;29(C) • Although the benefits of a gluten-free diet have not been proven in those with type 1 diabetes detected to have coeliac disease on routine screening,122;123 these children should be referred to a paediatric gastroenterologist and on confirmation of the diagnosis receive support from a paediatric dietitian with experience in gluten-free diets.13;40(C) 16. Foot Care • Health care professionals should be aware that the structural and functional abnormalities known to predispose adults with diabetes to plantar ulceration are already present in young people with diabetes.124-126(IV) • Young people presenting with plantar callus, or detected to have high plantar pressures or limited joint mobility need to be monitored closely for foot complications.13(C) • Orthosis, cushioning or both in combination may be used to treat high peak plantar pressure.127(IV) 17. Dental Health • Children and adolescents with type 1 diabetes should be informed that dental decay is increased when glycaemic control is poor.128(IV) • Health care professionals should be aware that diabetes is a risk factor for periodontal disease especially when metabolic control is poor or when diabetes duration is long.129132 (IV) • Children and adolescents with type 1 diabetes should be informed that tooth decay and gingivitis can be prevented and/or reversed by brushing and flossing teeth at least twice a day to remove plaque from the surfaces of the teeth and gingivae.13(C) • The mouth should be examined regularly (twice a year) for the presence of gingivitis or periodontitis.13(C) 18. Adolescent Health Issues • Health care professionals should be aware that glycaemic control is more difficult in adolescents with type 1 diabetes.38;45(II) • Adolescents with diabetes have specific health needs relating to physical, emotional, psychological and socio-cultural stages of adolescence.7;133(C) Executive Summary of Recommendations and Principles Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 19 • • • • • • • • • • • • The major risks faced by adolescents with diabetes include deterioration of glycaemic control, risk-taking behaviour, hypoglycaemia, recurrent diabetic ketoacidosis and accelerated microvascular complications.7(C) The transition from a paediatric to an adult service for the adolescent with diabetes is often difficult.134-140 Ideally the transfer to an adult service should be comprehensive and should involve:138(IV) A preparation phase which is planned well in advance by a special transition service and the adolescent and family. A formal transition phase to an adult clinic, with appropriate referral and clear directions for the patient and family (eg in case of emergencies). An evaluation phase. Adolescents should be taught to do a blood glucose estimation immediately before driving a car and to have rapidly absorbed carbohydrate (eg glucose tablets) readily accessible and to take these at the first indication of hypoglycaemia.141;142(C) Smoking should be actively discouraged in diabetes.143(C) Adolescents with diabetes need to be warned about the dangers of alcohol as part of their diabetes education.13;29(C) Issues surrounding sexuality should be approached with confidentiality and empathy.7(C) Assessment of sexual activity and the need for contraception should be a routine part of adolescent diabetes care.7;13(C) Health care professionals should be aware that the incidence of eating disorders is increased in males and females with type 1 diabetes144-146 and that adolescent females with type 1 diabetes and anorexia nervosa have a significantly increased mortality rate compared to patients with type 1 diabetes alone.147(IV) Health care professionals should be aware that intentional reduction or omission of insulin to achieve weight loss is common (so-called insulin purging).113;114(IV) Health care professionals should be aware that increased levels of retinopathy have been found in patients with type 1 diabetes and sub-clinical and clinical eating disorders.115;145;148(IV) Treatment of eating disorders should include medical, nutritional and psychological therapy by an experienced multidisciplinary team.149;150(C) 19. School • Parents/care-givers and teachers should be aware that discrimination or stigmatisation is unacceptable.7(C) • Parents/care-givers and teachers should be aware that diabetes should not be the cause of non-participation in any school activity.7;13(C) • Parents/care-givers should meet with the relevant school personnel as soon as practicable to discuss the issues involved in the care of their child at school.7(C) 151 • An individual care plan should be developed and reviewed regularly. (C) • Parents/care-givers and teachers should be aware how to recognise and treat hypoglycaemia.7;13(C) • An emergency supply of rapidly absorbed carbohydrate should be readily available in the classroom or wherever the school activity is undertaken.7;13(C) • During or following hypoglycaemia or suspected hypoglycaemia, a child must not be expected to walk to a ‘medical room’ nor left unaccompanied.7;13(C) • Parents/care-givers and teachers should be aware that cognitive function and mood may be affected for some hours after hypoglycaemia.152;153(IV) Executive Summary of Recommendations and Principles Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 20 • Parents/care-givers and teachers should be aware that decreased cognitive function may occur when hyperglycaemia is present.154(II) • Parents/care-givers and teachers should be aware that risk factors for cognitive dysfunction include a history of hypoglycaemic seizures,92;96;97 early age of onset and longer duration of diabetes.94;95;96;98;155;156(IV) • Parents/care-givers, teachers and students should be aware that students with diabetes sitting for the higher examinations may apply for special provisions.13(C) 20. Diabetes Camps for Children and Adolescents • Diabetes camps should be an integral component of overall care and support for diabetic children and adolescents in Australia.13;40(C) 7 • Diabetes camps must provide a safe environment for both campers and camp staff. (C) • Camps should be organised using an agreed set of standards and protocols. Standards and protocols should specify leader to camper ratios, levels of medical and paramedical support, dietary routines, injection routines, hierarchy and responsibility of camp organisers, leader and camper application processes, emergency and evacuation protocols and indemnity arrangements.157(C) • A standardised medical information form should be completed for each camper (by his/her family and the managing physician) prior to attending diabetes camp.157(C) 21. Travelling and Holidays • The detailed management of diabetes during visits to distant locations or foreign countries should be discussed with the diabetes educator or the physician well before the departure date.13;40(C) • The detailed management of diabetes on long flights crossing many time zones should be discussed with the diabetes educator or the physician well before the departure date.13;40(C) • The family should be advised to arrange enough insulin, syringes, pen needles, glucometer, blood and urine test strips for the duration of the anticipated stay plus an extra supply.13;40(C) • The family should be advised to have insulin, glucagon and testing equipment readily available in hand luggage, and to have essential supplies divided between two bags to avoid complete loss in case one bag is lost.13;40(C) • The child or adolescent with diabetes should be advised to have his/her own food supply and not rely on airline meal times.13;40(C) • The family should be advised that no major change to the insulin regimen is required for north-south travel.40(C) • The family should be advised that extra insulin may be required for westward travel as the day will be much longer and extra meals will require extra doses of insulin.158(IV) • The family should be advised that less insulin may be required during eastward travel as the day is cut short and the time between injections decreases therefore requiring a lower insulin dose.158(IV) • Switching to a simplified regimen of pre-meal injections of short-acting insulin during long haul flights should be considered as an option.159(IV) 22. Complementary and Alternative Medicine • Complementary and alternative medicine may include medicinal (herbal remedies, dietary supplements, vitamins and minerals, naturopathic and homeopathic remedies), or non-medicinal remedies (such as chiropractic, osteopathy and naturopathy).160(C) Executive Summary of Recommendations and Principles Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 21 • • • • • • Complementary and alternative medicine use is common within the community.160;161(IV) In order to improve clinical care health care professionals should aim to understand the use of complementary and alternative medicine within the family context.162;163(C) Families should be advised that no complementary and alternative medicine therapies have been shown to cure diabetes or improve control.162(C) Ketoacidosis and death have been described when insulin has been omitted as part of an alternative treatment.164 Parents should be warned that insulin should never be significantly reduced or omitted as part of an alternative treatment.(IV) Families should be advised that complementary and alternative medicine therapies have the potential for adverse effects and for interactions with conventional treatments or other complementary and alternative medicine therapies.162(C) Health care professionals are able to determine the constituents of any complementary or alternative medicine by enquiries to poisons centres and quoting the medicine’s AUST L or AUST R numbers.165 Drugs without an AUST L or AUST R number should not be considered for use in hospital.163(C) Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 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Journal of Developmental & Behavioral Pediatrics 6:326, 1985 Northam EA, Anderson PJ, Jacobs R, Hughes M, Warne GL, Werther GA: Neuropsychological profiles of children with type 1 diabetes 6 years after disease onset. Diabetes Care 24:1541-1546, 2001 Rovet J, Alvarez M: Attentional functioning in children and adolescents with IDDM. Diabetes Care 20:803-810, 1997 Executive Summary of Recommendations and Principles Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 24 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. Rovet JF, Ehrlich RM: The effect of hypoglycemic seizures on cognitive function in children with diabetes: a 7-year prospective study. Journal of Pediatrics. 134:503-506, 1999 Sansbury L: Predictors of cognitive functioning in children and adolescents with insulin-dependent diabetes mellitus: A preliminary investigation. Children's Health Care 26:210, 1997 Kovacs M, Goldston D, Obrosky DS, Iyengar S: Prevalence and predictors of pervasive non-compliance with medical treatment among youths with insulin-dependent diabetes mellitus. Journal of the American Academy of Child & Adolescent Psychiatry 31:1112-1119, 1992 Burroughs TE, Pontious SL, Santiago JV: The relationship among six psychosocial domains, age, health care adherence, and metabolic control in adolescents with IDDM. Diabetes Educator 19:396-402, 1993 Frank M: Factors associated with non-compliance with a medical follow-up regimen after discharge from a pediatric diabetes clinic. Canadian Journal of Diabetes Care 20:13-20, 1996 Goldston DB, Kelley AE, Reboussin DM, Daniel SS, Smith JA, Schwartz RP, Lorentz W, Hill C: Suicidal ideation and behavior and non-compliance with the medical regimen among diabetic adolescents. Journal of the American Academy of Child & Adolescent Psychiatry 36:1528-1536, 1997 Hentinen M, Kyngas H: Compliance of young diabetics with health regimens. Journal of Advanced Nursing 17:530-506, 1992 Jacobson AM, Hauser ST, Wolfsdorf JI, Houlihan J, Milley JE, Herskowitz RD, Wertlieb D, Watt E: Psychologic predictors of compliance in children with recent onset of diabetes mellitus. Journal of Pediatrics 110:805-811, 1987 Johnson SB, Freund A, Silverstein J, Hansen CA, Malone J: Adherence-health status relationships in childhood diabetes. Health Psychology 9:606-631, 1990 Johnson SB, Kelly M, Henretta JC, Cunningham W, Tomer A, Silverstein JH: A longitudinal analysis of adherence and health status in childhood diabetes. Journal of Pediatric Psychology 17:537-553, 1992 Kovacs M, Mukerji P, Iyengar S, Drash A: Psychiatric disorder and metabolic control among youths with IDDM. A longitudinal study. Diabetes Care 19:318-323, 1996 Kyngas H: Compliance of adolescents with diabetes. Journal of Pediatric Nursing 15:260-267, 2000 Littlefield CH, Craven JL, Rodin GM, Daneman D, Murray MA, Rydall AC: Relationship of self-efficacy and binging to adherence to diabetes regimen among adolescents. Diabetes Care 15:90-94, 1992 Ott J, Greening L, Palardy N, Holderby A, Debell WK: Self-efficacy as a mediator variable for adolescents' adherence to treatment for insulin-dependent diabetes mellitus. Children's Health Care 29:47-63, 2000 Tubiana-Rufi N, Moret L, Czernichow P, Chwalow J: The association of poor adherence and acute metabolic disorders with low levels of cohesion and adaptability in families with diabetic children. The PEDIAB Collaborative Group. Acta Paediatrica 87:741746, 1998 Wysocki T, Taylor A, Hough BS, Linscheid TR, Yeates KO, Naglieri JA: Deviation from developmentally appropriate self-care autonomy. Association with diabetes outcomes. Diabetes Care 19:119-125, 1996 Peveler RC, Fairburn CG, Boller I, Dunger D: Eating disorders in adolescents with IDDM: A controlled study. Diabetes Care 15:1356-1360, 1992 Rodin G, Craven J, Littlefield C, Murray M, Daneman D: Eating disorders and intentional insulin undertreatment in adolescent females with diabetes. Psychosomatics 32:171-176, 1991 Rydall AC, Rodin GM, Olmsted MP, Devenyi RG, Daneman D: Disordered eating behavior and microvascular complications in young women with insulin-dependent diabetes mellitus. New England Journal of Medicine 336:1849-1854, 1997 Grey M, Boland EA, Davidson M, Li J, Tamborlane WV: Coping skills training for youth with diabetes mellitus has long-lasting effects on metabolic control and quality of life. Journal of Pediatrics 137:107-113, 2000 Laffel L, Vangsness L, Connell A, Goebel-Fabbri A, Butler D, Anderson BJ: Impact of ambulatory, family-focused teamwork intervention on glycemic control in youth with type 1 diabetes. Journal of Pediatrics 142:409-416, 2003 Wysocki T, Greco P, Harris MA, Bubb J, White NH: Behavior therapy for families of adolescents with diabetes. Diabetes Care 24:441-446,2001 DCCT Research Group: Effect of intensive diabetes management on macrovascular events and risk factors in the Diabetes Control and Complications Trial. American Journal of Cardiology 75:894-903, 1995 National Health and Medical Research Council: Screening for Diabetic Retinopathy. In Clinical Practice Guidelines for the Management of Diabetic Retinopathy. Canberra, Australian Government Publishing Service, 1997, p. 23-33 American Diabetes Association: Management of Dyslipidemia in Children and Adolescents With Diabetes. Diabetes Care 26:21942197, 2003 Acerini CL, Ahmed ML, Ross KM, Sullivan PB, Bird G, Dunger DB: Coeliac disease in children and adolescents with IDDM: clinical characteristics and response to gluten-free diet. Diabetic Medicine 15:38-44, 1998 Saukkonen T, Vaisanen S, Akerblom HK, Savilahti E, Childhood Diabetes in Finland Study Group.: Coeliac disease in children and adolescents with type 1 diabetes: a study of growth, glycaemic control, and experiences of families. Acta Paediatrica 91:297-302, 2002 Barnett SJ, Shield JPH, Potter MJ, Baum JD: Foot pathology in insulin dependent diabetes. Archives of Disease in Childhood 73:151-153, 1995 Duffin AC, Donaghue KC, Potter M, McInnes A, Chan AK, King J, Howard NJ, Silink M: Limited joint mobility in the hands and feet of adolescents with Type 1 diabetes mellitus. Diabetic Medicine 16:125-130, 1999 Duffin AC, Lam A, Kidd R, Chan AKF, Donaghue KC: Ultrasonography of plantar soft tissues thickness in young people with diabetes. Diabetic Medicine 19:1009-1013, 2002 Duffin A, Kidd R, Chan A, Donaghue K: High plantar pressure and callus in diabetic adolescents. Journal of the American Podiatric Medical Association 93:214-220, 2003 Twetman S, Johansson I, Birkhed D, Nederfors T: Caries incidence in young type 1 diabetes mellitus patients in relation to metabolic control and caries-associated risk factors. Caries Research 36:31-35, 2002 Marin N, Loyola-Rodriguez JP, Valadez-Castillo FJ, Hernandez-Sierra JF, Jesus Pozos-Guillen A: Effect of metabolic control in diabetes mellitus type 1 patients and its association with periodontal disease. Revista de Investigacion Clinica 54:218-225, 2002 Miralles-Jorda L, Silvestre-Donat FJ, Grau Garcia-Moreno DM, Hernandez-Mijares A: Buccodental pathology in patients with insulin-dependent diabetes mellitus: a clinical study. Medicina Oral 7:298-302, 2002 Pinson M, Hoffman WH, Garnick JJ, Litaker MS: Periodontal disease and type I diabetes mellitus in children and adolescents. Journal of Clinical Periodontology 22:118-123, 1995 Takahashi K, Nishimura F, Kurihara M, Iwamoto Y, Takashiba S, Miyata T, Murayama Y: Subgingival microflora and antibody responses against periodontal bacteria of young Japanese patients with type 1 diabetes mellitus. Journal of the International Academy of Periodontology 3:104-111, 2001 Executive Summary of Recommendations and Principles Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 25 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166. 167. 168. 169. 170. Fleming E, Carter B, Gillibrand W: The transition of adolescents with diabetes from the children's health care service into the adult health care service: a review of the literature. Journal of Clinical Nursing. 11:560-567, 2002 Court JM: Issues of transition to adult care. Journal of Paediatrics & Child Health 29:S53-S55, 1993 Datta J: Transition to adult care. Moving up with diabetes. The transition from paediatric to adult care. London, NCB books, 2003 Eiser C, Flynn M, Green E, Havermans T, Kirby R, Sandeman D, Tooke JE: Coming of age with diabetes: patients' views of a clinic for under-25 year olds. Diabetic Medicine. 10:285-289, 1993 Jefferson IG, Swift PG, Skinner TC, Hood GK: Diabetes services in the UK: third national survey confirms continuing deficiencies. Archives of Disease in Childhood. 88:53-56, 2003 Kipps S, Bahu T, Ong K, Ackland FM, Brown RS, Fox CT, Griffin NK, Knight AH, Mann NP, Neil HA, Simpson H, Edge JA, Dunger DB: Current methods of transfer of young people with Type 1 diabetes to adult services. Diabetic Medicine 19:649-654, 2002 Pacaud D, McConnell B, Huot C, Aebi C, Yale J: Transition from pediatric care to adult care for insulin-dependent diabetes patients. Canadian Journal of Diabetes Care 20:14-20, 1996 Salmi J, Huupponen T, Oksa H: Metabolic control in adolescent insulin-dependent diabetics referred from pediatric to adult clinic. Annals of Clinical Research 18:84-87, 1986 Cox DJ, Penberthy JK, Zrebiec J, Weinger K, Aikens JE, Frier B, Stetson B, DeGroot M, Trief P, Schaechinger H, Hermanns N, Gonder-Frederick L, Clarke W: Diabetes and driving mishaps: frequency and correlations from a multinational survey. Diabetes Care 26:2329-2334, 2003 Cox DJ, Gonder-Frederick LA, Kovatchev BP, Julian DM, Clarke WL: Progressive hypoglycemia's impact on driving simulation performance. Occurrence, awareness and correction. Diabetes Care. 23:163-170, 2000 International Diabetes Federation. Position Statement. Diabetes and tobacco use: a harmful combination . 2003. Ref Type: Report Neumark-Sztainer D, Patterson J, Mellin A, Ackard DM, Utter J, Story M, Sockalosky J: Weight Control Practices and Disordered Eating Behaviors Among Adolescent Females and Males With Type 1 Diabetes: Associations with sociodemographics, weight concerns, familial factors, and metabolic outcomes. Diabetes Care 25:1289, 2002 Nielsen S: Eating disorders in females with type 1 diabetes: An update of a meta-analysis. European Eating Disorders Review 10:241-254, 2002 Svensson M, Engstrom I, Aman J: Higher drive for thinness in adolescent males with insulin-dependent diabetes mellitus compared with healthy controls. Acta Paediatrica 92:114-117, 2003 Nielsen S, Emborg C, Molbak AG: Mortality in concurrent type 1 diabetes and anorexia nervosa. Diabetes Care 25:309-312, 2002 Affenito SG, Backstrand JR, Welch GW, Lammi-Keffe CJ, Rodriguez NR, Adams CH: Subclinical and clinical eating disorders in IDDM negatively affect metabolic control. Diabetes Care 20:182-184, 1997 Daneman D, Olmsted M, Rydall A, Maharaj S, Rodin G: Eating disorders in young women with type 1 diabetes. Prevalence, problems and prevention. Hormone Research 50:79-86, 1998 National Institute for Clinical Excellence. Eating Disorders: Core interventions in the treatment and management of anorexia nervosa, bulimia nervosa, and related eating disorders. 2003. London. American Diabetes Association: Care of children with diabetes in the school and day care setting. American Diabetes Association. Diabetes Care 26:131-135, 2003 Puczynski MS, Puczynski SS, Reich J, Kaspar JC, Emanuele MA: Mental efficiency and hypoglycemia. Journal of Developmental & Behavioral Pediatrics 11:170-174, 1990 Matyka KA, Wigg L, Pramming S, Stores G, Dunger DB: Cognitive function and mood after profound nocturnal hypoglycaemia in prepubertal children with conventional insulin treatment for diabetes. Archives of Disease in Childhood 81:138-142, 1999 Davis EA, Soong SA, Byrne GC, Jones TW: Acute hyperglycaemia impairs cognitive function in children with IDDM. Journal of Pediatric Endocrinology & Metabolism. 9:455-461, 1996 Northam EA, Anderson PJ, Werther GA, Warne GL, Adler RG, Andrewes D: Neuropsychological complications of IDDM in children 2 years after disease onset. Diabetes Care. 21:379-384, 1998 Rovet JF, Ehrlich RM, Czuchta D: Intellectual characteristics of diabetic children at diagnosis and one year later. Journal of Pediatric Psychology. 15:775-788, 1990 American Diabetes Association: Management of diabetes at diabetes camps. Diabetes Care 26 Suppl 1:S136-S138, 2003 Sane T, Koivisto VA, Nikkanen P, Pelkonen R: Adjustment of insulin doses of diabetic patients during long distance flights. British Medicla Journal 301:421-422, 1990 Jones H, Platts J, Harvey JN, Child DF: An effective insulin regimen for long distance air travel. Practical Diabetes 11:157-158, 1994 National Center for Complementary and Alternative Medicine (NCCAM) and NIH. What Is Complementary and Alternative Medicine (CAM)? 2003. http://www.nccam.nih.gov/ Ernst E: Prevalence of complementary/alternative medicine for children: A systematic review. European Journal of Pediatrics 158:7-11, 1999 American Diabetes Association: Unproven Therapies. Diabetes Care 26:142S, 2003 Department of General Medicine, Royal Children's Hospital, and Melbourne. Use of Complementary and Alternative Medicines for Inpatients. 2003. http://www.rch.org.au/genmed/CAMguidelines.htm Gill GV, Redmond S, Garratt F, Paisey R: Diabetes and alternative medicine: Cause for concern. Diabetic Medicine 11:210-213, 1994 Therapeutic Goods Administration. Buying medicines? What's on the Label for me? 2003. http://www.health.gov.au/tga/docs/html/buymed.htm National Health and Medical Research Council: The Australian Immunisation Handbook. 8th Edition. 2003 Gilbertson HR, Brand-Miller JC, Thorburn AW, Evans S, Chondros P, Werther GA: The effect of flexible low glycemic index dietary advice versus measured carbohydrate exchange diets on glycemic control in children with type 1 diabetes. Diabetes Care 24:1137-1143, 2001 Gilbertson HR, Thorburn AW, Brand-Miller JC, Chondros P, Werther GA: Effect of low-glycemic-index dietary advice on dietary quality and food choice in children with type 1 diabetes. American Journal of Clinical Nutrition 77:83-90, 2003 Collier GR, Giudici S, Kalmusky J, Wolever TM, Helman G, Wesson V, Ehrlich RM, Jenkins DJ: Low glycaemic index starchy foods improve glucose control and lower serum cholesterol in diabetic children. Diabetes Nutrition and Metabolism 1:11-19, 1988 International Diabetes Federation Consultative Section on Diabetes Education. International Curriculum for Diabetes Health Professional Education. 2002. Brussels, International Diabetes Federation. Executive Summary of Recommendations and Principles Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 26 Chapter 1: Definition, Epidemiology and Classification Diabetes mellitus is the most common endocrine disease in childhood and adolescence. This handbook will predominantly deal with the topic of type 1 diabetes, previously known as insulin-dependent diabetes mellitus (IDDM). Fifty percent of individuals with type 1 diabetes are diagnosed before the age of 16 years. Definition The World Health Organization (WHO) defines diabetes mellitus as a metabolic disorder of multiple aetiologies characterised by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both.1 Type 1 diabetes is a chronic autoimmune disease in the vast majority and accounts for over 90 percent of childhood and adolescent diabetes in Australia. T-cell mediated destruction of the pancreatic beta cells leads to insulin deficiency.1 Susceptibility to autoimmune type 1 diabetes is determined by the interaction of multiple genes, with HLA genes having the strongest known association. Progressive beta cell destruction occurs at a variable rate and the disease becomes clinically symptomatic when approximately 90 percent of the pancreatic beta cells are destroyed.2 Insulin deficiency then manifests itself clinically as blood glucose levels rise to pathological levels. The onset of the disease is predictable, especially in the relatives of affected individuals, using a combination of auto-antibody measurements, intravenous glucose tolerance testing and genetic typing.3;4 The environmental triggers (chemical and/or viral) which start the process of autoimmune destruction of the pancreatic beta cells remain largely unknown. The pathological processes leading to type 1 diabetes are known to start from months to years before clinical symptoms become manifest (see chapter 2). Non-autoimmune type 1 diabetes has similar clinical features but is characterised by the lack of auto-antibodies against the antigens in the islets of Langerhans (islet cell antibodiesICA), or beta cell antigens (anti- insulin, anti-GAD65 or anti-IA2 antibodies).1 Epidemiology Epidemiological incidence studies define the ‘onset of type 1 diabetes’ by the date of the first insulin injection because of the variable time between the onset of symptoms and diagnosis. Figure 1 (data from the IDF Diabetes Atlas) shows annual incidence rates for childhood type 1 diabetes (0-14 years age group) comparing different countries of the world.5 Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 27 Figure 1.1: Annual Incidence Rates for Type 1 Diabetes (0-14 years age group) Comparing Different Countries in the World Source: International Diabetes Federation Diabetes Atlas 2003 Finland Sardinia Sweden Canada Norway Kuwait Denmark U.K. Australia (NSW) Rep. of Ireland New Zealand Iceland USA Netherlands Spain Germany Luxembourg Belgium Portugal Bangladesh Cyprus Hungary Italy Austria Greece Slovenia France Brazil Sudan Russia Poland Israel Algeria Romania Macedonia Cuba Japan China (H.K.) Korea Fiji * 17.8 per 100,000 population 0 5 10 15 20 25 Incidence Rate (cases per 100,000 population per year) Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 30 35 40 28 • • • • • • • • Incidence is expressed as the number of new cases per year per 100,000 children under the age of 15 years. There are significant variations in the incidence of childhood type 1 diabetes between countries - ranging from 0.1/100,000 in Fiji to 37.4/100,000 in Finland.5;6 In Europe incidence rates show a close correlation with the frequency of HLA susceptibility genes in the general population.7 The most recent data on the incidence of childhood diabetes in Australia indicate an incidence of 17.8 per 100,000 from 1990-1996, with an annual increase in incidence of 3.2% per year since 1990.8 There are two peaks of age of onset, the major peak at 10-12 years and a smaller peak at 5-6 years.9;10 A well documented rise in the incidence, especially in the group of those under the age of 5 years, has been noted in many countries.11-13 A seasonal variation in the presentation of new cases is well described, with the peak being in the winter months.14;15;16 Despite familial aggregation there is no recognisable pattern of inheritance. The risk of diabetes to an identical twin of a patient with type 1 diabetes is about 36 percent,17 compared to a life-time risk of 6 percent for a sibling or offspring (up to 30 years of age) and 0.5 percent for the general population.18 Type 1 diabetes is transmitted less frequently to the offspring of diabetic women than to those of diabetic men (1.3% compared with 6.1% of offspring).19 Classification In 1979, the US National Diabetes Data Group (NDDG), and in 1980, the WHO produced diagnostic criteria and a classification system for diabetes mellitus. This brought order to a chaotic situation in which nomenclature varied and diagnostic criteria showed enormous variations using different oral glucose loads. In 1985 WHO slightly modified their criteria to coincide more closely with the NDDG values. In 1997, the American Diabetes Association (ADA) published its recommendations on new diagnostic criteria for diabetes. WHO convened a Consultation on the same subject in December 1996 and published these in 1998 (table 1.1). In general, the ADA and WHO groups reached similar conclusions.1;20 The terms Insulin Dependent Diabetes Mellitus (IDDM) and Non Insulin Dependent Diabetes Mellitus (NIDDM) are no longer used as all forms of diabetes may require insulin therapy at some stage.1 The new classification encompasses both clinical stages and aetiological types of diabetes mellitus and other categories of hyperglycaemia. Clinical Staging of Diabetes The clinical staging of diabetes, regardless of its aetiology, reflects the new concepts that diabetes progresses through several clinical stages during its natural history:21 • Normoglycaemia. • Impaired glucose regulation (impaired fasting glycaemia or impaired glucose tolerance). • Diabetes mellitus. Moreover, individual subjects may move from stage to stage in either direction. Persons who have, or who are developing, diabetes mellitus can be categorised by the stage according to Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 29 clinical characteristics, even in the absence of information concerning the underlying aetiology. Aetiologic Classification of Diabetes The classification by aetiological type results from improved understanding of the causes of diabetes mellitus.1 Type 1 diabetes encompasses the cases which are primarily due to pancreatic islet betacell destruction and are prone to ketoacidosis. Type 1 includes those cases attributable to an autoimmune process, as well as those for which neither an aetiology nor a pathogenesis is known (ie idiopathic). It does not include those forms of beta-cell destruction or failure to which specific causes can be assigned (eg cystic fibrosis, mitochondrial defects, etc.). Type 2 diabetes includes the common major form of adult diabetes which results from defect(s) in insulin secretion, almost always with a major contribution from insulin resistance. The lean phenotype of type 2 diabetes mellitus in adults found in Japan and the Indian subcontinent may be very distinct from the more characteristic form of type 2 found in white Caucasians which is associated with increased visceral fat. Not enough information is available, however, to characterise such subjects separately. Malnutrition-related diabetes (MRDM) has been deleted in the new classification. Impaired Glucose Tolerance is now classified as a clinical stage of impaired glucose regulation, since it can be observed in any hyperglycaemic disorder, and is itself not diabetes. A clinical stage of Impaired Fasting Glycaemia has been introduced to classify individuals who have fasting glucose values above the normal range, but below the level diagnostic of diabetes. Gestational Diabetes now encompasses the groups formerly classified as Gestational Impaired Glucose Tolerance (GIGT) and Gestational Diabetes Mellitus (GDM). Table 1.1: Aetiological Classification of Disorders of Glycaemia1 Type 1 (beta-cell destruction, usually leading to absolute insulin deficiency) • Autoimmune • Idiopathic Type 2 (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with or without insulin resistance) Other specific types (see Table 1.2) Gestational diabetes Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 30 Table 1.2: Other Specific Types of Diabetes1 Genetic defects of beta-cell function • MODY 1-6 • Mitochondrial DNA mutation • Others Genetic defects in insulin action • Type A insulin resistance • Leprechaunism • Rabson-Mendenhall syndrome • Lipoatrophic diabetes • Others Diseases of the exocrine pancreas • Fibrocalculous pancreatopathy • Pancreatitis • Trauma / pancreatectomy • Agenesis • Cystic fibrosis • Haemochromatosis/thalassaemia • Others Endocrinopathies • Cushing syndrome • Acromegaly • Phaeochromocytoma • Glucagonoma • Hyperthyroidism • Somatostatinoma • Others Drug- or chemical-induced • Insulin deficiency (Alloxan, Streptozotocin, Vacor, L-Asparaginase, Tacrolimus, Cyclosporin, Diazoxide, others) • Insulin resistance (Glucocorticoids, Growth Hormone, Interferon-alpha, others) Infections • Congenital rubella • Cytomegalovirus • Others Uncommon forms of immune-mediated diabetes • Insulin autoimmune syndrome (antibodies to insulin) • Anti-insulin receptor antibodies • ‘Stiff Man’ syndrome • Polyendocrine autoimmune deficiencies APS I and II • Others Other genetic syndromes • Wolfram, Down, Klinefelter, Turner, Myotonic dystrophy, Friedreich ataxia, Prader Willi, Laurence-Moon-Biedl, Porphyria Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 31 Diagnostic Criteria for Diabetes in Childhood and Adolescence Diagnostic criteria for diabetes are based on:1 • Blood glucose measurements. and • The presence or absence of symptoms. According to these criteria a diagnosis of diabetes can be made if: • The characteristic symptoms and signs are present. and • Fasting venous plasma glucose concentration is greater than or equal to 7.0 mmol/L, and/or the random venous plasma glucose concentration taken at least 2 hours after eating is greater than or equal to 11.1 mmol/L. Diabetes in childhood usually presents with severe symptoms, very high blood glucose levels, marked glycosuria, ketonuria and frequently with ketoacidosis. The diagnosis is usually confirmed quickly by measurement of a marked elevation of the blood glucose level. In this situation treatment is urgent. Waiting another day to confirm the hyperglycaemia is neither necessary nor appropriate for diagnosis in such circumstances. (See chapter 2) In the absence of symptoms of diabetes both of the aforementioned plasma glucose criteria need to be met and repeated on another day for a diagnosis of diabetes to be made. In presence of mild symptoms, the diagnosis of diabetes should never be made on the basis of a single abnormal blood glucose value. Diagnosis may require continued observation with a fasting blood glucose measurement, 2 hour post-prandial blood glucose levels and/or an oral glucose tolerance test (OGTT). An OGTT should not be performed if diabetes can be diagnosed using fasting, random or post-prandial criteria as excessive hyperglycaemia can result. If doubt remains, periodic re-testing should be undertaken until the diagnosis is established. Table 1.3: WHO Criteria Values for Diagnosis of Diabetes Mellitus and Other Categories of Hyperglycaemia Glucose concentration, mmol/L Venous whole blood Capillary whole blood Venous plasma* Diabetes Mellitus: Fasting 6.1 6.1 7.0 Or 2-hr post glucose load 10.0 11.1 11.1 or both Impaired Glucose Tolerance (IGT): Fasting (if measured) <6.1 <6.1 <7.0 And 2-h post glucose load 6.7 and <10.0 7.8 and <11.1 7.8 and <11.1 Impaired Fasting Glycaemia (IFG): Fasting 5.6 and <6.1 5.6 and <6.1 6.1 and <7.0 And (if measured) 2-h post glucose load <6.7 <7.8 <7.8 * Corresponding values (mmol/L) for capillary plasma are: for Diabetes Mellitus, fasting 7.0, 2-h 12.2; for Impaired Glucose Tolerance, fasting <7.0 and 2-h 8.9 and <12.2; and for Impaired Fasting Glycaemia 6.1 and <7.0 and if measured, 2-h <8.9. Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 32 Oral Glucose Tolerance Test (OGTT) An oral glucose tolerance test (OGTT) is rarely indicated in making the diagnosis of type 1 diabetes in childhood and adolescence. If doubt exists, it is easier to monitor the child or adolescent regularly with urine testing for glycosuria and to perform a fasting plasma glucose or post-prandial blood tests to detect hyperglycaemia.1 The OGTT is used more frequently in the evaluation of possible glucose intolerance in a child or adolescent suspected of having the metabolic syndrome or type 2 diabetes. Typical clinical scenarios include an obese adolescent with acanthosis nigricans, a girl with the polycystic ovary syndrome, an obese child with a family history of type 2 diabetes or an obese child from a high risk ethnic background for type 2 diabetes. The dose of glucose used in the OGTT is 1.75 gm/kg of body weight to a maximum of 75 gm.1 The glucose load or partial hydrolysate of starch of equivalent carbohydrate content is administered in 250-300 ml water over a 5 minute period. The OGTT should be performed strictly under the following conditions: • The child or adolescent should not be suffering from any obvious intercurrent illness or be on any medication known to affect blood glucose levels. • Venous plasma glucose levels are preferred instead of whole blood or capillary glucose levels for which different criteria are used (see table 1.3). • Glucose estimations should be performed in NATA accredited laboratory using laboratory instrumentation rather than glucose meters for bedside or home use. • Blood specimens should be collected using sodium oxalate, sodium/potassium EDTA or heparin as anticoagulants and centrifuged immediately or kept on ice if there is delay. This is necessary as the presence of cells reduces the glucose levels by 5 percent per hour at room temperature. Alternatively the specimen can be collected into sodium fluoride or sodium iodoacetate tubes, which inhibit glycolysis and prevent the metabolism of glucose by cells. • The test should be done in the morning after fasting overnight. • The diet in the preceding 3 days should be high in carbohydrate. Interpretation of OGTT The major change recommended by the WHO and the American Diabetes Association in the revised diagnostic criteria for diabetes mellitus is the lowering of the diagnostic value of the fasting venous plasma glucose concentration to 7.0 mmol/ l, from the former level of 7.8 mmol/ l.1;20 It is important to note that different criteria apply for capillary whole blood, venous whole blood and venous plasma. For whole blood, the proposed new level is 6.1 mmol /l, from the former 6.7 mmol/ l. It is recommended that venous plasma levels be used for consistency. Despite the fact that children tend to have lower blood glucose levels than adults, the OGTT criteria used for a diagnosis of diabetes mellitus in children and adolescents are the same as for adults ie • Elevated fasting venous plasma glucose (7.0 mmol/L). and/or • Elevated venous plasma glucose at 2 hours (11.1 mmol/L). IFG and IGT both indicate glucose intolerance but are not equivalent in that they measure different parameters. IFG is a measure of disturbed carbohydrate metabolism in the basal Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 33 state whilst the IGT is a dynamic measure of carbohydrate intolerance after a standardised glucose load. Children and adolescents with a fasting venous plasma glucose 6.1 mmol/L and <7.0 mmol/L have impaired fasting glycaemia. Children and adolescents with a fasting venous plasma glucose <7.0 mmol/L AND 2 hour OGTT values between 7.8 and <11.1 mmol/L are classified as having impaired glucose tolerance (IGT). The American Diabetes Association has classified both IFG and IGT as being pre-diabetes as both categories indicate a high risk of progressing to type 2 diabetes over the next 5-10 years. For IGT, the risk for progression to diabetes for adults, remaining IGT or reverting to normal are all approximately 33% over 5-10 years.22 In borderline diagnostic situations the presence of autoimmune markers such as antibodies against islet cell antigens (ICA), IA-2 and GAD are of assistance in confirming type 1 diabetes. In type 1 diabetes, insulin and C-Peptide levels taken during the OGTT are low for the accompanying blood glucose levels, whereas in type 2 diabetes they are usually elevated. Intravenous Glucose Tolerance Test (IVGTT) The IVGTT is a research tool. Interpretation of the test can be difficult. The main use of IVGTT is to measure the early insulin response following an intravenous glucose load. In type 1 diabetes intervention studies, the IVGTT responses help to determine insulin reserve in pre-diabetic individuals with elevated islet antibodies and other autoimmune markers. In studies of the metabolic syndrome (including IFG and IGT), the IVGTT is used to obtain measures of insulin sensitivity, glucose disposal and beta cell function (minimal model).23 Metabolic Syndrome Although there is no international consensus on the definition of the Metabolic Syndrome, the WHO has suggested the following working definition for adults. The Metabolic Syndrome consists of glucose intolerance (impaired glucose tolerance or diabetes mellitus) and/or insulin resistance with two or more of the following:1 • Raised arterial blood pressure 140/90 mmHg. • Raised plasma triglycerides and/or low HDL cholesterol. • Central obesity (males: waist to hip ratio >0.90; females: waist to hip ratio >0.85) and/or BMI >30 kg/m2. • Microalbuminuria (urinary albumin excretion rate 20 µg/min or albumin:creatinine ratio 30 mg/g or >2.5 mg/mmol. Other components not necessary for the recognition of the condition include hyperuricaemia and coagulation disorders. Persons with hypertension, central obesity, and dyslipidaemia, with or without hyperglycaemia, are at high risk of macrovascular disease. Management should include controlling blood glucose, and reducing the other cardiovascular risk factors (dyslipidaemia, hypertension, smoking, obesity and hypercoagulability). Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 34 Type 2 Diabetes Type 2 diabetes is rapidly increasing in children and adolescents, accounting for approximately 5 percent of diabetes in this age group in Australia.24 The aetiology is unknown. There may be predominantly insulin resistance with relative insulin deficiency or a predominantly secretory defect (non-autoimmune mediated) with or without insulin resistance. The possibility of type 2 diabetes should be considered in children and adolescents who: • Are obese. • Have a strong family history of type 2 diabetes. • Come from an ethnic background at high risk for diabetes. • Produce little or no ketonuria. • Show evidence of insulin resistance (acanthosis nigricans or polycystic ovary syndrome). The rising incidence of type 2 diabetes is associated with the epidemic of obesity. Aborigines and Torres Strait Islanders are at high risk.25 Lifestyle factors such as little exercise and overeating leading to obesity have profound effects. Whilst many indigenous ethnic groups are liable to type 2 diabetes (eg Pima Indians in Arizona, Cree-Ojibee Indians in Canada, Pacific islanders, Australian Aborigines, Torres Strait islanders), the increased risk is now being seen in many populations (eg Indians and Indian communities originating from the Indian subcontinent, Chinese, Africans, Afro-Americans, Arabs and HispanicAmerican).25 A positive family history for type 2 diabetes is present in over 80%. Identical twins have a concordance rate for type 2 diabetes approaching 100 percent.26 Type 2 diabetes is often asymptomatic but may present with ketosis and even mild to moderate ketoacidosis.27;28 It may be the underlying cause of hyperglycaemia associated with infections and severe illness in some patients (see Stress Hyperglycaemia). Treatment is difficult because of the chronicity and the need to incorporate lifestyle changes. The long term microvascular complications of diabetes occur as frequently, as quickly, and as severely as in type 1 diabetes.29 Because type 2 diabetes may have a prolonged asymptomatic phase screening for complications should start at diagnosis or soon after.31 The risks for macrovascular complications are also increased and reflect the underlying Metabolic Syndrome in type 2 diabetes. The principles of treatment for type 2 diabetes are:28 • Weight reduction if the patient is obese. • Exercise and a healthy lifestyle. • Carbohydrate- and fat-controlled diet. • Metformin. • Occasionally insulin replacement. • Occasionally sulphonylurea or other oral hypoglycaemics. • Occasionally insulin sensitisers (eg thiazolidinediones). • Occasionally combination therapy of above medications. • Control of associated macrovascular risk factors (hypertension, dyslipidemia, avoiding smoking). Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 35 Screening for Type 2 Diabetes Population screening for type 2 diabetes in children and adolescents cannot be justified in Australia because of the low prevalence (in Japan, however, annual school glycosuria screening programmes are in place). Targeted screening (fasting plasma glucose or 2 hour post-prandial glucose) is recommended at the point of medical contact if high risk factors are present (obesity, strong family history of type 2 diabetes, high risk ethnic group, acanthosis nigricans, polycystic ovary syndrome).28;30;31 The Consensus Panel of the American Diabetes Association recommends that testing of high risk subjects should be done every 2 years starting at age 10 years or at onset of puberty, whichever is earlier.28 The World Health Organization states that opportunistic screening, as described above, may be justified provided the individual being tested is appropriately informed and counselled, and the health care system has the capacity to manage positive cases.32 There is no indication for haphazard screening.32 Other Types of Diabetes The possibility of other types of diabetes should be considered in children and adolescents who: • Have an autosomal dominant family history of diabetes. • Have associated conditions such as deafness, optic atrophy or syndromic features. • Have marked insulin resistance or require little or no insulin outside the partial remission phase. • Have been exposed to drugs known to be toxic to beta cells or cause insulin resistance. Maturity Onset Diabetes of the Young (MODY) Maturity onset diabetes of the young (MODY) is a disorder with the following characteristics:33;34 • Onset before 25 years of age. • Nonketotic diabetes mellitus. • Autosomal dominant inheritance. • Primary defect in the function of the pancreatic beta cells. MODY is genetically heterogenous and includes at least 6 forms, all dominantly inherited.33;34 There is great variation in the degree of hyperglycaemia, need for insulin and risk for future complications. Apart from MODY 2, all other forms of MODY are due to transcription factor gene mutations.33;34 It is likely that other genetic causes for the MODY phenotype will be defined in the future. Gene diagnosis is now possible but expensive to obtain. • MODY 1- mutations of Hepatic Nuclear Factor-4 (HNF-4) gene on chromosome 20.33;34 • MODY 2 - mutations of the glucokinase gene (GCK) on the short arm of chromosome 7. Glucokinase is a beta cell enzyme which appears to function as the glucose sensor of the beta cell. Patients with MODY 2 tend to present late, have mild hyperglycaemia, a low risk for diabetes complications and may not require treatment (unless they are homozygous for the condition).33;34 • MODY 3 - mutations of HNF-1 gene on chromosome 12. These patients have a severe defect in insulin secretion and major hyperglycaemia.33;34 Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 36 • MODY 4 - mutations of IPF-1 (Insulin Promoter Factor-1) gene on chromosome 7. Homozygous patients have pancreatic aplasia.33;34 33;34 • MODY 5 - mutations of HNF-1 gene on chromosome 17. • MODY 6 - mutations of Neurogenic Differentiation Factor-1 (beta 2- NeuroD1) gene.33;34 33;34 • MODY X - others. Adults with MODY are liable to the same microvascular and macrovascular complications of diabetes as patients with type 2 diabetes. Complications are rare in MODY 2.33;34 The principles of treatment in MODY are the same as for type 2 diabetes: • Weight reduction if the patient is obese. • Exercise and a healthy lifestyle. • Carbohydrate- and fat-controlled diet. • Sulphonylurea drugs or metformin (MODY 3 may be very sensitive to small doses of sulphonylureas.34 • Insulin replacement. DIDMOAD Syndrome (Wolfram Syndrome) DIDMOAD syndrome (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness) is a rare autosomal recessive condition associated with non-autoimmune degeneration of the pancreatic beta cells.35 The Wolfram gene (WSF-1) has been cloned and is on chromosome 4. Diabetes is usually the first manifestation and all cases reported also have optic atrophy. Other manifestations are more variable and include: • Diabetes mellitus (median age 8.2 years). • Optic atrophy (median age 13.1 years). • Diabetes insipidus (median age 14.1 years). • Sensorineural deafness (median age 15.0 years). • Neurological degeneration (with CNS atrophy on MRI). • Psychiatric disturbances. • Death (median age 28 years). Mitochondrial Diabetes Maternal transmission of mutated mitochondrial DNA (mtDNA) can result in maternally inherited diabetes. Although several mutations have been implicated, the strongest evidence relates to a point substitution at nucleotide position 3243 (A to G) in the mitochondrial tRNA (leu(UUR)) gene. Mitochondrial diabetes is commonly associated with sensorineural deafness and often presents with progressive non-autoimmune beta-cell failure.36 Neonatal Diabetes Insulin-requiring hyperglycaemia in the first month of life is known as neonatal onset diabetes mellitus. This rare condition (1/400,000 births) may be associated with intrauterine growth retardation.37 Approximately half of the cases are temporary and have been associated with paternal isodisomy of chromosome 6.38;39 The permanent cases are associated with pancreatic aplasia, mutations of Insulin Promoter Factor-1 (chromosome 7), complete glucokinase deficiency (chromosome 7)40 and mutations of the FOXP3 gene (T cell regulatory gene) as part of the IPEX syndrome.41 Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 37 Cystic Fibrosis and Diabetes Diabetes in Cystic Fibrosis is primarily due to insulin deficiency. However, insulin resistance secondary to infections and medications (bronchodilators and glucocorticoids) may contribute significantly during acute illness. Diabetes tends to occur late in the disease, typically in adolescence and early adulthood.42 Concurrent cirrhosis, if present, may contribute to insulin resistance. The onset of diabetes is a poor prognostic sign. Poorly controlled diabetes will interfere with immune responses to infection and promote catabolism. Screening recommendations vary from testing a random blood glucose level annually in all children with cystic fibrosis 14years old, to performing an oral glucose tolerance test annually in all those >10years old.42;43 Insulin therapy initially may only be needed during respiratory infections due to acute on chronic infective episodes, but eventually ongoing therapy is frequently necessary. Initially insulin doses are small (supplemental rather than total insulin replacement). In some patients, early insulin therapy prior to symptoms of hyperglycaemia may provide metabolic effects beneficial to growth, weight and pulmonary function.44;45 Drug Induced Diabetes The most frequent scenarios for drug induced diabetes occur in neurosurgery, chemotherapy for malignancies and immunosuppression post transplant. In neurosurgery, large doses of dexamethasone are frequently used to prevent cerebral oedema (eg dexamethasone 24 mg per day). The additional stress of the surgery may add to the drug-induced insulin resistance, and cause a relative insulin deficiency, sufficient to cause a transient form of diabetes. This will be exacerbated if large volumes of intravenous dextrose are given for diabetes insipidus. An intravenous insulin infusion is the optimal way to control the hyperglycaemia which is usually transient. In oncology, protocols which employ L-asparaginase, high dose glucocorticoids, cyclosporin or tacrolimus (FK506) may be associated with diabetes. L-asparaginase usually causes a reversible form of diabetes.46 Tacrolimus and cyclosporin may cause a permanent form of diabetes possibly due to islet cell destruction.47 Often the diabetes is cyclic and associated with the chemotherapy cycles, especially if associated with large doses of glucocorticoids. In transplantation medicine, secondary diabetes most frequently occurs with the use of high dose steroids and tacrolimus.48;49 Stress Hyperglycaemia Stress hyperglycaemia is hyperglycaemia detected in the presence of fever, infection, surgery, respiratory distress, head trauma, or other stress. It is usually transitory and should not be regarded as diagnostic of diabetes.1 One large study describes the occurrence of stress hyperglycaemia in up to 5% of children presenting to an emergency department with acute illness or injury, and identifies traumatic injuries, febrile seizures and elevated body temperature (>39 degrees) as the most commonly associated features.50 Of 41 children with stress hyperglycaemia, none had developed diabetes after a mean follow-up period of 3.5years. In other smaller studies, the reported incidence of progressing to overt diabetes varied from 0% to 33%.51-56 Children who develop hyperglycaemia without a serious illness are more likely to develop diabetes than those who have hyperglycaemia in response to a serious illness.53 Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 38 Follow-up of patients with a history of stress hyperglycaemia varies from centre to centre. Autoantibody screening for antipancreatic antibodies is a practical and useful method of follow-up. Islet cell antibodies and insulin autoantibodies have a high positive predictive value for type 1 diabetes in children with stress hyperglycaemia.53 The Evidence The evidence on the prevalence/incidence of type 1 diabetes in children in Australia and worldwide is shown in Evidence table 1.1. • Worldwide the incidence of type 1 diabetes in children under the age of 15 ranges from 0.1 - 37.4 per 100,000.5;6(IV) • The most recent data on the incidence of childhood type 1 diabetes in Australia (New South Wales) indicates an incidence of 17.8 per 100,000 from 1990-1996, with an annual increase in incidence of 3.2% per year since 1990.8;16 (IV) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence table 1.2. Recommendations and Principles • The diagnosis of diabetes in children and adolescents should be based on the World Health Organization criteria (1999).1(T) • Worldwide the incidence of type 1 diabetes in childhood varies greatly (0.1 - 37.4 per 100,000), with the Australian incidence being 17.8 and increasing by 3.2% per year since 1990.5;6;8;16(IV) • Diabetes can be diagnosed if the characteristic symptoms and signs are present and fasting venous plasma glucose concentration is greater than or equal to 7.0 mmol/L, and/or the random venous plasma glucose concentration taken at least 2 hours after eating is greater than or equal to 11.1 mmol/L.1(T) • The possibility of type 2 diabetes should be considered in children and adolescents who are obese, have a strong family history of type 2 diabetes, come from an ethnic background at high risk for diabetes, produce little or no ketonuria and show evidence of insulin resistance (acanthosis nigricans or polycystic ovary syndrome).1;28(T,C) • The possibility of other types of diabetes should be considered in children and adolescents who have any of the following: an autosomal dominant family history of diabetes, have associated conditions such as deafness, optic atrophy or syndromic features, have marked insulin resistance or require little or no insulin outside the partial remission phase or have been exposed to drugs known to be toxic to beta cells or cause insulin resistance.1;57(T,C) • An oral glucose tolerance test (OGTT) is rarely indicated in making the diagnosis of type 1 diabetes in childhood and adolescence.1;57(T,C) • The OGTT may be used in the evaluation of possible glucose intolerance in a child or adolescent suspected of having the metabolic syndrome eg an obese adolescent with acanthosis nigricans, a girl with the polycystic ovary syndrome, an obese child with a family history of type 2 diabetes or an obese child from a high risk ethnic background for type 2 diabetes.28;32(T,C) • Targeted screening for type 2 diabetes (fasting plasma glucose or 2 hour post-prandial glucose) is recommended at the point of medical contact if high risk factors are present (obesity, strong family history of type 2 diabetes, high risk ethnic group, acanthosis nigricans, polycystic ovary syndrome) and every 2 years thereafter.31;32(T,C) IV = Evidence from case series, either post-test or pre-test and post-test T = WHO technical report produced by expert panels C = Consensus statement endorsed by professional organisations Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 39 Reference List 1. World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Report of a WHO Consultation. Part 1:Diagnosis and Classification. WHO/NCD/NCS/99.2. 1999. Geneva, World Health Organization. 2. Gepts W: Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14:619-633, 1965 3. Kulmala P, Savola K, Reijonen H, Veijola R, Vahasalo P, Karjalainen J, Tuomilehto-Wolf E, Ilonen J, Tuomilehto J, Akerblom HK, Knip M: Genetic markers, humoral autoimmunity, and prediction of type 1 diabetes in siblings of affected children. Childhood Diabetes in Finland Study Group. Diabetes 49:48-58, 2000 4. Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, Chase HP, Eisenbarth GS: Prediction of type I diabetes in firstdegree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 45:926-933, 1996 5. International Diabetes Federation: Diabetes Atlas 2nd Edition. Brussels, Belguim, IDF, 2003 6. Karvonen M, Viik-Kajander M, Moltchanova E, Libman I, LaPorte R, Tuomilehto J: Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care 23:1516-1526, 2000 7. Ilonen J, Reijonen H, Green A, Reunanen A, Knip M, Simell O, Akerblom HK: Geographical differences within Finland in the frequency of HLA-DQ genotypes associated with type 1 diabetes susceptibility. The Childhood Diabetes in Finland Study Group. European Journal of Immunogenetics 27:225-230, 2000 8. Craig ME, Howard NJ, Silink M, Chan A: The rising incidence of childhood type 1 diabetes in New South Wales, Australia. Journal of Pediatric Endocrinology & Metabolism 13:363-372, 2000 9. Patterson CC, Thorogood M, Smith PG, Heasman MA, Clarke JA, Mann JI: Epidemiology of type 1 (insulin-dependent) diabetes in Scotland 1968-1976: evidence of an increasing incidence. Diabetologia 24:238-243, 1983 10. Staines A, Bodansky HJ, Lilley HE, Stephenson C, McNally RJ, Cartwright RA: The epidemiology of diabetes mellitus in the United Kingdom: the Yorkshire Regional Childhood Diabetes Register. Diabetologia 36:1282-1287, 1993 11. EURODIAB ACE Study Group: Variation and trends in incidence of childhood diabetes in Europe. EURODIAB ACE Study Group. Lancet 355:873-876, 2000 12. Karvonen M, Pitkaniemi J, Tuomilehto J: The onset age of type 1 diabetes in Finnish children has become younger. The Finnish Childhood Diabetes Registry Group. Diabetes Care 22:1066-1070, 1999 13. Shaltout AA., Moussa MA, Qabazard M, Abdella N, Karvonen M. Al-Khawari M, Al-Arouj M, Al-Nakhi A, Tuomilehto J, ElGammal A: Kuwait Diabetes Study Group. Further evidence for the rising incidence of childhood Type 1 diabetes in Kuwait. Diabetic Medicine 19:522-525, 2002 14. Levy-Marchal C, Patterson C, Green A: Variation by age group and seasonality at diagnosis of childhood IDDM in Europe. The EURODIAB ACE Study Group. Diabetologia 38:823-830, 1995 15. Green A, Patterson CC: Trends in the incidence of childhood-onset diabetes in Europe 1989-1998. Diabetologia 44:B3-B8, 2001 16. Verge CF, Silink M, Howard NJ: The incidence of childhood IDDM in New South Wales, Australia. Diabetes Care 17:693-696, 1994 17. Olmos P, A'Hern R, Heaton DA, Millward BA, Risley D, Pyke DA, Leslie RD: The significance of the concordance rate for type 1 (insulin-dependent) diabetes in identical twins. Diabetologia 31:747-750, 1988 18. Lorenzen T, Pociot F, Hougaard P, Nerup J: Long-term risk of IDDM in first-degree relatives of patients with IDDM. Diabetologia 37:321-327, 1994 19. Warram JH, Krolewski AS, Gottlieb MS, Kahn CR: Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and diabetic fathers. New England Journal of Medicine 311:149-152, 1984 20. American Diabetes Association: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 26:5-20, 2003 21. Kuzuya T, Matsuda A: Classification of diabetes on the basis of etiologies versus degree of insulin deficiency. Diabetes Care 20:219220, 1997 22. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M: Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. New England Journal of Medicine 344:1343-1350, 2001 23. Bergman RN: Lilly Lecture: Toward Physiological Understanding of Glucose Tolerance. Minimal Model Approach. Diabetes 38:1512-1527, 1989 24. Broyda V, Craig ME, Crock P, Howard NJ: Incidence of Type 2 Diabetes in New South Wales and the Australian Capital Territory, Australia (Abstract). ADA 2003 25. Sing, R, Shaw, J., and Zimmet, P. Type 2 diabetes in the Young (International Diabetes Institute). 2002. Ref Type: Report 26. Medici F, Hawa M, Ianari A, Pyke DA, Leslie RD: Concordance rate for type II diabetes mellitus in monozygotic twins: actuarial analysis. Diabetologia 42:146-150, 1999 27. Pinhas-Hamiel O, Dolan LM, Zeitler PS: Diabetic ketoacidosis among obese African-American adolescents with NIDDM. Diabetes Care 20:484-486, 1997 28. American Diabetes Association: Type 2 Diabetes in Children and Adolescents. Pediatrics 105:671-680, 2000 29. Yokoyama H, Okudaira M, Otani T, Watanabe C, Takaike H, Miuira J, Yamada H, Mutou K, Satou A, Uchigata Y, Iwamoto Y: High incidence of diabetic nephropathy in early-onset Japanese NIDDM patients. Risk analysis. Diabetes Care 21:1080-1085, 1998 30. Fagot-Campagna A, Saaddine JB, Engelgau MM: Is testing children for type 2 diabetes a lost battle? Diabetes Care 23:1442-1443, 2000 31. American Diabetes Association: Screening for Type 2 Diabetes. Diabetes Care 26:21-24, 2003 32. World Health Organization. Screening for Type 2 Diabetes. Report of a World Health Organization and International Diabetes Federation meeting. WHO/NMH/MNC/03.1. 2003. Geneva, World Health Organization. 33. Fajans SS, Bell GI, Polonsky K.S: Mechanisms of Disease: Molecular Mechanisms and Clinical Pathophysiology of Maturity-Onset Diabetes of the Young. New England Journal of Medicine 345:971-980, 2001 34. Owen K, Hattersley AT: Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. Best Practice & Research Clinical Endocrinology & Metabolism 15:309-323, 2001 35. Barrett TG, Bundey SE: Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet 346:1458-1463, 1995 36. Alcolado JC, Laji K, Gill-Randall R: Maternal transmission of diabetes. Diabetic Medicine 19:89-98, 2002 37. von Muhlendahl KE, Herkenhoff H: Long-term course of neonatal diabetes. New England Journal of Medicine 333:704-708, 1995 38. Hermann R, Laine AP, Johansson C, Niederland T, Tokarska L, Dziatkowiak H, Ilonen J, Soltesz G: Transient but not permanent neonatal diabetes mellitus is associated with paternal uniparental isodisomy of chromosome 6. Pediatrics 105:49-52, 2000 Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 40 39. Metz C, Cave H, Bertrand AM, Deffert C, Gueguen-Giroux B, Czernichow P, Polak M: NDM French Study Group: Neonatal diabetes mellitus. Neonatal diabetes mellitus: chromosomal analysis in transient and permanent cases. Journal of Pediatrics 141:483489, 2002 40. Njolstad PR, Sovik O, Cuesta-Munoz A, Bjorkhaug L, Massa O, Barbetti F, Undlien DE, Shiota C, Magnuson MA, Molven A, Matschinsky FM, Bell GI: Neonatal diabetes mellitus due to complete glucokinase deficiency. New England Journal of Medicine 344:1588-1592, 2001 41. Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly T, Saulsbury FT, Chance PF, Ochs HD: The immune dysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genetics 27:20-21, 2001 42. Riggs AC, Seaquist ER, Moran A: Guidelines for the diagnosis and therapy of diabetes mellitus in cystic fibrosis. Current Opinion in Pulmonary Medicine 5:378-382, 1999 43. Lanng S, Hansen A, Thorsteinsson B, Nerup J, Koch C: Glucose tolerance in patients with cystic fibrosis: five year prospective study. British Medical Journal 311:655-659, 1995 44. Dobson L, Hattersley AT, Tiley S, Elworthy S, Oades PJ, Sheldon CD: Clinical improvement in cystic fibrosis with early insulin treatment. Archives of Disease in Childhood 87:430-431, 2002 45. Nousia-Arvanitakis S, Galli-Tsinopoulou A, Karamouzis M: Insulin improves clinical status of patients with cystic-fibrosis-related diabetes mellitus. Acta Paediatrica 90:515-519, 2001 46. Pui CH, Burghen GA, Bowman WP, Aur RJ: Risk factors for hyperglycemia in children with leukemia receiving L-asparaginase and prednisone. Journal of Pediatrics 99:46-50, 1981 47. Drachenberg CB, Klassen DK, Weir MR, Wiland A, Fink JC, Bartlett ST, Cangro CB, Blahut S, Papadimitriou JC: Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Transplantation 68:396-402, 1999 48. Maes BD, Kuypers D, Messiaen T, Evenepoel P, Mathieu C, Coosemans W, Pirenne J, Vanrenterghem YF: Posttransplantation diabetes mellitus in FK-506-treated renal transplant recipients: analysis of incidence and risk factors. Transplantation 72:1655-1661, 2001 49. Al-Uzri A, Stablein DM, A Cohn R: Posttransplant diabetes mellitus in pediatric renal transplant recipients: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation 72:1020-1024, 2001 50. Valerio G, Franzese A, Carlin E, Pecile P, Perini R, Tenore A: High prevalence of stress hyperglycaemia in children with febrile seizures and traumatic injuries. Acta Paediatrica 90:618-622, 2001 51. Shehadeh N, On A, Kessel I, Perlman R, Even L, Naveh T, Soloveichik L, Etzioni A: Stress hyperglycemia and the risk for the development of type 1 diabetes. Journal of Pediatric Endocrinology & Metabolism 10:283-286, 1997 52. Bhisitkul DM, Vinik AI, Morrow AL, She JX, Shults J, Powers AC, Maclaren NK: Prediabetic markers in children with stress hyperglycemia. Archives of Pediatrics & Adolescent Medicine 150:936-941, 1996 53. Herskowitz-Dumont R, Wolfsdorf JI, Jackson RA, Eisenbarth GS: Distinction between transient hyperglycemia and early insulindependent diabetes mellitus in childhood: a prospective study of incidence and prognostic factors. Journal of Pediatrics 123:347-354, 1993 54. Schatz DA, Kowa H, Winter WE, Riley WJ: Natural history of incidental hyperglycemia and glycosuria of childhood. Journal of Pediatrics 115:676-680, 1989 55. Herskowitz RD, Wolfsdorf JI, Ricker AT, Vardi P, Dib S, Soeldner JS, Eisenbarth GS: Transient hyperglycemia in childhood: identification of a subgroup with imminent diabetes mellitus. Diabetes Research 9:161-167, 1988 56. Vardi P, Shehade N, Etzioni A, Herskovits T, Soloveizik L, Shmuel Z, Golan D, Barzilai D, Benderly A: Stress hyperglycemia in childhood: a very high risk group for the development of type I diabetes. Journal of Pediatrics 117:75-77, 1990 57. International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Chapter 1: Definition, Epidemiology and Classification Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 41 Chapter 2: Phases of Diabetes Type 1 diabetes is characterised by: • Preclinical diabetes. • Presentation of diabetes. • Partial remission or honeymoon phase. • Chronic phase of lifelong dependency on administered insulin. Preclinical Diabetes Preclinical diabetes refers to the months or years preceding the clinical presentation of type 1 diabetes when islet antibodies can be detected as markers of beta cell autoimmunity. In addition to these immunological markers, the risk of type 1 diabetes can further be determined by genetic markers. The parameters currently helping to define the preclinical phase include: • Islet cell autoantibodies. • Glutamic acid decarboxylase autoantibodies (65K GAD isoform). • IA2 (also known as ICA 512 or tyrosine phosphatase) autoantibodies. • Insulin autoantibodies. • HLA typing. Risks of progression to diabetes Genetic markers conferring increased or decreased risk include: a) HLA DR3 - DQA1*0501 - DQB1* 0201 (susceptible genotype). b) HLA DR4 - DQA1*0301 - DQB1* 0302 (susceptible genotype). c) HLA DR2 - DQA1*0102 - DQB1* 0602 (protective genotype). Islet autoimmunity can be transient and one raised islet antibody alone has little prognostic value.1-3 If an individual is under 45 years and does not have HLA DR2 - DQA1*0102 DQB1* 0602 then: • Impaired first phase insulin release on intravenous glucose tolerance testing confers a 60% risk over the next 5 years.4 • Two or more islet antibodies raised without impaired first phase insulin release confer a 25-50% risk over the next 5 years.5;6 Neither screening of any population nor intervention in the preclinical phase should occur outside the context of defined clinical studies.7 Individuals who screen positive for genetic or immunological markers of type 1 diabetes should have access to appropriate counselling and to centres participating in intervention and other defined studies. Intervention studies should be registered as part of an international network of investigation and information about ongoing studies should be readily available.7 To date, all clinical trials attempting to prevent or delay the onset of type 1 diabetes in those at high risk have been unsuccessful. The most important of these intervention studies are: • European Nicotinamide Diabetes Intervention Trial (ENDIT), a multinational randomised placebo-controlled, double blinded intervention study, in which nicotinamide did not delay or prevent the onset of type 1 diabetes in high-risk firstdegree relatives.8 • Diabetes Prevention Trial (DPT), in which low dose subcutaneous insulin therapy did not delay or prevent the onset of clinical diabetes in first-degree relatives.4 Chapter 2: Phases of Diabetes Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 42 The one proven environmental trigger of type 1 diabetes is congenital rubella.9;10 Other potential environmental triggers are enteroviral infections (particularly coxsackie) and ECHO viruses), casein, cow’s milk protein and gluten. Low levels of intercurrent infection and improved hygiene may be associated with increased risk. International trials following children at increased genetic risk from birth are investigating potential trigger and protective factors.11;12 Presentation of Type 1 Diabetes Prospective follow-up of high-risk subjects shows that diagnosis of type 1 diabetes can be made in asymptomatic individuals in the majority of cases.4 In the Diabetes Prevention Trial (DPT), when high-risk individuals were followed up, 73% of participants who were diagnosed with diabetes were asymptomatic.4 A child presenting with a classical history of increasing polyuria, polydipsia and weight loss over 2-6 weeks does not usually pose a diagnostic difficulty. Failure to consider the possibility of diabetes or atypical presentations may result in late diagnosis. Some children may have a rapid onset of symptoms and present within a few days in diabetic ketoacidosis, but others may have a slow onset of symptoms over several months. Urinary ‘dipstick’ testing for glycosuria and ketonuria provides a simple and sensitive tool for excluding diabetes with less typical presentation. A blood glucose measurement (plasma glucose >11.1 mmol/L) would confirm the diagnosis. The blood glucose measurement should be a laboratory estimation rather than a bedside reading. Non-emergency presentations Non-emergency presentations of diabetes include: • Recent onset of enuresis in a previously toilet-trained child, which may be misdiagnosed as a urinary tract infection or the result of excessive fluid ingestion. • Vaginal candidiasis, especially in prepubertal girls. • Vomiting, which may be misdiagnosed as gastroenteritis. • Chronic weight loss or failure to gain weight in a growing child. • Irritability and decreasing school performance. • Recurrent skin infections. Emergency presentations The usual emergency presentation of diabetic ketoacidosis in a child or adolescent includes the following clinical features: • Severe dehydration. • Shock (rapid pulse rate, poor peripheral circulation, mottling and peripheral cyanosis). • Hypotension (a late sign and rare in children with diabetic ketoacidosis). • Frequent vomiting. • Continuing polyuria despite the presence of dehydration. • Weight loss due to fluid loss and loss of muscle and fat. • Flushed cheeks due to the ketoacidosis. • Acetone detected on the breath. • Hyperventilation of diabetic ketoacidosis (Kussmaul respiration) is characterised by a high respiratory rate and large tidal volume of each breath, which gives it a sighing quality. • Disordered sensorium (disoriented, semicomatose or rarely comatose). Chapter 2: Phases of Diabetes Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 43 Diagnostic difficulties leading to late diagnosis The following situations may result in a late diagnosis of diabetic ketoacidosis: • The very young child may present in severe ketoacidosis because of a more rapid onset of severe insulin deficiency13 and because the diagnosis was not considered early. • The hyperventilation of ketoacidosis may be misdiagnosed as pneumonia or asthma (cough and breathlessness distinguish these conditions from diabetic ketoacidosis). • The abdominal pain associated with ketoacidosis may simulate an acute abdomen and lead to referral to a surgeon. • The polyuria and enuresis may be misdiagnosed as a urinary tract infection. • The polydipsia may be thought to be psychogenic. • The vomiting may be misdiagnosed as due to gastroenteritis or sepsis. Untreated, diabetic ketoacidosis is fatal. Therapy is urgent and referral to specialised services is essential. Differentiating between type 1 and type 2 diabetes at diagnosis Features suggesting the diagnosis of type 2 diabetes rather than type 1 diabetes at diagnosis are:14;15 • Obesity. • Strong family history of type 2 diabetes. • Acanthosis nigricans. • High risk racial or ethnic group. • Undetectable islet antibodies. • Normal to high C-Peptide levels. Partial Remission or Honeymoon Phase In approximately 80 percent of children and adolescents, insulin requirements decrease transiently following initiation of treatment.16 Most studies define a partial remission phase as that when the patient requires less than 0.5 units of insulin per kg of body weight per day and has a HbA1c <7%.16 The partial remission phase commences within days or weeks of the start of insulin therapy and may last for weeks to months. During this phase blood glucose levels are frequently stable within the normal range, despite fluctuations in diet and exercise. It is important for the families to be advised of the transient nature of the partial remission phase so as to avoid the false hope that the diabetes is spontaneously remitting. Intensive therapy (continuous subcutaneous insulin infusion) has not been shown to prolong the partial remission phase.17 In a few children and adolescents, requirements for insulin may decrease to the point of being able to withdraw insulin therapy temporarily and still maintain normoglycaemia. As low dose subcutaneous insulin therapy does not prolong residual beta cell function in the preclinical phase,4 it is unlikely to do so in the remission phase. Therefore, continuing insulin seems unlikely to prolong endogenous insulin production, or provide any other advantage other than maintaining established diabetes routines for the child. Ketoacidosis at presentation18 and young age16 reduce the likelihood of a remission phase. Chronic Phase of Lifelong Dependence on Insulin The progression from the partial remission phase into the chronic phase of lifelong dependence on insulin is usually gradual but can be accelerated by an intercurrent illness. Chapter 2: Phases of Diabetes Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 44 Exogenous insulin replacement remains the only form of replacement therapy for children and adolescents with type 1 diabetes. As mentioned in the previous section whilst intensive therapy for type 1 diabetes has not been shown to prolong the partial remission phase there is evidence it helps sustain some endogenous insulin secretion (measured by C-Peptide level), which, in turn, is associated with better metabolic control.19 Intervention trials from diagnosis are in progress as part of an international network of intervention trials to preserve beta cell function either in the pre-clinical phase or from diagnosis. Transplantation Islet transplantation has become more successful since the introduction of less beta cell toxic immunosuppressive agents and refined techniques to harvest adequate numbers of viable beta cells.20 The numbers of subjects who remain insulin independent falls with follow-up and several donor pancreases are required for adequate beta cell numbers in the transplant.21 The induction of immunologic tolerance without the need for chronic immunosuppressive therapy is a major goal and the potential use of haematopoietic stem cell therapy for induction of tolerance and islet cell neogenesis in vitro are rapidly expanding research directions. Pancreas transplantation provides high rates of graft survival at 1 year but there are significant surgical risks and the requirement for long term immunosuppression precludes its use in children and adolescents.22 The Evidence The evidence on intervention trials to delay or prevent the onset of type 1 diabetes is listed in Evidence Table 2.1. • European Nicotinamide Diabetes Intervention Trial (ENDIT), a multinational quasirandomised placebo-controlled, double blinded intervention study, demonstrated that nicotinamide did not delay or prevent the onset of type 1 diabetes in high-risk first-degree relatives.8(III-1) • The National Institute of Health Diabetes Prevention Trial (DPT) demonstrated in a randomised controlled trial that low dose subcutaneous insulin therapy did not delay or prevent the onset of clinical diabetes in high-risk first-degree relatives.4(II) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence table 2.2. Recommendations and Principles • Health care professionals should be aware that there are no interventions shown to delay or prevent the onset of type 1 diabetes.4;8(II) • Neither screening of any population nor intervention in the preclinical phase should occur outside the context of defined clinical studies.7(C) • Type 1 diabetes is characterised by a preclinical, clinical, partial remission and chronic phase.23(C) • Clinical presentation of diabetes can vary from non-emergency presentations (eg polydipsia, polyuria, weight loss, enuresis) to severe dehydration, shock and diabetic ketoacidosis.23;24(C,T) • Parents and children with type 1 diabetes should be informed that the partial remission phase of diabetes is transient and does not indicate remission of diabetes.23(C) II = NHMRC Level II: Evidence from at least one properly-designed RCT IV = Evidence obtained from case series T = WHO technical reports produced by expert panels C = Consensus statements endorsed by professional organisations Chapter 2: Phases of Diabetes Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 45 Reference List 1. Colman PG, Steele C, Couper JJ, Beresford SJ, Powell T, Kewming K, Pollard A, Gellert S, Tait B, Honeyman M, Harrison LC: Islet autoimmunity in infants with a Type I diabetic relative is common but is frequently restricted to one autoantibody. Diabetologia 43:203-209, 2000 2. Kimpimaki T, Kulmala P, Savola K, Kupila A, Korhonen S, Simell T, Ilonen J, Simell O, Knip M: Natural history of beta-cell autoimmunity in young children with increased genetic susceptibility to type 1 diabetes recruited from the general population. Journal of Clinical Endocrinology & Metabolism 87:4572-4579, 2002 3. Knip M: Natural course of preclinical type 1 diabetes. Hormone Research 57:6-11, 2002 4. Diabetes Prevention Trial-Type 1 Diabetes Study Group: Effects of Insulin in Relatives of Patients with Type 1 Diabetes Mellitus. New England Journal of Medicine 346:1685-1691, 2002 5. Bingley PJ, Christie MR, Bonifacio E, Bonfanti R, Shattock M, Fonte MT, Bottazzo GF, Gale EA: Combined analysis of autoantibodies improves prediction of IDDM in islet cell antibody-positive relatives. Diabetes 43:1304-1310, 1994 6. Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, Chase HP, Eisenbarth GS: Prediction of type I diabetes in firstdegree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 45:926-933, 1996 7. American Diabetes Association: Prevention of Type 1 Diabetes Mellitus. Diabetes Care 26:140, 2003 8. The European Nicotinamide Diabetes Intervention Trial (ENDIT) Group: Intervening before the onset of Type 1 diabetes: baseline data from the European Nicotinamide Diabetes Intervention Trial. Diabetologia 46(3):339-46, 2003 9. Ginsberg-Fellner F, Witt ME, Fedun B, Taub F, Dobersen MJ, McEvoy RC, Cooper LZ, Notkins AL, Rubinstein P: Diabetes mellitus and autoimmunity in patients with the congenital rubella syndrome. Reviews of Infectious Diseases 7 Suppl 1:S170-S176, 1985 10. McIntosh ED, Menser MA: A fifty-year follow-up of congenital rubella. Lancet 340:414-415, 1992 11. Juvenile Diabetes Research Foundation (JDRF) Center for Prevention of Type 1 Diabetes in Finland. Type 1 Diabetes Prediction and Prevention Project (DIPP). http://www.utu.fi/research/dipp/ 2003. 12. TRIGR study group. Trial to reduce IDDM in the Genetically at risk (TRIGR) 2003. http://www.trigr.org/ Ref Type: Electronic Citation 13. Keskinen PK: First-phase insulin response in young healthy children at genetic and immunological risk for Type I diabetes. Diabetologia 45:1639-1648, 2002 14. American Diabetes Association: Type 2 Diabetes in Children and Adolescents. Pediatrics 105:671-680, 2000 15. American Diabetes Association: Screening for Type 2 Diabetes. Diabetes Care 26:21-24, 2003 16. Lombardo F, Valenzise M, Wasniewska M, Messina MF, Ruggeri C, Arrigo T, De Luca F: Two-year prospective evaluation of the factors affecting honeymoon frequency and duration in children with insulin dependent diabetes mellitus: the key-role of age at diagnosis. Diabetes, Nutrition & Metabolism - Clinical & Experimental 15:246-251, 2002 17. de Beaufort CE, Houtzagers CM, Bruining GJ, Aarsen RS, den Boer NC, Grose WF, van Strik R, de Visser JJ: Continuous subcutaneous insulin infusion (CSII) versus conventional injection therapy in newly diagnosed diabetic children: two-year follow-up of a randomized, prospective trial. Diabetic Medicine 6:766-771, 1989 18. Bober E, Dundar B, Buyukgebiz A: Partial remission phase and metabolic control in type 1 diabetes mellitus in children and adolescents. Journal of Pediatric Endocrinology & Metabolism 14:435-441, 2001 19. The Diabetes Control and Complications Trial Research Group: Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized controlled trial. Annals of Internal Medicine 128:517-523, 1998 20. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV: Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. New England Journal of Medicine 343:230-238, 2000 21. Ryan EA, Lakey JR, Paty BW, Imes S, Korbutt GS, Kneteman NM, Bigam D, Rajotte RV, Shapiro AM: Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 51:2148-2157, 2002 22. Odorico JS, Sollinger HW: Technical and immunosuppressive advances in transplantation for insulin-dependent diabetes mellitus. World Journal of Surgery 26:194-211, 2002 23. International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 24. World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Report of a WHO Consultation. Part 1:Diagnosis and Classification. WHO/NCD/NCS/99.2. 1999. Geneva, World Health Organization. Chapter 2: Phases of Diabetes Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 46 Chapter 3: Medical Management Every child and adolescent with type 1 diabetes, including those from rural and remote areas, deserves to have access to optimal medical management. A child cannot fight for these rights. Health care professionals looking after children must make advocacy for the child one of their key responsibilities.1;2 Suboptimal medical management leads to poor diabetes control which may impair growth, delay puberty and lead to irreversible long-term diabetic microvascular and macrovascular complications.3 Quality of life and life expectancy may be significantly reduced under these circumstances. Poor metabolic control, younger age of onset and lower socioeconomic group are predictors of re-hospitalisation rates which may indicate poor adjustment to diabetes.4 These outcomes occur for a variety of reasons but many are potentially preventable. Aims of Diabetes Management The aims of diabetes management are to have: • Optimal psychosocial adjustment. • Optimal metabolic (glycaemic) control. • Normal growth and development. • An individualised plan of diabetes care incorporating the particular needs of the child or adolescent and the family. Hospital versus Ambulatory Stabilisation At diagnosis the decision should be made between hospital admission or ambulatory initiation of treatment. A systematic review and other studies have concluded that in appropriately chosen patients there are no disadvantages of ambulatory management compared to inpatient management of children and adolescents with newly diagnosed type 1 diabetes.5-12 Older children and adolescents who develop diabetes but are not dehydrated or acidotic may be successfully managed out of hospital if expert diabetes support teams are available. The importance of expert care at diagnosis cannot be over-emphasised. In a questionnaire survey parents reported that care provided by paediatricians without a special interest in diabetes is more likely to result in a longer hospital admission, whilst parental satisfaction with the outpatient care and school liaison is lower than in those cared for by paediatricians with a special interest in diabetes.13 Relative contra-indications to ambulatory initiation of insulin therapy include:2;14 • Very young age (under 2 years). • Ketoacidosis • Dehydration (moderate or severe). • Profound grief reaction in family. • Geographic isolation. • No telephone in the home. • Language or other communication difficulties. • Significant psychological or psychiatric problems within the family. Children, if hospitalised, should be admitted to paediatric hospital wards.15 Following the treatment of acidosis or dehydration it is often possible to continue management on an Chapter 3: Medical Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 47 ambulatory basis. Children should not be admitted to adult wards. Adolescents, if requiring hospitalisation, should preferably be accommodated in adolescent wards. The parents should always be allowed open and free access to their child at all times. The Australian Diabetes Educators Association have published minimum national standards for the ambulatory initiation of insulin.16 These standards are not specific to paediatric care, however, they describe process standards required in Australia to initiate insulin effectively and safely.16 Children and adolescents should have access to care by a multidisciplinary team trained in childhood and adolescent diabetes.2;17-19 It should be recognised that the members of the management team include the patient with diabetes and his/her family. The members of the team are therefore: • The patient and his/her family. • Paediatric endocrinologist or physician trained in the care of children and adolescents with diabetes. • Diabetes educator. • Dietitian. • Psychologist/social worker. Care provided by a specialised diabetes multidisciplinary team has been shown to result in:2025 • • • • • Fewer days in hospital. Higher level of diabetes self care practices. Decreased re-admission rates. Lower HbA1c. Delayed development of complications. After the initial period of diagnosis and education (when frequent contact may be required), the child should be regularly reviewed throughout the year. This should be no less than 3-4 times per year), including one major annual review (paying particular attention to review of regular growth data, blood pressure, puberty, associated conditions, nutrition and complications) with the multidisciplinary team.2;18;19 More frequent reviews by expert teams may result in improved control.26;27 Foundations of Diabetes Management The foundations of successful diabetes management include: • Diabetes education. • Insulin replacement. • Blood glucose monitoring. • Nutritional plan. • Psychological adjustment and wellbeing of the whole family. In addition, exercise should be encouraged because of its beneficial effects on glycaemic control and wellbeing. Diabetes Education Ideally diabetes and nutritional education should be provided by Credentialled Diabetes Educators and dietitians who have undertaken specialised training in paediatric diabetes Chapter 3: Medical Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 48 education and nutrition.2 If specialised diabetes and nutritional education is not available, options include transfer to a centre with the necessary expertise or shared care with such a centre able to provide outreach support. Educational interventions have beneficial effects on diabetes management outcomes.28 Education is a continuous process and should be provided to the child or adolescent and their family at diagnosis and repeated as required at follow up. Diabetes education is more than a transfer of knowledge and should aim to result in the appropriate behaviour changes needed for achieving and maintaining diabetes control. Education should also be appropriate to the age and developmental level of the child or adolescent. Initial diabetes education is usually with the educator and the child and parent, but continuing education can be provided in group settings. The relative merits of individual versus group education have not been studied. Diabetes education can either be provided in a hospital setting or on an ambulatory basis if there are no contra-indications to day care. Diabetes education should also be made available to other care-providers such as grandparents, teachers and staff in childcare centres. Education should be adapted to each individual’s age, maturity, stage of diabetes, lifestyle and culture.1;2 The following topics should be covered: • The cause of diabetes. • Insulin storage. • Insulin injection techniques. • Blood glucose measurement. • Insulin adjustment. • Exercise. • Psychological and family adjustment. • Hypoglycaemia, prevention and its management. • Diabetes management during illness. • Travel. • Diabetes and exercise. • Dietetic principles. • Contraception. • Alcohol and Drugs. • Diabetes complications. When age appropriate • Driving. • Smoking. Insulin Replacement Therapy The terms ‘conventional’ and ‘intensive’ insulin replacement regimens are becoming historical terms and are losing their meaning as the emphasis has shifted from simply equating intensified management with the number of injections given. The aim is to achieve the best possible control of glycaemia in all children and adolescents with diabetes. See Chapter 5 for details of various insulin regimens. Immunisation It is recommended that children and adolescents with type 1 diabetes should be immunised according to the Australian Standard Immunisation Schedule29 unless a contra-indication is present. Diabetes is not a contra-indication to immunisation. Chapter 3: Medical Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 49 In addition to the routine immunisations, the use of the Influenza and Pneumococcal vaccines is being evaluated in people with diabetes.30;31 Outreach Services In rural and geographically remote areas with low population density and very small numbers of children with diabetes, it may not be possible to provide a local multidisciplinary team. In these situations, care may be successfully provided by a local paediatrician/physician with access to resources, support and advice from a tertiary centre diabetes team.32;33 In an audit of almost 1200 children with type 1 diabetes living in New South Wales and the Australian Capital Territory, there was no significant difference in glycaemic control between those from urban and those from rural areas. HbA1c and the incidence of severe hypoglycaemia were used as measures of glycaemic control. This audit confirmed homogeneity of metabolic control regardless of location or system of care in NSW/ACT.32 Support to isolated patients may be in the form of outreach clinics or telemedicine consultations including access to telephone support 24 hours a day and regular telephone contact.32;34-36 Where local resources are lacking, the annual review should be performed by a tertiary centre diabetes team. Transition to Adult Services The importance of an effective transition process for adolescents cannot be overemphasised (see Chapter 18). Cost Issues The cost of hospitalisation for children and adolescents with type 1 diabetes in New South Wales was estimated to be approximately $1.5 million per year in 1990.37 The management of type 1 diabetes in children and adolescents with type 1 diabetes results is significant health care costs at diagnosis and for subsequent readmissions to hospital.37 Since this analysis was done ambulatory care at diagnosis has become more common, however no Australian study has reassessed the cost implications of the changing pattern of care. Two relevant studies were located addressing the cost of ambulatory care versus hospital care at diagnosis. One RCT found that although ambulatory care increased hospital costs mainly by increasing nursing consultation costs and the requirement for telephone support, this increase was offset by significant cost savings for parents.38;39 Overall there was no significant cost difference between the two modes of care. This study was in the Canadian health care system and may not be directly applicable to the Australian setting. A second study (also in Canada) retrospectively compared the costs of hospital care versus ambulatory care and found that hospital costs were much higher for hospital care, however nurse education, parental and societal costs were not accounted for.11 The Evidence The evidence for the benefits of ambulatory care versus hospital inpatient care of patients with newly diagnosed type 1 diabetes is listed in Evidence Table 3.1. • A Cochrane systematic review and other studies have concluded that in appropriately chosen patients there are no disadvantages of ambulatory management compared to Chapter 3: Medical Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 50 inpatient management of children and adolescents with newly diagnosed type 1 diabetes.512 (I) The evidence comparing metabolic control in urban and rural children and adolescents with type 1 diabetes is listed in Evidence Table 3.2. • In a population based audit of children with type 1 diabetes living in New South Wales and the Australian Capital Territory, there was no significant difference in glycaemic control between those from urban and those from rural areas. This audit confirmed homogeneity of metabolic control regardless of location or system of care in NSW/ACT.32 Similar results were obtained in an audit of Victorian urban and rural diabetic youths.33(IV) The evidence on the effect of educational interventions on glycaemic control and psychosocial outcome is listed in Evidence table 3.3. • A Health Technology Assessment has concluded that educational interventions have beneficial effects on diabetes management outcomes.28(I) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence table 3.4. Recommendations and Principles • Every child and adolescent with type 1 diabetes, including those from rural and remote areas, should have access to optimal medical management.1;2;14(C) • Health care professionals who look after children should make advocacy for the child one of their key responsibilities.14(C) • Older children and adolescents who develop diabetes but are not dehydrated or acidotic may be considered for management out of hospital if expert diabetes support teams are available.5-12(I) • Relative contraindications to ambulatory initiation of insulin therapy include very young age (under 2 years), ketoacidosis, dehydration (moderate or severe), geographic isolation, no telephone at home, language or other communication difficulties, profound grief reaction and significant psychological or psychiatric problems within the family.2;14(C) • Children and adolescents with type 1 diabetes should have access to care by a multidisciplinary team trained in childhood diabetes.2;17;18;19(C) • The older child and the family should be recognised as being part of the management team.(C) • Diabetes education should be part of the management of type 1 diabetes in children and adolescents. Educational interventions have beneficial effects on diabetes management outcomes.28(I) • Education should be adapted to each individual’s age, maturity, stage of diabetes, lifestyle and culture.2(C) • After the initial period of diagnosis and education (when frequent contact may be required), the child should be regularly reviewed throughout the year. This should be no less than 3-4 times per year), including one major annual review (paying particular attention to growth, blood pressure, puberty, associated conditions, nutrition and complications) with the multidisciplinary team.2;18;19(C) • Children and adolescents with type 1 diabetes should be immunised according to the Australian Standard Immunisation Schedule29 unless a contra-indication is present. Diabetes is not a contra-indication to immunisation.(C) • In rural and geographically remote areas within the Australian health care system, children with diabetes may be successfully cared for by a local paediatrician/physician with Chapter 3: Medical Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 51 training and experience in paediatric diabetes access to resources, support and advice from a tertiary centre diabetes team.32;33(IV) I = Evidence obtained from a systematic review of all relevant randomized controlled trials III-3 = Evidence from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group IV = Evidence obtained from case series, either post-test or pre-test and post-test C = Consensus statement endorsed by professional organisations T = Technical Report Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. International Diabetes Federation Consultative Section on Diabetes Education. International Curriculum for Diabetes Health Professional Education. 2002. Brussels, International Diabetes Federation. Ref Type: Report International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. New England Journal of Medicine 329:977-986, 1993 Charron-Prochownik D, Kovacs M, Obrosky DS, Stiffler L: Biomedical and psychosocial predictors of early rehospitalization among children with insulin-dependent diabetes mellitus: a longitudinal study. Diabetic Medicine 11:372-377, 1994 Clar C, Waugh N, Thomas S: Routine hospital admission versus out-patient or home care in children at diagnosis of type 1 diabetes mellitus. Cochrane Database of Systematic Reviews 2003 Srinivasan S, Craig ME, Beeney L, Hayes R, Harkin N, Ambler GR, Donaghue KC, Cowell CT: An ambulatory stabilisation program for children with newly diagnosed type 1 diabetes. Medical Journal of Australia 180:277-280, 2004 Forsander GA SJPB: Influence of the initial management regimen and family social situation on glycemic control and medical care in children with type 1 diabetes mellitus. Acta Paediatrica 89:1462-1468, 2000 Kirk J, Thomas E, McEvilly A, Shaw N: Extension of a pediatric diabetes home care service. Practical Diabetes International 20:125-128, 2003 Lee PD: An outpatient-focused program for childhood diabetes: design, implementation, and effectiveness. Texas Medicine 88:6468, 1992 Schneider AJ: Starting insulin therapy in children with newly diagnosed diabetes. American Journal of Diseases of Children 137:782-786, 1983 Spaulding RH, Spaulding WB: The diabetic day-care unit. II. Comparison of patients and costs of initiating insulin therapy in the unit and a hospital. Canadian Medical Association Journal 114:780-783, 1976 Swift PG, Hearnshaw JR, Botha JL, Wright G, Raymond NT, Jamieson KF: A decade of diabetes: keeping children out of hospital. British Medical Journal 307:96-98, 1993 Lessing DN, Swift PG, Metcalfe MA, Baum JD: Newly diagnosed diabetes: a study of parental satisfaction. Archives of Disease in Childhood 67:1011-1013, 1992 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Association for the Welfare of Child Health. Health Care Policy Relating to Children and their Families. 1999. Ref Type: Report Australian Diabetes Educators Association. National Standards for the Development and Quality Assessment of Services Initiating Insulin in the Ambulatory Setting. 2004. American Diabetes Association: Standards of Medical Care for Patients With Diabetes Mellitus. Diabetes Care 26:33S, 2003 NSW Health Department: Principles of Care and Consensus Guidelines for the Management of Diabetes Mellitus in Children and Adolescents. 1998 Queensland Health: Best practice guidelines for the management of Type 1 Diabetes in children and Adolescents. 2002 Bloomfield S, Farquhar JW: Is a specialist paediatric diabetic clinic better? Archives of Disease in Childhood 65:139-140, 1990 Laron Z, Galatzer A, Amir S, Gil R, Karp M, Mimouni M: A multidisciplinary, comprehensive, ambulatory treatment scheme for diabetes mellitus in children. Diabetes Care 2:342-348, 1979 Levetan CS, Salas JR, Wilets IF, Zumoff B: Impact of endocrine and diabetes team consultation on hospital length of stay for patients with diabetes. American Journal of Medicine 99:22-28, 1995 Likitmaskul S, Wekawanich J, Wongarn R, Chaichanwatanakul K, Kiattisakthavee P, Nimkarn S, Prayongklin S, Weerakulwattana L, Markmaitree D, Ritjarean Y, Pookpun W, Punnakanta L, Angsusingha K, Tuchinda C: Intensive diabetes education program and multidisciplinary team approach in management of newly diagnosed type 1 diabetes mellitus: a greater patient benefit, experience at Siriraj Hospital. Journal of the Medical Association of Thailand 85:S488-S495, 2002 Zgibor JC, Songer TJ, Kelsey SF, Weissfeld J, Drash AL, Becker D, Orchard TJ: The association of diabetes specialist care with health care practices and glycemic control in patients with type 1 diabetes: A cross-sectional analysis from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care 23:472-476, 2000 Zgibor JC, Songer TJ, Kelsey SF, Drash AL, Orchard TJ: Influence of health care providers on the development of diabetes complications: long-term follow-up from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care 25:15841590, 2002 DCCT Research Group: Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. Journal of Pediatrics 125:177-188, 1994 Dorchy H, Roggemans MP, Willems D: Glycated hemoglobin and related factors in diabetic children and adolescents under 18 years of age: a Belgian experience. Diabetes Care 20:2-6, 1997 Hampson SE: Effects of educational and psychosocial interventions for adolescents with diabetes mellitus: a systematic review. Health Technology Assessment 5:1-79, 2001 National Health and Medical Research Council: The Australian Immunisation Handbook. 8th Edition. 2003 American Diabetes Association: Immunization and the Prevention of Influenza and Pneumococcal Disease in People With Diabetes. Diabetes Care 26:126S, 2003 Chapter 3: Medical Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 52 31. 32. 33. 34. 35. 36. 37. 38. 39. Smith SA, Poland GA: Use of influenza and pneumococcal vaccines in people with diabetes. Diabetes Care 23:95, 2000 Handelsman P, Craig ME, Donaghue KC, Chan A, Blades B, Laina R, Bradford D, Middlehurst A, Ambler G, Verge CF, Crock P, Moore P, Silink M: NSW/ACT HbA1c Study Group: Homogeneity of metabolic control in New South Wales and the Australian Capital Territory, Australia. Diabetes Care 24:1690-1691, 2001 Cameron FJ, Clarke C, Hesketh K, White EL, Boyce DF, Dalton VL, Cross J, Brown M, Thies NH, Pallas G, Goss PW, Werther GA: Regional and urban Victorian diabetic youth: clinical and quality-of-life outcomes. Journal of Paediatrics & Child Health 38:593-596, 2002 Biermann E, Dietrich W, Standl E: Telecare of diabetic patients with intensified insulin therapy. A randomized clinical trial. Studies in Health Technology & Informatics 77:327-332, 2000 Gelfand KG: Intensive telehealth management of five at-risk adolescents with diabetes. Journal of Telemedicine & Telecare 9:117121, 2003 Howells L, Wilson AC, Skinner TC, Newton R, Morris AD, Greene SA: A randomized control trial of the effect of negotiated telephone support on glycaemic control in young people with Type 1 diabetes. Diabetic Medicine 19:643-648, 2002 Sutton L, Plant AJ, Lyle DM: Services and cost of hospitalization for children and adolescents with insulin-dependent diabetes mellitus in New South Wales. Medical Journal of Australia 152:130-136, 1990 Dougherty G, Schiffrin A, White D, Soderstrom L, Sufrategui M: Home-based management can achieve intensification costeffectively in type I diabetes. Pediatrics 103:122-128, 1999 Dougherty GE, Soderstrom L, Schiffrin A: An economic evaluation of home care for children with newly diagnosed diabetes: results from a randomized controlled trial. Medical Care 36:586-598, 1998 Chapter 3: Medical Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 53 Chapter 4: Insulin Preparations and Storage Children and adolescents with type 1 diabetes are dependent on insulin for survival.1 There is no alternative to treatment with insulin. Insulin is not normally used in combination with any other hypoglycaemic agents. Insulin Action Despite the published data on the duration of action of the various insulin preparations there is much inter- and intra-individual variation2 (see Table 4.1 and Figure 4.1). The onset, peak effect and duration of insulin action may vary both between individuals and for the same individual depending on a number of factors including:3-6 • Age. • Fat mass. • Pubertal stage. • The dose of insulin used. • The site of the injection. • Exercise. • Insulin concentration, type and formulation. • Ambient and body temperature. Types of Insulin Until the development of recombinant DNA technology in the 1980s, insulin was purified from porcine or beef pancreatic tissue. Human recombinant insulins are now the most widely used forms and are the recommended first line preparations in the paediatric age group. Human recombinant insulins are preferred because of their availability through modern manufacturing techniques using recombinant DNA technology and because of their low immunogenicity. A Cochrane Collaboration systematic review of 45 RCT’s (including 4 paediatric studies) found no significant differences in metabolic control or hypoglycaemic episodes between animal or human insulins.7 Porcine insulins are now only available in Australia under the ‘Special Access Scheme’ (SAS) provisions. Requests for porcine insulin need to be forwarded to the Therapeutic Goods Administration (TGA) before requesting the stock from the company. These insulins are occasionally useful in children with allergic reactions attributable to human recombinant insulin preparations. Beef insulin is still available in Australia (isophane and short-acting). It is occasionally tried in children with type 1 diabetes not able to be satisfactorily stabilised on human insulin. The types of insulin currently available are outlined in the table below: Chapter 4: Insulin Preparations and Storage Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 54 Table 4.1: Insulins Currently in Use in Australia Insulin Preparation Human Bovine Analogue Biphasic Short-acting (neutral) Intermediate-acting (isophane) Intermediate-acting (lente) Long-acting (ultralente) Short-acting (neutral) Intermediate-acting (isophane) Rapid-acting Basal (glargine) Basal (detemir)* Short-acting/intermediate Onset of Action (h) 0.5-1 1-2 1-2.5 4-8 0.5-1 2 0.25-0.5 2-4 1-2 0.5 Peak of Action (h) 2-4 4-12 6-15 12-24 3-6 6-12 1-3 None 6-12 1-12 Duration of Action (h) 5-8 16-24 24 20-30 6-8 18 3-5 24 20-24 16-24 0.5 1-12 16-24 Ratio 20/80 Ratio 30/70 Ratio 50/50 Rapid-acting analogue/intermediate Ratio 25/75 Ratio 30/70 *Anticipated availability in 2004/2005 Rapid-acting insulin Insulin has a tendency to aggregate into dimers and hexamers which retard the absorption and biological availability. Insulin lispro and insulin aspart are now widely used rapid-acting insulin analogues which prevent the insulin molecule from forming dimers or hexamers. These monomeric insulins are clear solutions that have a very rapid onset of action, peak within 1 hour and have duration of action of up to 5 hours. In accordance with the manufacturers’ recommendations rapid-acting insulin should be injected at the time of a meal. Rapid-acting insulins are used in: • Twice daily insulin regimens. • Basal-bolus insulin regimens. These analogues are effective in other specific situations such as: • Rapid-acting insulin given at afternoon tea reduces high blood glucose levels commonly seen before the evening meal in children and adolescents on twice daily injections of rapid-acting or regular insulin in combination with an isophane insulin.8 • Rapid-acting insulin has been shown to be effective when given post-prandially in prepubertal children with type 1 diabetes with unpredictable eating habits (eg infants, toddlers and preschool children).9 However, its effect on post-prandial blood glucose levels has been variable.10 The NICE Guidelines on Diagnosis and Management of Type 1 Diabetes in Children and Young People have indicated that post-prandial rapid–acting insulin is an option in the management of these patient groups.30 • Rapid-acting insulin analogues are used in continuous subcutaneous insulin infusion (CSII) therapy.11;12 • Rapid-acting insulin analogues may also be used for the management of hyperglycaemia and ketosis during sick days. Chapter 4: Insulin Preparations and Storage Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 55 Short-acting insulin Short-acting insulin is also known as ‘soluble’ or ‘regular’ insulin and is a clear solution. It is used in the management of diabetic ketoacidosis and as a component of daily replacement therapy. It can be used by itself as a pre-meal bolus injection in a basal-bolus regimen or in combination with intermediate-acting insulin in a twice-daily injection regimen. Data are inconsistent on the optimal timing of short-acting insulin in relation to meals. However, in accordance with the manufacturers’ recommendations, short-acting insulin should be injected 15-20 minutes before a meal. The American Diabetes Association discourages eating within a few minutes after (or before) injecting short-acting insulin as the likelihood of a rapid rise of blood glucose is increased and it may increase the risk of delayed hypoglycaemia.13 Intermediate-acting insulin These insulins are present in the form of a suspension and are therefore referred to as ‘cloudy’ insulins. Their time-course of action makes them suitable for twice-daily insulin regimens and for pre-bed dosage in basal-bolus regimens. The vials need to be gently but properly mixed prior to each use to ensure a uniform concentration. Pens containing isophane need to be tipped at least 20 times for adequate mixing, however, vigorous mixing may cause protein degradation. The two principal preparations currently used are: • Isophane or NPH (Neutral Protamine Hagedorn) insulins. • Crystalline zinc-acetate insulins (lente insulins). To avoid confusion and prescribing errors, the use of the terms ‘clear’ to describe rapidacting or short-acting insulin and ‘cloudy’ to describe intermediate- or long-acting insulin, should be discouraged as the long-acting insulin analogues, glargine and detemir, are clear solutions. Long-acting insulins These preparations may be used to meet basal insulin requirements, especially in basal bolus injection regimens. Basal insulin analogues Insulin glargine is a new long-acting basal insulin analogue (see Table 4.1 and Figure 4.1). It is a soluble insulin which precipitates in situ after injection. It is important to note that insulin glargine cannot be mixed with any other insulin. This modified insulin molecule has a stable and smooth 24-hour profile.14 In a multicentre randomised study, insulin glargine was compared with NPH insulin in children aged 5 to 16 on a basal-bolus regimen.15 The glargine treated group had a greater reduction in fasting blood glucose levels, although overall HbA1c improvement was similar in both groups. Glargine may decrease the risk of severe nocturnal hypoglycaemia in children and adolescents.15-17 A recent Technology Appraisal Guidance from the UK National Institute of Clinical Excellence concluded that insulin glargine should be considered as a treatment option for people with type 1 diabetes.16 Insulin detemir is another basal insulin (see Table 4.1 and Figure 4.1). It is an acylated insulin which binds to albumin. Preliminary studies in adults suggest that it has advantages over isophane insulins when used in a basal/bolus regimen, with a significant reduction in hypoglycaemia despite comparable HbA1c levels.18 A recent study of the pharmacokinetics of insulin detemir showed no difference in serum concentration of insulin with time when Chapter 4: Insulin Preparations and Storage Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 56 comparing children aged 6 to 12 years with adolescents aged 13-17 years and adults aged over 18 years. There was less variability in response to insulin detemir compared with NPH.19 Premixed insulin preparations Several premixed combinations of rapid-acting, short-acting and isophane insulins are available in Australia with variable ratios available as detailed in Table 4.1. In Australia, premixed insulin preparations are not generally recommended for first line use in childhood and adolescent diabetes because of changing needs in the ratios of the two insulins. Their use generally indicates a compromise; however the premixed combinations may be helpful in some situations: • When there are difficulties in accurately drawing up and mixing insulins. • When ratios remain stable. • When there are severe individual or family psychosocial problems disturbing diabetes management. • When adolescents are experiencing difficulty in complying with insulin regimens. Typical action profiles of the various insulin preparations are illustrated in figure 4.1, although there is much inter- and intra-individual variation. Local Reactions to Insulin Local reactions to insulin injections are uncommon, but when they do occur they are more likely to be due to sensitivity to the added preservatives (metacresol, phenol or methylhydroxybenzoate) than to the insulin itself.20;21 Two types of reaction have been reported, a localised wheal and flare with itching due to histamine reactions, and generalised anaphylaxis, which is extremely rare. A trial of insulin with a different preservative may solve this problem. Formal identification of the preservative is possible using preservativeonly preparations available from the manufacturers. Antihistamine creams can also assist with localised reactions. Cold-sensitivity urticaria should also be considered if the patient develops a local reaction on using a vial directly from the refrigerator. Latex sensitivity (due to transfer of latex particles from the septum of the insulin bottle) should also be considered.22 Mixing Insulins In order to maintain uniformity, short/rapid-acting insulin should be drawn up into the syringe before the intermediate- or long-acting insulin. This strategy prevents contamination of the short/rapid-acting insulin by the longer-acting insulin and eliminates the possibility of converting the short/rapid-acting insulin into a longer-acting form. Isophane insulin can be premixed with rapid-acting or short-acting insulin in the same syringe or vial without altering the absorption profile of the rapid-acting or short-acting insulin.23;24 Lente insulin can be safely given together with rapid-acting or short-acting insulins in the same syringe providing the injection is administered immediately after mixing.25 Lente insulin should never be premixed with rapid-acting or short-acting insulin and stored in the same syringe or in a vial because of conversion of the short-acting insulin into a longer-acting form.23 Isophane and lente insulins should never be mixed in the one syringe or vial. Insulin glargine cannot be mixed with any other insulin. Chapter 4: Insulin Preparations and Storage Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 57 Insulin Concentrations One unit of insulin corresponds to approximately 36 micrograms or 6 nanomoles of insulin. Australia and New Zealand have a single insulin concentration of 100 U/ml (U 100). Insulins must be administered by insulin syringes calibrated to the concentration of the insulin. The availability of insulins of other concentrations (eg U 40) still exists in some countries overseas. This is important information for Australian patients travelling internationally. In very young children with very low insulin requirements, the insulin preparations may need to be diluted in order to deliver doses accurate to 0.1 unit safely. The diluents are obtained from the insulin manufacturers (the physician needs to obtain approval from the Department of Health under the Special Access Scheme). The diluted preparations can be stored for 3 months under refrigeration although the vial that is in use must be discarded after 1 month whether stored under refrigeration or at room temperature. When using diluted insulins, special care must be taken to ensure that the correct dose is administered when using standard insulin syringes. 25-unit syringes are extremely useful when small doses need to be given. Storage Conditions The following storage conditions should be recognised: • Insulin is stable at room temperature for several weeks providing there are no extremes of temperature. • Unused vials should be refrigerated (stored at 4 to 8°C) but never frozen. • Insulin may lose its potency after opening the vial or when exposed to high temperatures (eg in the tropics or if left in the car). • Insulin vials should be discarded after 3 months of opening if kept refrigerated and after 1 month if kept at room temperature. • Penfill cartridges and disposable insulin pens should be discarded after 21-28 days at room temperature as per the manufacturer’s instructions for storage. • The manufacturer’s expiry date should be adhered to. Adjunct Therapy with Oral Antidiabetic Drugs There is only limited experience of using metformin as an adjunct therapy to insulin in children and adolescents with type 1 diabetes exhibiting insulin resistance. One randomised controlled trial involving 27 adolescents with type 1 diabetes resulted in a decrease in HbA1c of 0.6%, a slight decrease in insulin requirements, but also a slight increase in mild hypoglycaemia.26 Another randomised controlled trial reported a decrease in HbA1c of 0.9% over 3 months of metformin treatment however this change was not significant when the changes in the pre- and post-test differences in HbA1c were re-calculated between the trial arms .27 A non-randomised, uncontrolled study involving 10 adolescents and young adults showed a decrease in HbA1c (for 7 of the 10 patients) after 6 months of metformin treatment.28 This decrease did not reach statistical significance. After stopping metformin, those who did respond to metformin showed a return of HbA1c to pre-treatment levels.28 Chapter 4: Insulin Preparations and Storage Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 58 Figure 4.1: Schematic Action Profiles of Insulin Preparations (profiles will vary with dosage, injection site, depth of injection and other factors-see text) Chapter 4: Insulin Preparations and Storage Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 59 Cost Issues A recent Health Technology Appraisal assessed the clinical and cost-effectiveness of the long-acting insulin analogue glargine in the management of diabetes.16 They found no relevant economic evaluations in the medical literature. The manufacturer’s submission included only 2 economic models relevant to type 1 diabetes, which the reviewers felt were significant underestimates of the incremental cost effectiveness ratio (that is, insulin glargine may be significantly less cost effective than is suggested by the manufacturer’s analysis). However, on the balance of effectiveness and cost effectiveness evidence, the reviewers concluded that insulin glargine could be considered as a treatment option in people with type 1 diabetes.16 This appraisal was conducted with the UK health system in mind and was not specific to paediatrics, and, therefore, may not be generalisable to Australia. The Evidence The evidence comparing animal insulin with human insulin use in children and adolescents with type 1 diabetes is listed in Evidence Table 4.1. • A Cochrane Collaboration systematic review of 45 RCT’s (including 4 paediatric studies) found no significant differences in metabolic control or hypoglycaemic episodes between animal or human insulins.7(I) The evidence on insulin glargine use in children and adolescents with type 1 diabetes is listed in Evidence Table 4.2. • A recent Technology Appraisal Guidance from the UK National Institute of Clinical Excellence concluded that insulin glargine should be considered as a treatment option for people with type 1 diabetes.16(I) The evidence on metformin as an adjunct therapy to insulin in children and adolescents with type 1 diabetes is listed in Evidence Table 4.3. • There is only limited experience of metformin as an adjunct therapy to insulin in children and adolescents with type 1 diabetes exhibiting insulin resistance One randomised controlled trial involving 27 adolescents with type 1 diabetes resulted in a decrease in HbA1c of 0.6% compared with placebo, a slight decrease in insulin requirements, but also a slight increase in mild hypoglycaemia.26 Another randomised controlled trial showed a non-significant decrease in HbA1c of 0.9% over 3 months of metformin treatment.27(II) • A non-randomised, uncontrolled study involving 10 adolescents and young adults showed a non statistically significant decrease in HbA1c (for 7 of the 10 patients) after 6 months of metformin treatment.28(IV) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 4.4. Recommendations and Principles • Health care professionals, parents and children and adolescents with type 1 diabetes should be informed that insulin is essential for survival. There is no alternative to treatment with insulin.1(T) • Children and adolescents with type 1 diabetes should be treated with human insulin as animal insulin has no advantage over human insulin in terms of metabolic control or hypoglycaemia.7(I) • A wide variety of human, analogue and bovine insulins are available in Australia for use in children and adolescents with type 1 diabetes.29(C) Chapter 4: Insulin Preparations and Storage Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 60 • • • • • • • • Rapid-acting insulin should be injected at the time of a meal and short-acting insulin should be injected 15-20 minutes before a meal.13;30(C) Rapid-acting insulin can be administered post-prandially in prepubertal children with type 1 diabetes with unpredictable eating habits (eg infants, toddlers and preschool children).30(C) Insulin glargine is a long-acting basal insulin analogue which has recently been introduced as a treatment option.16(I) To avoid confusion and prescribing errors, the use of the terms ‘clear’ to describe rapidacting or short-acting insulin and ‘cloudy’ to describe intermediate- or long-acting insulin, should be discouraged as the long-acting analogues, glargine and detemir, are clear solutions. The action profile of the various insulin preparations is subject to inter- and intraindividual variation. The action profile is also affected by storage conditions and the manufacturer’s storage instruction should be followed.30(C) All children should have rapid/short-acting insulin available for sick-day management.30;31(C) Families need to ensure that a small supply of spare insulin is always available so that supply is uninterrupted.31(C) As there is limited and inconsistent evidence on the use and efficacy of metformin as an adjunct therapy in type 1 diabetes, it should only be considered as an adjunct for difficult to control patients with evidence of insulin resistance. Patients should be warned of and closely monitored for hypoglycaemia during the stabilisation period and the efficacy monitored.26;27;28(II) I = Evidence from a systematic review of all relevant controlled trials II = Evidence from at least one properly-designed RCT C = Consensus statement endorsed by professional organisations T = WHO technical reports produced by expert panels Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Report of a WHO Consultation. Part 1:Diagnosis and Classification. WHO/NCD/NCS/99.2. 1999. Geneva, World Health Organization. Heinemann L: Variability of insulin absorption and insulin action. Diabetes Technology & Therapeutics 4:673-682, 2002 Fernqvist E L: Effects of physical exercise on insulin absorption in insulin-dependent diabetics. A comparison between human and porcine insulin. Clinical Physiology 6:489-497, 1986 Sindelka G, Heinemann L, Berger M, Frenck W, Chantelau E: Effect of insulin concentration, subcutaneous fat thickness and skin temperature on subcutaneous insulin absorption in healthy subjects. Diabetologia 37:377-380, 1994 Bantle JP: Effects of the anatomical region used for insulin injections on glycemia in type I diabetes subjects. Diabetes Care 16:1592-1597, 1993 Frid A, Linde B: Clinically important differences in insulin absorption from abdomen in IDDM. Diabetes Research & Clinical Practice 21:137-141, 1993 Richter B, Neises G: 'Human' insulin versus animal insulin in people with diabetes mellitus (Cochrane Review). The Cochrane Library Issue 4: 2003 Martin D, Licha-Muntz G, Grasset E, Greneche MO, Nouet D, Francois L, Legrand C, Polak M, Augendre-Ferrante B, TubianaRufi N, Robert JJ: Efficacy of Humalog injections before an afternoon meal and their acceptance by children and adolescents with Type 1 diabetes. Diabetic Medicine 19:1026-1031, 2002 Deeb LC, Holcombe JH, Brunelle R, Zalani S, Brink S, Jenner M, Kitson H, Perlman K, Spencer M: Insulin lispro lowers postprandial glucose in prepubertal children with diabetes. Pediatrics 108:1175-1179, 2001 Tupola S, Komulainen J, Jaaskelainen J, Sipila I: Post-prandial insulin lispro vs. human regular insulin in prepubertal children with Type 1 diabetes mellitus. Diabetic Medicine 18:654-658, 2001 Renner R, Pfutzner A, Trautmann M, Harzer O, Sauter K, Landgraf R: Use of insulin lispro in continuous subcutaneous insulin infusion treatment. Results of a multicenter trial. German Humalog-CSII Study Group. Diabetes Care 22:784-788, 1999 Pickup J, Mattock M, Kerry S: Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: Meta-analysis of randomised controlled trials. British Medical Journal 324:705-708, 2002 American Diabetes Association: Insulin Administration. Diabetes Care 26:121S, 2003 Heinemann L, Linkeschova R, Rave K, Hompesch B, Sedlak M, Heise T: Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care 23:644-649, 2000 Schober E S: Comparative trial between insulin glargine and NPH insulin in children and adolescents with type 1 diabetes. Journal of Pediatric Endocrinology & Metabolism 15:369-376, 2002 National Institute for Clinical Excellence. Guidance on the use of long-acting insulin analogues for the treatment of diabetes-insulin glargine. 2002. Chapter 4: Insulin Preparations and Storage Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 61 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. Mohn A, Strang S, Wernicke-Panten K, Lang AM, Edge JA, Dunger DB: Nocturnal glucose control and free insulin levels in children with type 1 diabetes by use of the long-acting insulin HOE 901 as part of a three-injection regimen. Diabetes Care 23:557559, 2000 Vague P, Selam JL, Skeie S, De Leeuw I, Elte JW, Haahr H, Kristensen A, Draeger E: Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal-bolus regimen with premeal insulin aspart. Diabetes Care 26:590-596, 2003 Danne T, Walte K, Von Schuetz W, Gall MA: Insulin detemir is characterized by a consistent pharmacokinetic profile across agegroups in children, adolescents, and adults with type 1 diabetes. Diabetes Care 26:3089-3092, 2003 Dunning T, Rosen S, Alford F: Insulin allergy: a diagnostic dilemma. Journal of Diabetic Nursing 2: 1998 Williams P: Adverse effects of exogenous insulin: clinical features, management and prevention. Drug Safety 8:427-444, 1993 Hoffman RP: Latex hypersensitivity in a child with diabetes. Archives of Pediatrics & Adolescent Medicine 154:281-282, 2000 Heine RJ, Bilo HJ, Fonk T, van der Veen EA, van der MJ: Absorption kinetics and action profiles of mixtures of short- and intermediate-acting insulins. Diabetologia 27:558-562, 1984 Joseph SE KB: The action profile of lispro is not blunted by mixing in the syringe with NPH insulin. Diabetes Care 21:2098-2102, 1998 Bastyr EJ, III, Holcombe JH, Anderson JH, Clore JN: Mixing insulin lispro and ultralente insulin. Diabetes Care 20:1047-1048, 1997 Hamilton J, Cummings E, Zdravkovic V, Finegood D, Daneman D: Metformin as an Adjunct Therapy in Adolescents With Type 1 Diabetes and Insulin Resistance: A randomized controlled trial. Diabetes Care 26:138-143, 2003 Sarnblad S, Kroon M, Aman J: Metformin as additional therapy in adolescents with poorly controlled type 1 diabetes: randomised placebo-controlled trial with aspects on insulin sensitivity. European Journal of Endocrinology. 149:323-329, 2003 Gomez R, Mokhashi MH, Rao J, Vargas A, Compton T, McCarter R, Chalew SA: Metformin adjunctive therapy with insulin improves glycemic control in patients with type 1 diabetes mellitus: a pilot study. Journal of Pediatric Endocrinology & Metabolism 15:1147-1151, 2002 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 National Institute for Clinical Excellence. Type 1 Diabetes (Childhood): Diagnosis and Management of Type 1 Diabetes in Children and Young People (DRAFT). 2004. International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Chapter 4: Insulin Preparations and Storage Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 62 Chapter 5: Insulin Regimens and Delivery The ultimate aim of insulin therapy is to provide physiological insulin replacement. However, commonly used insulins and delivery methods have approximated this very poorly. The availability of new (and future) insulin analogues and alternate delivery methods (eg insulin pumps) offers the potential more closely to approximate normal physiology in suitable subjects. The choice of insulin types and regimen has to be guided by a variety of factors,1 including: • Age of the patient. • Lifestyle factors. • Patient and family preferences and management skills. • Metabolic targets. • Duration of diabetes. • Experience of the health care team. • Affordability and sustainability. • Associated complications, including hypoglycaemia. Any insulin regimen has to be considered in the wider context of a total diabetes management package, which must include dietary management, exercise, blood glucose monitoring, initial and ongoing education, regular medical follow-up and psychological care. The use of terms such as conventional insulin therapy and intensive insulin therapy is becoming blurred and less useful as management options increase. Insulin Regimens The insulin regimen needs to aim to: • Provide appropriate basal insulin requirements to cover the needs across 24 hours. • Provide sufficient insulin levels when needed to cover food intake. • Have adequate provision for adjustment and correction when needed. • Minimise blood glucose fluctuation and risk of hypoglycaemia and hyperglycaemia. • Achieve short-term and long-term metabolic targets. Many regimens are in common use and there are many more that have had limited trials or are in occasional use. The most commonly used regimens are listed and discussed below. Children and adolescents will often evolve from one regimen to another in order to meet the goals of therapy. • One injection daily: Either intermediate-acting insulin or short/rapid-acting plus intermediate-acting insulin. Such a regimen is rarely appropriate for children and adolescents with type 1 diabetes, although is occasionally seen for short periods in those experiencing a profound remission phase. • Two injections daily: A mixture of short/rapid-acting and intermediate-acting insulin given before breakfast and before the main-evening meal. This can be custom mixed or supplied in a variety of premixed insulins. This regimen is commonly used in younger children. Chapter 5: Insulin Regimens and Delivery Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 63 • Three injections per day: A mixture of short/rapid-acting and intermediate-acting insulin given before breakfast, short/rapid-acting insulin before the afternoon snack or main evening meal and intermediate-acting insulin in the evening. This regimen is commonly used in older children and teenagers when a 2 injection per day regimen is inadequate. • Four injections per day (basal-bolus regimen): Short/rapid-acting insulin given before main meals, with intermediate-acting insulin given in the evening or in the morning and evening, or with glargine given once daily (morning or evening). This regimen is used extensively in adolescents and adults with type 1 diabetes. There are many variations of multiple injection regimens that are being tried. • Insulin pump therapy (continuous subcutaneous insulin infusion – CSII) The pump contains a rapid-acting insulin analogue only and is programmed to deliver basal rates to match the individual’s needs. To cover meals and correct hyperglycaemia bolus doses are activated by the patient. It should be noted that short-acting insulins are not suitable for use in this regimen. • Other less common regimens Other insulin regimens may be suitable for some patients based on their individual circumstances (eg 5 injections per day). Some of these are reported in the literature, but will not be further discussed here. In a recent audit in NSW of type 1 diabetes in the 0-15 years age group, 61.3% were treated with 2 injections per day, 23.1% with three injections per day, 12.1% with four or more injections daily, 3.2% with one injection and 0.2% with insulin pumps2 (it should be noted that insulin pump programs have increased since this time). In an international multicentre audit, number of injections per day increased with age and duration of diabetes as expected.3 Use of Short-Acting Insulin In the above regimens, short-acting or rapid-acting insulins may be used. This is selected according to the individual’s needs, especially considering food intake and energy expenditure. The administration of rapid-acting analogues immediately before meals has been considered to be preferable to patients and families and data suggest reductions in postprandial glucose rise.4,5 Insulin regimens using rapid-acting insulin analogues have been shown to be associated with improved metabolic control compared to those using regular insulin, however limited data in children has not confirmed this advantage.6 Patients using rapid-acting analogues in physiological regimens overall have fewer hypoglycaemic episodes than those using traditional insulins,7 however a review of studies in children including physiological and non-physiological regimens did not show an overall difference between rapid-acting analogues and short-acting insulin.62 In considering the timing of insulin injections, data are inconsistent on the optimal timing of short-acting insulin in relation to meals, however pharmacokinetic data suggest that shortacting insulin should be given before meals and preferably up to 30 minutes prior.8;63 It is recommended that rapid-acting insulins be given immediately prior to meals (within 15 minutes) to avoid hypoglycaemia.7 Giving rapid-acting insulin after meals has been shown to be a useful option, particularly in infants and young children with unpredictable eating patterns, allowing the dose to be judged after the amount of food ingested has been observed.5 Chapter 5: Insulin Regimens and Delivery Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 64 Use of Intermediate and Long-Acting Insulins Intermediate-acting insulin is generally isophane insulin, however intermediate-acting lente insulins are preferred by some, and some of the above regimens are also used with longacting insulins. It is likely that new long-acting insulin analogues will find a major role in insulin regimens. One of the major limitations of regimens using conventional intermediateacting or long-acting insulins is the known intra-individual variation in absorption, which is up to 45% in healthy subjects.9 These insulins are also problematical in that their peak of action may not suit the individual and they have dose dependent pharmacokinetics - ie peak effect and duration of effect vary with dose. Insulin glargine is characterised by reproducibly flat basal profiles without significant dose effects on pharmacokinetics and is the first long-acting analogue available in Australia. Adult studies indicate similar HbA1c levels with insulin glargine but reduction in hypoglycaemia.10 There are insufficient data to draw conclusions on the efficacy of insulin glargine in children and adolescents, although data to date suggests similar efficacy but less hypoglycaemia.11 Glargine seems most suited to use in basal-bolus regimens. However, trials are under way to investigate its use as the evening long-acting insulin in twice daily regimens in children.12 Detemir insulin is another basal analogue under clinical trial. It is reported to have a more reproducible profile of action compared to isophane insulins13 and preliminary studies suggest reduction in hypoglycaemia with comparable HbA1c levels.14 Regimens using Pre-mixed Insulins Studies have not demonstrated any difference in glycaemic control between pre-mixed or custom-mixed insulin doses.15,16 Pre-mixed insulins are used in some centres for children on twice-daily injections and also to have a simplified regimen when adherence difficulties are present. They are usually used in pen devices. The potential disadvantage is that independent adjustment of the component insulins is not possible, thereby reducing adjustment flexibility. Number of Injections per Day In adults with type 1 diabetes, it is clearly established that multiple injection regimens (basalbolus regimens) are superior to simpler injection regimens, preferably using rapid-acting analogues as the bolus insulin.7 In adolescents in the DCCT, the intensively treated group also had improved metabolic control and complication reduction, although this was part of a broader intensive management package. Weight gain and hypoglycaemia rates were increased in the intensively treated group. Most adolescents with type 1 diabetes should receive intensive therapy aimed at achieving glycaemic control as close to normal as possible to reduce the risk of microvascular complications.17,18 In the pre-adolescent age group, the superiority of multiple injection regimens has not been clearly established and there continues to be wide differences in practice. It has been common in children to use the simplest insulin regimen that achieves the goals of therapy and thus many children are treated with 2 injections per day regimens. An additional rationale for this approach is that most children enter a partial remission phase making achievement of satisfactory glycaemia relatively easy during this time. However there are some paediatric centres that advocate multiple injection regimens for all children and adolescents from the start of therapy.19 A cross-sectional, multi-centre study of 2873 children and adolescents (age range 1–18 years) from 18 countries demonstrated no effect of the number of insulin injections per day on metabolic control.3 One large RCT (n=186, age 10-18 yrs) reported improved metabolic control with a 3 injections per day regimen compared to 2 injections per Chapter 5: Insulin Regimens and Delivery Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 65 day.20 In a recent NSW audit including 1190 subjects, number of injections was not a predictor of HbA1c, however multiple injections (more than 3 injections per day) was a predictor of hypoglycaemia.2 Total Daily Insulin Dosage and Distribution Insulin doses are tailored for each patient’s individual circumstances and requirements and change often in children and adolescents. Factors affecting insulin doses are age, weight, stage of puberty, duration of diabetes, food intake and distribution, exercise patterns, daily routines, results of monitoring and intercurrent illness. As a general guide, total daily insulin doses21 are as follows: • Partial remission phase (any age): <0.5 unit/kg/day. • Pre-adolescent children (beyond remission phase): 0.7 to 1 unit/kg/day. • During puberty (beyond remission phase): 1.2-1.5 units/kg/day or higher. The distribution of the total daily insulin dose varies greatly between individuals and requires individual titration. Typical distributions are discussed.21 Twice daily insulin injection regimens: typically approximately 60-75% of the total daily insulin dose is given in the morning and 25-40% at night with approximately 30% of each dose being short-acting insulin. Basal-bolus regimens: typically 40-60% of the total daily insulin dose is given as intermediate acting or long-acting insulin before bed, with the remainder divided up into premeal boluses. Insulin pump therapy: typically 45-60% (lower end of this range in young children and higher end of this range often in adolescents) of the total daily insulin is given as basal insulin and the remainder is provided by pre-meal boluses.22 Basal insulin requirements are usually considerably reduced (about 20%) when using physiological regimens involving glargine or insulin pumps.7 Insulin Administration Insulin absorption The rate of absorption of insulin is affected by many factors as follows: • Insulin type • Injection site Soluble insulin is absorbed more slowly and consistently from the subcutaneous site compared to intramuscular injections.23 There is less difference with rapid-acting analogues64. Thus subcutaneous injections are preferred. Insulin is also absorbed at different rates from different anatomical locations.24 Absorption is quickest from the abdomen, followed by the buttock and slowest from the thigh (non-exercising). However, these differences are less pronounced with both rapid-acting and long-acting analogues.65;66;67 Thus it is recommended that short/rapid-acting insulin or mixed doses of insulin be injected in the abdomen. It is recommended that evening doses of intermediate-acting insulin be given in the (non-exercising) thigh to optimise the overnight profile of action.25 The upper arm is used by some for injections, however this is not generally recommended in younger children because of the thin layer of subcutaneous tissue at this site and the increased risk of intramuscular injection. Rotation between different anatomical sites from day to day is not recommended since this has been shown to be associated with higher and more variable blood glucose levels.26 Chapter 5: Insulin Regimens and Delivery Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 66 Figure 5.1: Recommended Injection Sites • Injection depth Table 5.1: Mean Cutis/Subcutis Thickness Mean cutis/subcutis thickness (mm) [measured by ultrasound without compression] Site Male Child Female Child Abdomen 9 15 - thigh anterolateral 10 14 - thigh anterior 10 13 Buttock 19 26 Adapted from Birkebaek NH, Johansen A, Solvig J. Diabetic Medicine 1998; 15(11):965-971.27 In assessing the suitability of different injection sites, studies have examined subcutaneous tissue thickness and site of deposition of injections.27-29 There is a significant risk of intramuscular injections (and hence more rapid absorption) which is increased in lean individuals, especially boys. This can be minimised by using a two finger pinch technique and an injection angle of 45 degrees. Shorter needles reduce the risk of intramuscular injections.30 In general most children and adolescents should use 8 mm needles with a pinch-technique and 45 degree angle, and if lean and using pens, 5 or 6 mm needles may be appropriate. Intramuscular injection of insulin can increase absorption from the thigh by up to 50%, but it has been reported that there is no difference between subcutaneous and intramuscular absorption from the abdomen.31 • Insulin dose Insulin has dose-dependent absorption kinetics. Small doses are absorbed more quickly than large doses.32 • Temperature Chapter 5: Insulin Regimens and Delivery Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 67 Insulin absorption is increased with increased ambient and body temperature, related to increased subcutaneous blood flow.32 Therefore care should be taken in hot weather and warm baths/saunas after insulin injections. • Exercise Exercise increases insulin absorption, again predominantly related to increased subcutaneous blood flow. For this reason the thigh is not recommended prior to exercise.32 • Age of child and fat mass Large fat mass is associated with increased subcutaneous tissue thickness and therefore slower absorption. Since younger children are often leaner, insulin absorption is often faster. • Presence of lipohypertrophy or lipoatrophy Adverse changes at the injection site can considerably affect absorption. Lipohypertrophy is a common problem in diabetes management and absorption of insulin from these sites is delayed and erratic.33 This can be avoided by moving the injection site from day to day within the same anatomical area of the body, or periodically moving to another anatomical site. Prevalence of lipohypertrophy has been estimated at 20-30% in patients with type 1 diabetes.34 Other factors associated with risk of lipohypertrophy are presence of insulin antibodies. Lipoatrophy is now much less common with modern pure insulins. However, it still occurs in a small number of subjects and also leads to erratic insulin absorption.35 An immunological basis has been suggested, including sensitivity to components of the insulin preparation or latex. Insulin Delivery Devices Insulin syringes and pens Insulin syringes are disposable plastic syringes, designed for single use only and are available in a range of sizes (25, 50 and 100 units) and needles lengths (8 mm, 12 mm and 12.7 mm). The lowest volume syringe that will hold the required dose should be used to increase accuracy of dose. It is common for children receiving mixed injections of insulin to have these drawn up into the same syringe to reduce the number of injections. Not all insulin types are compatible for mixing - (see chapter 4). U100 insulin is exclusively used in Australia, although occasionally dilution is performed for babies or infants requiring very small doses. Insulin pens are also available which contain pre-filled cartridges of insulin. Cartridges are available for the rapid-acting analogues, short-acting and isophane insulins but not for lente and ultralente insulins which are not stable in pen systems. Needle lengths available are 5, 6, 8, 12 and 12.7 mm. Families should know how to use an insulin syringe even if the delivery device is primarily a pen in case of unexpected failure of the pen. Disposable pens are also available for some insulin types which gives added convenience of being able to have pens stored in various locations. Increased satisfaction with pens has been shown in some studies.36 Side-effects are not different between syringe or pen delivery. The accuracy of pen versus syringe delivery has been studied. In one study,37 attempting a dose of 1 unit of insulin was found on average to deliver a mean of 0.89 units with a pen and 1.23 units with an insulin syringe (small but significant differences). Another study found pens more accurate than syringes for doses less than 5 units,38 but no differences for larger doses. Available pens generally are adjustable in 1 unit increments, although one pen is available that can be adjusted in 0.5 unit dose increments. Chapter 5: Insulin Regimens and Delivery Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 68 Automatic injection devices Devices that automatically insert the needle into the skin are available for attachment to some pens or for syringes. These may be preferred by some patients who find it difficult to insert the needle through the skin and also because the needle is hidden until the device is activated. Reduced pain perception has been reported with the use of an automatic injection device.68 Jet injection devices A jet injector uses high pressure to form a thin stream of insulin that penetrates the skin. Metabolic control has been reported to be similar in the short-term but patient acceptance is less than for needle injections39 and higher adverse event rates are reported.40 Jet injectors may have an occasional role for extreme needle phobia. Indwelling cannulas Indwelling subcutaneous cannulas are in use in some centres as an alternative to repeated needle injections to reduce injection pain, especially at the onset of diabetes.69 Cannulas are usually replaced very 4 to 5 days. Insulin absorption and metabolic control has been reported to be unchanged,41,42 making this a possible option if preferred by the patient. Insulin pumps (CSII) Insulin pumps have been proposed as offering more physiological insulin delivery and therefore advantages in metabolic control, reduction in hypoglycaemia and improvement in lifestyle flexibility and patient acceptability (see also insulin pump adjustments). A meta-analysis of 12 RCT’s, mainly in adults but with some adolescents, reported that pump patients had lower mean BG level by 1.0mmo/L, lower HbA1c by 0.51% and lower insulin requirements by 14% compared to patients on optimised insulin injections.43 In another meta-analysis including 52 studies with 1547 adult, adolescent and paediatric subjects, improvement in glycaemic control was also reported.44 Overall, hypoglycaemia is markedly less frequent with pumps than in intensive injection regimens.45 It has been suggested that pump therapy increases the risk of diabetic ketoacidosis, but this may only be with pumps used prior to 1993. There are limited RCT’s in adolescents and none exist for children. Observational studies have reported significant improvements in HbA1c, reduction in hypoglycaemia and higher satisfaction,46-48 but not in all studies. A NICE technical appraisal recommended that insulin pump therapy should be available as an option for people with type 1 diabetes who have failed multiple-dose insulin therapy (HbA1c >7.5% or >6.5% in the presence of complications, or disabling hypoglycaemia).49 Full economic analysis that takes into account possible long-term reduction in morbidity and mortality has not been possible. However, insulin pump therapy costs more than injection therapy in the short-term. Management with insulin pump therapy is increasing in Australia, however not all patients are suitable and individual units should have suitability assessment criteria. Accessibility to this therapy is also currently significantly limited by financial costs. Additional training and expertise for health care professionals is required for units initiating and maintaining insulin pump therapy. Practical Aspects of Insulin Administration Disinfection of the skin is not necessary prior to insulin injections. However, injections should be given through clean, healthy skin.7 Some patients inject through clothing at times for reasons of convenience and no significant problems have been reported with this practice.50 Chapter 5: Insulin Regimens and Delivery Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 69 The age at which children can reliably draw up and administer an insulin injection or use an insulin pen varies markedly between children.70 Many children assist in the insulin injection routine from 9-10 years of age and many can easily use an insulin pen from that age. Drawing up of two different insulin types into a syringe requires more concentration and dexterity and is often not appropriately mastered until sometime after 10 years of age. Appropriate supervision by carers is recommended to avoid insulin dose errors or omissions which have not been quantified, but practical experience suggests that these are common. While insulin syringes and needles are recommended for single use only, surveys indicate that some patients re-use syringes and needles and that this is not associated with increased infections or other adverse events. Insulin syringes and pen needles need to be disposed of in a safe and hygienic way. Needles should not be recapped to avoid the risk of needle-stick injury. Approved sharps containers should be provided and disposed of according to local authority regulations. Unfortunately there are not yet uniform or appropriate arrangements for sharps disposal in all areas of Australia. Thorough re-suspension of intermediate-acting and long acting insulins that are in suspension (all currently available types, except glargine) is critical to avoid dosage error and variation and many patients re-suspend inadequately.51 Pens containing isophane need to be tipped at least 20 times for adequate mixing. Insulin Adjustment Appropriate adjustment of insulin doses is critical if goals of diabetes therapy are to be achieved. This is particularly important in children and adolescents in whom insulin requirements can change rapidly with growth and puberty and changes are also needed to cope with variations in activity and food intake and intercurrent illness. However insulin adjustment is a skill that is often not well mastered by patients and families with diabetes.52 Insulin adjustment by a diabetes nurse educator has been shown to improve glucose control53 and strategies employing electronic transmission of glucose monitoring to a diabetes centre for advice have been reported to be successful.54 Children and their families need to acquire skills in the following areas of insulin adjustment:55 Adjusting usual doses of insulin based on blood glucose patterns over several days or longer Patients on insulin injection therapy are advised to make adjustments to the appropriate dose in approximately 10% increments and observe the effects of this over several days before making further changes. Half unit increments can be made in patients on small doses (<5 units). Patients on insulin pump therapy need to evaluate whether changes need to be made in basal or bolus doses from their monitoring and basal rate tests; incremental changes of 5-10% are also appropriate. More rapid changes may be appropriate in some circumstances eg severe hypoglycaemia. The routine use of sliding scales for daily insulin adjustment has not been systematically studied. However, it is generally not recommended as a primary tool for insulin adjustment because of its retrospective nature. Used in in-patients, sliding scales have been shown to be inferior to alternative management strategies.56;57 Chapter 5: Insulin Regimens and Delivery Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 70 Pro-active day to day adjustments to insulin based on activity and food intake These adjustments should be pro-active and, as far as possible, take into account activity levels and meals during the period of action of the dose. Larger short-term adjustments can sometimes be needed eg up to 50% reductions for vigorous or prolonged exercise. Adjustments to correct the current BG level when it is outside the desired range Patients and families should have skills to correct high BG levels when these are not transient. Recommendations are usually to give an additional short/rapid-acting insulin dose of between 5% and 10% of the total daily insulin dose to correct high BG levels without significant ketones. However, higher doses may be required for ketosis and sick days (see chapter 11). Formulas are also available to guide correction doses and these are often used by patients on insulin pumps.22 Patients who give additional corrective doses when needed between usual doses have been shown to have improved metabolic control.58 Insulin pump adjustments Insulin pump therapy should be initiated and supervised by a specialised multi-disciplinary team trained in pump therapy in children and adolescents with diabetes. Rapid-acting insulin analogues are recommended for pump use. As a guide, patients starting on insulin pump therapy have the previous total daily dose on injections reduced by approximately 25%. The pump is initially programmed to deliver 45-60% of the new total daily dose as the basal insulin. Often, a single hourly basal rate is used over the 24 hours and this is subsequently modified on the basis of blood glucose monitoring. Adjustments to hourly rates are usually no more than 10% at a time. Most pump users have 2-5 different basal rates for different periods of the day. For example, it is common for people to need a little less basal insulin in the late evening (between 8pm and 2 am) and during the day when more active (between 10 am and 4 pm). Slightly higher basal rates are often needed in the early evening (from 4 pm to 8 pm) and morning hours (from 2 am to 10 am) because of the tendency of the blood glucose to rise toward morning (the dawn phenomenon). Many prepubertal children need a higher basal rate late in the evening (9 pm to 12 midnight).71 Bolus doses are needed for meals and for correction of hyperglycaemia. A useful guide to estimate bolus doses for meals is to employ the ‘500’ rule (the total daily dose is divided into 500 to estimate the number of gm of carbohydrate that 1 unit of insulin will cover).72 This is then used to derive a more practical figure of how many units of insulin are needed to cover each 15 gm exchange of carbohydrate in each meal or snack (for a patient on 50 units of insulin per day, a 1.5 unit bolus would be needed for each 15 gm exchange of carbohydrate). It is recommended that calculations be made at least to the half exchange, and some advocate calculations to the gram if practical. Correction boluses to correct hyperglycaemia can be given at any time or added to meal boluses. A useful guide to estimate correction doses is to employ the ‘100’ rule (the total daily dose is divided into 100 to estimate the number of mmol/L that the blood glucose will fall by giving 1 unit of insulin).72 For example, for a patient on 50 units of insulin per day, the blood glucose should fall by approximately 2 mmol/L for each additional 1 unit of insulin. This calculation can also be used to estimate a negative correction to correct for hypoglycaemia (in a patient on 50 units of insulin a day, giving 1 unit less at meal times should allow the blood glucose to rise by 2 mmol/L). Correction doses given for hyperglycaemia should take into consideration the residual effect of any previous meal or correction bolus dose. A useful guide is to use the ‘unused bolus rule’ (approximately 30% of a rapid-acting insulin bolus is absorbed each hour). The correction dose should be reduced accordingly. For example, if 5 units had been given as a meal bolus 2 hours previously, 60% would have been absorbed and the remaining 40% or 2 Chapter 5: Insulin Regimens and Delivery Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 71 units would still be exerting an effect. This should be subtracted from any correction dose. The pump should not be used to correct hyperglycaemia when ketones are present - control should be regained with an insulin injection via pen or syringe (see chapter 11). Basal rates, meal bolus doses and correction bolus doses calculated by the above methods are a starting point. Fine-tuning adjustments are then made on the basis of blood glucose response and patterns. Adjustment of basal rates is assisted by doing basal rate tests, which involve testing different periods of the day by omitting or having a carbohydrate-free main meal and snack and monitoring blood glucose frequently during that period - if the basal rate is appropriate, the blood glucose should remain steady or rise or fall only minimally during that time. Pumps are becoming available that assist the user in making many of the adjustment calculations. Cost Issues A recent Health Technology Assessment attempted to establish the cost effectiveness of Continuous Subcutaneous Insulin Infusion versus Multiple Daily Injections.59 The results were inconclusive due to the paucity of reliable information about cost effectiveness derived from the formal clinical evidence.59 Another cost effectiveness analysis using a Markov model concluded that Continuous Subcutaneous Insulin Infusion was most cost effective in patients who required more frequent admission to hospital and had more frequent severe hypoglycaemic events.60 Both studies were based on the UK health system and may not be generalisable to the Australian health care system. The Evidence The evidence relating to the number of daily injections to diabetes control is listed in Evidence Table 5.1. • In adolescents in the DCCT, the intensively treated group had improved metabolic control and complication reduction, although this was part of a broader intensive management package.17;18(II) • A cross-sectional, multi-centre study of 2873 children and adolescents (age range 1-18 years) from 18 countries demonstrated no effect of the number of insulin injections per day on metabolic control.3(IV) • One large RCT (n=186, age 10-18 yrs) reported improved metabolic control with a 3 injections per day regimen compared to 2 injections per day.20(II) • A NSW audit including 1190 subjects, number of injections was not a predictor of HbA1c, however multiple injections (more than 3 injections per day) was a predictor of hypoglycaemia.2(IV) The evidence on the length of needle for the injection for insulin therapy in the treatment of children with type 1 diabetes is contained in Evidence Table 5.2. • A randomised controlled trial in 50 children with type 1 diabetes demonstrated that using shorter needles (8 mm compared to 12.7 mm) resulted in significantly fewer accidental intramuscular injections of insulin.30(II) The evidence on whether children and adolescents with type 1 diabetes should be treated with insulin pump therapy is contained in Evidence Table 5.3. • A meta-analysis of 12 RCT’s mainly in adults but with some adolescents reported that pump patients had lower mean BG level by 1.0 mmol/L, lower HbA1c by 0.51% and lower insulin requirements by 14% compared to patients on optimised insulin injection.43(I) Chapter 5: Insulin Regimens and Delivery Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 72 • In another meta-analysis including 52 studies with 1547 adult, adolescent and paediatric subjects on insulin pumps, improvement in glycaemic control was also reported.44(I) • This meta-analysis found that hypoglycaemic episodes are less frequent with pumps than in intensive injection regimens.44(I) • A National Institute of Clinical Excellence (NICE) Technology Appraisal Report from the UK referred to in Evidence Table 5.3 recommended that insulin pump therapy should be available as an option for people with type 1 diabetes who have failed multiple-dose insulin therapy (HbA1c >7.5% or >6.5% in the presence of complications, or disabling hypoglycaemia).49(T) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence table 5.4. Recommendations and Principles 2;3;20 • There is a variable effect of the number of daily injections on metabolic control. (II, IV) • Intensive management (including multiple daily injections or pump therapy, education, intensive monitoring and psychosocial support) of type 1 diabetes in adolescents improves metabolic control and reduces the risk of microvascular complications.17;18(II) • Many insulin regimens are used in the treatment of type 1 diabetes in children and adolescents. Any insulin regimen has to be considered in the wider context of a total diabetes management package, which must include dietary management, exercise and physical activity, blood glucose monitoring, initial and ongoing education, regular medical follow-up and psychological care.1;61(C) • Insulin doses should be tailored for each patient’s individual circumstances and requirements, taking into account age, weight, stage of puberty, duration of diabetes, food intake and distribution, exercise patterns, daily routines, results of monitoring and intercurrent illness.1;61(C) • It is recommended that insulin be injected in the abdomen, buttock or non-exercising thighs. The upper arm is generally not recommended because of the thin layer of subcutaneous tissue at this site and the increased risk of intramuscular injection.1;61(C) • There is a significant risk of accidental intramuscular injections (and hence more rapid absorption) especially in lean individuals. This can be minimised by using a two finger pinch technique, an injection angle of 45 degrees and 8 mm needles.30(II) 55;62 • 5 or 6 mm needles may be appropriate in lean children or those using pens. (C) 43;44;49 • Insulin pumps should be considered as a treatment option. (I) • Insulin pump therapy should be initiated and supervised by a specialised multi-disciplinary team trained in pump therapy in children and adolescents with diabetes.49(C) • Insulin syringes and pen needles need to be disposed of in a safe and hygienic way. Needles should not be recapped to avoid the risk of needle-stick injury. Approved sharps containers should be provided and disposed of according to local authority regulations.55(C) • Health care professionals should educate and encourage children and their families to acquire skills in insulin adjustment.55(C) I = Evidence from a systematic review of all relevant controlled trials II = Evidence from at least one properly-designed RCT C = Consensus statement endorsed by professional organisations Reference List 1. Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Chapter 5: Insulin Regimens and Delivery Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 73 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. Craig ME, Handelsman P, Donaghue KC, Chan A, Blades B, Laina R et al. 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The addition of insulin glargine to lower hypoglycemic events and A1c levels in children and adolescents with type 1 diabetes. American Diabetes Association 63rd Scientific Sessions 2003. Danne T, Lupke K, Walte K, Von Schuetz W, Gall MA. Insulin detemir is characterized by a consistent pharmacokinetic profile across age-groups in children, adolescents, and adults with type 1 diabetes. Diabetes Care 26(11):3087-3092, 2003 Vague P, Selam JL, Skeie S, De L, I, Elte JW, Haahr H et al. Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal-bolus regimen with premeal insulin aspart. Diabetes Care 26(3):590-596, 2003 Arslanoglu I, Saka N, Bundak R, Gunoz H, Darendeliler F. A comparison of the use of premixed insulins in pen-injectors with conventional patient-mixed insulin treatment in children and adolescents with IDDM. Is there a decreased risk of night hypoglycemia? 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Absorption of NPH (isophane) insulin in resting diabetic patients: evidence for subcutaneous injection in the thigh as the preferred site. Diabetic Medicine 8(5):453-457, 1991 Bantle JP, Weber MS, Rao SM, Chattopadhyay MK, Robertson RP. Rotation of the anatomic regions used for insulin injections and day-to-day variability of plasma glucose in type I diabetic subjects. Journal of American Medical Association 263(13):18021806, 1990 Birkebaek NH, Johansen A, Solvig J. Cutis/subcutis thickness at insulin injection sites and localization of simulated insulin boluses in children with type 1 diabetes mellitus: need for individualization of injection technique? Diabetic Medicine 15(11):965-971, 1998 Frid A, Linden B. Where do lean diabetics inject their insulin? A study using computed tomography. British Medical Journal (Clinical Research Edition) 292(6536):1638, 1986 Smith CP, Sargent MA, Wilson BP, Price DA. Subcutaneous or intramuscular insulin injections. Archives of Disease in Childhood 66(7):879-882, 1991 Tubiana-Rufi N, Belarbi N, Du Pasquier-Fediaevsky L, Polak M, Kakou B, Leridon L et al. Short needles (8 mm) reduce the risk of intramuscular injections in children with type 1 diabetes. Diabetes Care 22(10):1621-1625, 1999 Frid A, Gunnarsson R, Guntner P, Linde B. Effects of accidental intramuscular injection on insulin absorption in IDDM. Diabetes Care 11(1):41-45, 1988 Binder C, Lauritzen T, Faber O, Pramming S. Insulin pharmacokinetics. Diabetes Care 7(2):188-199, 1984 Young RJ, Hannan WJ, Frier BM, Steel JM, Duncan LJ. Diabetic lipohypertrophy delays insulin absorption. Diabetes Care 7(5):479-480, 1984 Hauner H, Stockamp B, Haastert B. Prevalence of lipohypertrophy in insulin-treated diabetic patients and predisposing factors. Experimental Clinical Endocrinology & Diabetes 104(2):106-110, 1996 Richardson T, Kerr D. Skin-related complications of insulin therapy: epidemiology and emerging management strategies. American Journal of Clinical Dermatology 4(10):661-667, 2003 Cefalu WT. Evaluation of alternative strategies for optimizing glycemia: progress to date. American Journal of Medicine 113 Suppl 6A:23S-35S, 2002 Gnanalingham MG, Newland P, Smith CP. Accuracy and reproducibility of low dose insulin administration using pen-injectors and syringes. Archives of Disease in Childhood 79(1):59-62, 1998 Chapter 5: Insulin Regimens and Delivery Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 74 38. Lteif AN, Schwenk WF. Accuracy of pen injectors versus insulin syringes in children with type 1 diabetes. Diabetes Care 22(1):137-140, 1999 39. Houtzagers CM, Visser AP, Berntzen PA, Heine RJ, van der Veen EA. The Medi-Jector II: efficacy and acceptability in insulindependent diabetic patients with and without needle phobia. Diabetic Medicine 5(2):135-138, 1988 40. Theintz GE, Sizonenko PC. Risks of jet injection of insulin in children. European Journal of Pediatrics 150(8):554-556, 1991 41. Hanas SR, Carlsson S, Frid A, Ludvigsson J. Unchanged insulin absorption after 4 days' use of subcutaneous indwelling catheters for insulin injections. Diabetes Care 20(4):487-490.,1997 42. Hanas SR, Ludvigsson J. Metabolic control is not altered when using indwelling catheters for insulin injections. Diabetes Care 17(7):716-718, 1994 43. Pickup J, Mattock M, Kerry S. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials. British Medical Journal 324(7339):705, 2002 44. Weissberg-Benchell J, Antisdel-Lomaglio J, Seshadri R. Insulin pump therapy: a meta-analysis. Diabetes Care 26(4):1079-1087, 2003 45. Pickup J, Keen H. Continuous subcutaneous insulin infusion at 25 years: evidence base for the expanding use of insulin pump therapy in type 1 diabetes. Diabetes Care 25(3):593-598, 2002 46. Boland EA, Grey M, Oesterle A, Fredrickson L, Tamborlane WV. Continuous subcutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescents with type 1 diabetes. Diabetes Care 22(11):1779-1784, 1999 47. Litton J, Rice A, Friedman N, Oden J, Lee MM, Freemark M. Insulin pump therapy in toddlers and preschool children with type 1 diabetes mellitus. Journal of Pediatrics 141(4):490-495, 2002 48. Plotnick LP, Clark LM, Brancati FL, Erlinger T. Safety and effectiveness of insulin pump therapy in children and adolescents with type 1 diabetes. Diabetes Care 26(4):1142-1146, 2003 49. National Institute for Clinical Excellence (NICE). Guidance on the use of subcutaneous insulin infusion for diabetes. 1-23. 2003. London. Technology Appraisal Guidance (57). 50. Fleming DR, Jacober SJ, Vandenberg MA, Fitzgerald JT, Grunberger G. The safety of injecting insulin through clothing. Diabetes Care 20(3):244-247, 1997 51. Jehle PM, Micheler C, Jehle DR, Breitig D, Boehm BO. Inadequate suspension of neutral protamine Hagendorn (NPH) insulin in pens. Lancet 354(9190):1604-1607, 1999 52. Bonnet C, Gagnayre R, d'Ivernois JF. Learning difficulties of diabetic patients: a survey of educators. Patient Education and Counseling 35(2):139-147, 1998 53. Thompson DM, Kozak SE, Sheps S. Insulin adjustment by a diabetes nurse educator improves glucose control in insulin-requiring diabetic patients: a randomized trial. Canadian Medical Association Journal 161(8):959-962, 1999 54. Biermann E, Dietrich W, Standl E. Telecare of diabetic patients with intensified insulin therapy. A randomized clinical trial. Study of Health Technology Information 77:327-332, 2000 55. Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 56. Queale WS, Seidler AJ, Brancati FL. Glycemic control and sliding scale insulin use in medical inpatients with diabetes mellitus. Annuls of Internal Medicine 157(5):545-552, 1997 57. Gearhart JG, Duncan JL, III, Replogle WH, Forbes RC, Walley EJ. Efficacy of sliding-scale insulin therapy: a comparison with prospective regimens. Family Practice Research Journal 14(4):313-322, 1994 58. Denker PS, Leonard DR, DiMarco PE, Maleski PA. An easy sliding scale formula. Diabetes Care 18(2):278, 1995 59. UK NHS National Coordinating Centre for Health Technology Assessment (NCCHTA). The clinical effectiveness and cost effectiveness of insulin pump therapy. Technology Assessment Report (project). 2003. 60. Scuffham P, Carr L: The cost-effectiveness of continuous subcutaneous insulin infusion compared with multiple daily injections for the management of diabetes. Diabetic Medicine 20:586-593, 2003. 61. International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 62. National Institute for Clinical Excellence. Type 1 Diabetes (Childhood): Diagnosis and Management of Type 1 Diabetes in Children and Young People. 2004 63. Sackey AH, Jefferson IG: Interval between insulin injection and breakfast in diabetes. Archives of Disease in Childhood. 71:248250, 1994 64. Rave K, Heise T, Weyer C, Herrnberger J, Bender R, Hirschberger S, Heinemann L: Intramuscular versus subcutaneous injection of soluble and lispro insulin: comparison of metabolic effects in healthy subjects. Diabetic Medicine. 15:747-751, 1998 65. ter Braak EW, Woodworth JR, Bianchi R, Cerimele B, Erkelens DW, Thijssen JH, Kurtz D: Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin. Diabetes Care. 19:1437-1440, 1996 66. Mudaliar SR, Lindberg FA, Joyce M, Beerdsen P, Strange P, Lin A, Henry RR: Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin: absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects. Diabetes Care. 22:1501-1506, 1999 67. Owens DR, Coates PA, Luzio SD, Tinbergen JP, Kurzhals R: Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites. Diabetes Care. 23:813-819, 2000 68. Diglas J, Feinbock C, Winkler F, Egger T, Weitgasser R, Pieber T, Lytzen L, Irsigler K: Reduced pain perception with Pen Mate(TM), an automatic needle insertion device for use with an insulin pen. Practical Diabetes International 16:39-41, 1999 69. Hanas R: Indwelling catheters used from the onset of diabetes decrease injection pain and pre-injection anxiety. Journal of Pediatrics 140:315-320, 2002 70. Wysocki T, Meinhold PM, Taylor A, Hough BS, Barnard MU, Clarke WL, Bellando BJ, Bourgeois MJ: Psychometric properties and normative data for the parent version of the diabetes independence survey. Diabetes Educator 22:587-591, 1996 71. Conrad SC, McGrath MT, Gitelman SE: Transition from multiple daily injections to continuous subcutaneous insulin infusion in type 1 diabetes mellitus. Journal of Pediatrics. 140:235-240, 2002 72. Walsh J and Roberts R: Pumping insulin. Everything you need for success with an insulin pump. Torrey Pines, 2000 Chapter 5: Insulin Regimens and Delivery Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 75 Chapter 6: Glycaemic Control Intensive Diabetes Management The Diabetes Control and Complications Trial (DCCT) confirmed the benefit of maintaining near normoglycaemia in reducing the development and progression of diabetic microvascular complications in adolescents and adults.1;2 Even in patients with the same HbA1c intensive therapy was superior to conventional.3 In the DCCT there was no lower threshold of HbA1c below which the risk of complications was eliminated, and any improvement in HbA1c conferred a reduction in risk.3;4 Longer follow up of patients after the completion of the DCCT, in the EDIC (Epidemiology of Diabetes Interventions and Complications) study showed increasing reduction of microvascular and macrovascular complications with optimal early metabolic control.5;6 Achieving excellent glycaemic control is more difficult in children and adolescents than in many adults because of the following factors: • Insulin deficiency is often more complete. • Variable food intake. • Recurrent infections during childhood. • Variable exercise patterns. • Varying rates of growth and development. • Hormonal changes, including insulin resistance during puberty, necessitating high and changing insulin requirements. • Behavioural problems associated with psychosocial difficulties. • Conflict between being dependent upon parental involvement and wish for increased independence during adolescence. • Difficulty with adherence to diabetes regimens, particularly during adolescence when insulin omission and infrequent blood glucose monitoring is common (thereby preventing the benefits of more intensive insulin regimens). Risks and Side Effects of Intensive Diabetes Management Long-term benefits of intensifying management need to be weighed against the risks of: 2 • Increased frequency and severity of hypoglycaemia. In a longitudinal Australian study, severe hypoglycaemia was associated with lower verbal and full-scale intelligence quotient scores. Attention, processing speed, and executive skills were particularly affected in children with younger onset of diabetes.7 2 • Weight gain. • Increased risk of precipitating rebellion and rejection of diabetes routines altogether. Indicators of Poor Glycaemic Control The indicators of poor glycaemic control may include the following clinical and biochemical features: • Polyuria and polydipsia. • Enuresis and nocturia. • Blurred vision. • Weight loss or failure to gain weight with growth. • Poor growth. Chapter 6: Glycaemic Control Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 76 • • • • • • Pubertal delay. Skin infections (staphylococcal and candidal). Deteriorating school performance and absenteeism. Signs of diabetes complications. Elevated HbA1c and fructosamine. Elevated blood lipids. Glycaemic Goals The National Institute of Clinical Excellence Guideline ‘Type 1 Diabetes (Childhood): Diagnosis and Management of Type 1 Diabetes in Primary and Secondary Care’ makes the following recommendation: Children with type 1 diabetes and their parents should be informed that the optimal target for long-term glycaemic control is an HbA1c level of less than 7.5% without an increase in hypoglycaemia. In England an audit of children (0-16years) with type 1 diabetes found that in all age groups fewer than 20% of children managed to achieve a HbA1c level of 7.5% or below.8 In 1999 in NSW, fewer than 25% of children and adolescents had a HbA1c levels <7.5%, with the median HbA1c being 8.2% [interquartile range 7.6-9.1%].9;10 In order to achieve an HbA1c <7.5%, everyday blood glucose targets (ie. glycaemic goals) need to be defined and while they still need to be individualised reasonable values to aim for are: 11 • A pre-prandial blood glucose level of 4-8 mmol/L. 11 • A post-prandial blood glucose level of less than 10 mmol/L. In very young children, in whom there is the greatest concern about the effects of hypoglycaemia on the developing brain, glycaemic targets need to be at the upper part of these ranges or a little higher. Glycaemic targets need to take into account such additional factors as: • Hypoglycaemia unawareness. • Unpredictability of hypoglycaemia in some children. • Past history of recurrent severe hypoglycaemia. • Ability to comply with blood glucose monitoring. • Presence of psychological or psychiatric disturbances. • Presence of any coexisting disease which may affect the diabetes (eg infections). • Presence of any coexisting disease (eg epilepsy). Realistic goals for individual patients have to be reassessed at each visit. Appropriate therapeutic strategies to reach the goals have to be clearly formulated, taking into consideration the psychosocial and developmental aspects of the child and family. Patients during the pubertal phase may have particular difficulties in maintaining good control due to physiological and psychological changes, and therefore frequently require special counselling services and support. While blood glucose testing provides much data on glycaemic control, it also has placed a very great burden on the child, adolescent and family in the quest for achieving optimal blood glucose levels. Health care professionals must avoid using judgemental terms such as good or bad control and aim to achieve good communication, understanding and cooperation. Chapter 6: Glycaemic Control Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 77 Parameters of Glycaemic Control Prior to 1978 urine testing was the only means of monitoring glycaemic control. Unfortunately urine tests do not reliably reflect blood glucose values.11-14 Several different parameters are used to measure glycaemic control. These include: • Blood glucose levels. • Glycated haemoglobin (eg HbA1c). • Glycated serum protein (eg fructosamine). Blood Glucose Monitoring Blood glucose measurement is essential in the management of children and adolescents with diabetes for the following reasons: • To monitor daily control. • To detect hypoglycaemic and hyperglycaemic episodes. • To make possible the safe management of acute illnesses at home. The frequency of blood glucose monitoring should be adapted to the insulin regimen, the age of the child and the stability of the diabetes. Frequent daily blood glucose monitoring as part of a package of care is associated with improved glycaemic control.11;15 Older children and adolescents will be able to measure their own blood glucose levels while the younger child will be dependent on his/her parent or care giver for glucose monitoring. Information obtained from blood glucose monitoring should be used in association with HbA1c and clinical parameters to evaluate and modify management to improve glycaemic control. Timing of blood glucose testing The blood glucose levels should be measured: • At different times of the day pre- and post-prandially in order to obtain a profile over the 24 hours. • Before, during and after sport. • During intercurrent illnesses. • If hypoglycaemia is suspected. • Following treatment for hypoglycaemia. Most children on two injections a day do 3-4 tests a day; pre-breakfast, pre-dinner and the third test at varying times to obtain pre-lunch, bedtime and night-time data. More tests may be needed in multiple dose insulin regimens11 or for insulin pump use. If the diabetes is very stable, then the frequency of testing may be reduced (eg to obtain a profile over the day several times a week).11 Similarly if there is resistance to regular blood glucose testing then a compromise situation of reduced testing should be negotiated with the older child or adolescent. Options for reduced testing include a: • Full profile over the day several times a week with no intervening tests. • Composite profile obtained by a single blood test each day taken at different time points. Chapter 6: Glycaemic Control Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 78 Techniques for blood glucose testing Test strips and meters are sufficiently accurate and precise when used properly according to the manufacturer’s instructions. Correct technique includes: • Following manufacturer’s instructions. • Washing and drying of hands (to reduce infection risk and to wash glucose off fingers). • Calibrating the meter for the lot number of the reagent strips. • Using control solutions periodically with known glucose concentrations to assess meter accuracy. • Performing the test within defined temperature and humidity limits. • Use of sufficient blood for the strip. • Proper storage of blood glucose reagent strips and use before expiry date. Devices for blood glucose testing Meters and Reagent Strips Meters are available for bedside or self-monitoring of blood glucose levels. They are used in conjunction with blood glucose reagent strips which can be divided into those which result in a: • Change of colour. • Change in electrical current (bioelectric). Those that depend on a change of colour can be read either visually against calibrated colour blocks or with a reflectance blood glucose meter. Reflectance meters have largely been superseded. Most modern meters employ bioelectric strips that can only be read in the meter and cannot be read visually. Bioelectric strips usually require less than 5 microlitres blood (a large drop of blood measures 50 microlitres). Many meters are able to store results of previous readings, including date and time of the reading. Some meters are able to download the data to a computer and appropriate software programmes are able to transform the data into a variety of display formats. All children and adolescents should have an appropriate meter. Rebates for meters are available to those in most health insurance plans. Families suffering financial hardship are able to obtain these devices through various government safety-net schemes (details available through diabetes centres and Diabetes Australia). Finger-prickers and other prickers Special spring-loaded finger-pricking devices are available in order to reduce pain. Some devices are able to vary the depth of penetration by the lancet or utilise lancets with finer gauges. These are highly recommended for use in children and adolescents. Other devices are available which allow blood to be sampled from other parts of the body (eg forearm). There is a strong correlation between forearm blood glucose monitoring and finger blood glucose monitoring.16-20 Continuous glucose monitoring systems (CBGM) Intermittent capillary blood glucose monitoring gives a limited glimpse of blood glucose levels. CBGM may be a useful tool in giving detailed information on blood glucose trends during stabilisation of diabetes or during initiation and monitoring of insulin pump therapy.21 Invasive and non-invasive types of CBGM exist. Both types of CBGM need to be calibrated against capillary samples. Chapter 6: Glycaemic Control Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 79 Invasive CBGM Invasive CBGM monitoring systems available in Australia measure interstitial blood glucose via an indwelling sensor in the subcutaneous tissue of the abdomen or buttocks. The glucose levels measured by this technique correlate well with those obtained by conventional blood glucose monitoring.22-25 These monitors give useful insight into the individual blood glucose profile and are especially useful in detecting asymptomatic hypoglycaemia26;27 and may assist in stabilisation and motivation of patients.28 At present they are only available for short-term use in individual patients attending large paediatric centres. Non-invasive CBGM These devices have not been released in Australia. • Electrochemical enzyme sensor This device is worn like a wristwatch and provides frequent glucose readings. Glucose is extracted non-invasively via reverse iontophoresis for collection in a gel disc biosensor.29 The blood glucose readings correspond well with conventional finger prick blood glucose monitoring (r = 0.85 in the clinic setting and 0.90 in the home settings).30 Mild skin reactions can occur at the site of the adhesive pad.31 • Infrared spectroscopy Infrared spectroscopy technology is also being developed to measure blood glucose non-invasively.32-34 Record keeping and review of records A daily record of all testing performed should be kept in a logbook and this should be reviewed frequently to ensure optimal adjustments in management are made. The use of memory-glucose meters without daily reviewing of glucose levels is not recommended as patterns of glycaemic changes may not be appreciated by the child or adolescent and the family, and appropriate changes in insulin dosage may not be made. The record should be available at the time of consultation and should contain: • Blood glucose levels. • Time and date of test. • Insulin dosage. • Events which could influence metabolic control, such as birthday parties, illness, exercise, menses, etc. • Hypoglycaemic episodes. A variety of logbooks are provided by different companies. It is necessary to choose the most suitable for the child’s care. Depending on the child’s age, it is helpful to encourage his/her involvement in documenting blood glucose levels and activities. There are logbooks for young children that include stickers or diaries for teenagers which include a section for recording blood glucose levels, insulin doses and activities. The family should understand that the record book is not a ‘report card’ on which their efforts will be judged, but rather a diary of blood glucose levels, insulin dosages and special comments. The causes of a discrepancy between the logbook and other indices of glycaemic control (clinical, HbA1c) include: • Poor technique of blood glucose measurements. • Falsification of results. Chapter 6: Glycaemic Control Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 80 • Failure to test at different times in order to detect episodes of unsuspected hyperglycaemia (eg testing pre-prandially only). • Malfunction of the meter. HbA1C The most appropriate measure of long-term glycaemic control is the use of HbA1c, a subfraction of glycated haemoglobin. It is the only measure of glycaemic control that has been shown to be associated with long-term complications of diabetes and best reflects glycaemic levels over the preceding 2-3 months.15;35 Glycated haemoglobin (HbA1) occurs in several variants and can be measured using several different methods. Haemoglobin A1 contributes <10% of the total haemoglobin. Use of cation-exchange chromatography has shown that haemoglobin A1 can be separated into at lease three components HbA1a, HbA1b and HbA1c. These components have been found to be elevated in diabetic patients. Studies have found a strong relationship between HbA1c and fasting blood glucose levels over the preceding weeks in both adults and children with diabetes, and in non-diabetic subjects.36;37 HbA1c is the most frequently used measure of glycated haemoglobin in clinical practice. HbA1c is detected by high-pressure cation-exchange chromatography, electrophoresis or immunoturbidometric methods.15 The non-diabetic reference range for HbA1c should be established by each laboratory but is approximately 4-6%. The International Federation of Clinical Chemistry and Laboratory Medicine has recommended the adoption of new reference ranges for HbA1c based on more accurate mass spectroscopy methods. These would reduce the non-diabetic reference range for HbA1c by 1.5-2.0%. Currently the IFCC recommendations are being considered and if adopted, extensive education would need to be provided to both patients and health care professionals.38 The American Diabetes Association recommends measuring the HbA1c at least twice per year in patients who are meeting treatment goals, and more frequently (quarterly) in those whose treatment has changed or who are not meeting glycaemic goals.12 Other professional bodies suggest similar monitoring.11;39 In Australia Medicare reimburses the cost of four HbA1c measurements in any 12 month period. However in children under the age of 6 years with unstable diabetes, Medicare reimburses six HbA1c measurements annually. HbA1c results should be available at the time of the clinic visit, as this influences the outcome of the consultation in a substantial proportion of cases.39;40 Although a HbA1c <7.5% should be aimed for, the target that is achieved for an individual will depend on the interaction of the many factors. In children under the age of 6 years, the HbA1c target may be set a little higher because of the dangers of hypoglycaemia to the developing brain. HbA1c values need to be interpreted in the context of blood glucose readings and clinical parameters (eg a child with a low HbA1c may be experiencing asymptomatic hypoglycaemia). Whilst treatment aims to achieve near normoglycaemia, it must be noted that even in the DCCT, the mean HbA1c of the intensively treated adult group was still elevated at 7.2% (nondiabetic range <6.05%) and was 8.1% in the adolescent cohort of the study. It is relevant that adolescents in the DCCT had significantly higher HbA1c levels than adults in both intensively treated and conventionally treated groups. Despite these higher HbA1c levels they experienced more severe and moderate hypoglycaemic episodes underlining the difficulties in achieving ideal metabolic control in this age group.1;2 Children whose HbA1c is rising or persistently elevated should have all aspects of their diabetes management reassessed. Chapter 6: Glycaemic Control Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 81 Fructosamine Fructosamine measures the glycation of serum proteins. The term ‘fructosamine’ refers to the nature of the chemical bond between glucose and the amino acid on the protein and has nothing to do with fructose. Because the turnover of albumin is more rapid than that of haemoglobin, HbA1c and fructosamine measurements reflect different periods of blood glucose control (3 months versus 3 weeks).12 Urine Testing for Glucose Urinary glucose measurements are not recommended for monitoring glycaemic control because of poor correlations between glucose levels in the blood and urine.11-14 Urinary glucose levels will not provide any information about hypoglycaemia (the renal threshold for glycosuria is usually approximately 10 mmol/L).12 If blood glucose monitoring is not possible because of psychological reasons, then urine tests using glucose-specific strips will at least provide some information. The testing of urine for glucose reflects glycaemia a few hours preceding the test. The accuracy of the test in evaluating glucose control may be increased if a urine test is performed on a second specimen of urine obtained 30 minutes after initially emptying the bladder. Urine testing for glucose is relatively inexpensive and is performed using glucose-specific dipsticks for glucose alone, or combined with ketonuria testing or as part of a multiple urinetesting strip. The manufacturer’s instructions suggest that a urinary glucose reading of: • 5.5 mmol/L corresponds to a trace of glycosuria. • 14 mmol/L corresponds to + of glycosuria. • 28 mmol/L corresponds to + + of glycosuria. • 55 mmol/L corresponds to + + + of glycosuria. • 111 mmol/L corresponds to + + + + of glycosuria. Testing for Ketones Ketone acids include acetoacetic acid and beta-hydroxybutyric acid. Acetoacetic acid spontaneously degrades to form a molecule of acetone and carbon dioxide. The blood levels of beta-hydroxybutyric acid are usually four times that of acetoacetic acid.41 During hypoxia, severe shock or when there is lactic acidosis, this ratio may be greatly increased and a measure of the acetoacetic acid level may greatly underestimate the actual total level of ketone acids. The recently released meter and strips for bedside or home blood ketone testing measures beta-hydroxybutyrate levels whereas urine ketone strips only measure acetoacetic acid. Blood ketones A meter that reliably measures blood ketone (beta-hydroxybutyrate) levels is available for home or bedside use. Specific strips for this purpose need to be used. The manufacturer’s instructions need to be followed carefully. The same meter, using different strips, can also be used to measure blood glucose. In a study of children measuring ß-hydroxybutyrate 8 times per day for 2 weeks, only 6.0% of the ß-hydroxybutyrate measurements were 0.2 mmol/L.42 Chapter 6: Glycaemic Control Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 82 As a general guide to aid interpretation of blood ketone readings the manufacturer’s recommendations indicate: • The normal range is <0.6 mmol/L. • 0.6 - 1.5 mmol/L indicates developing ketosis. • 1.5 mmol/L is significantly elevated and at risk of developing diabetic ketoacidosis. Urine ketones The testing of urine for the presence of ketonuria is an essential part of diabetes monitoring. Urine test trips need to be stored in an airtight container and used within their expiry date as per the manufacturer’s instructions. The manufacturer’s instructions suggest that a urinary ketone reading of: • 0.5 mmol/L corresponds to a trace of ketones. • 1.5 mmol/L corresponds to small ketones. • 4 mmol/L corresponds to moderate ketones. • 8 mmol/L corresponds to large ketones. Urine should be tested for ketones in the following circumstances:12;13;39;42 • If vomiting occurs. • Any time the blood glucose is above 15 mmol/L, especially if the child or adolescent is unwell and especially if the blood glucose has been high for more than 24 hours. • If inappropriate drowsiness is present. • In the presence of high temperature, vomiting or diarrhoea, even when the blood glucose is <15 mmol/L. • If abdominal pains occur. • If breathing is rapid and suggestive of ketoacidosis. • If the child or adolescent has flushed cheeks. Ketonuria in the presence of hyperglycaemia is indicative of severe insulin deficiency and calls for urgent therapy to prevent progression into ketoacidosis (see Chapter 9 and Chapter 11). Ketonuria in the presence of low blood glucose levels is indicative of a starvation state or is the result of a counter-regulatory response to hypoglycaemia. Persistent ketonuria in the presence of hypoglycaemia may be seen in prolonged nausea and vomiting states. It is best managed by an infusion of 5-10% dextrose in N/2 Saline at maintenance rates (plus correction of dehydration if indicated) together with insulin to maintain the blood glucose at 5-10 mmol/L. The Evidence The evidence for the benefits of near patient testing of HbA1c at outpatient visits is listed in Evidence Table 6.1. • A quasi-randomised trial found that having the HbA1c result available at the time of the clinic visit, influences the outcome of the consultation in a substantial proportion of cases.40(III-1) The evidence for the benefits of improved glycaemic control on development of microvascular and macrovascular complications is listed in Evidence Table 6.2. • The Diabetes Control and Complications Trial (DCCT) confirmed the benefit of maintaining near normoglycaemia in reducing the development and progression of diabetic microvascular complications in adolescents and adults.1;2(II) Chapter 6: Glycaemic Control Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 83 • In the DCCT there was no lower threshold of HbA1c below which the risk of complications was eliminated, and any improvement in HbA1c conferred a reduction in risk.3;4(II) • Longer follow up of patients after the completion of the DCCT, in the EDIC (Epidemiology of Diabetes Interventions and Complications) study showed increasing reduction of microvascular and macrovascular complications with optimal early metabolic control.5;6(II) • In 1999 in NSW, fewer than 25% of children and adolescents had HbA1c levels <7.5%, with the median HbA1c being 8.2% [interquartile range 7.6-9.1%].9;10(IV) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence table 6.3. Recommendations and Principles • Diabetes control should be optimised as much as possible as improved glycaemic control reduces the risk of development and progression of microvascular and macrovascular complications in adolescents and adults.1;2;3;4;5;6(II) • Frequent daily blood glucose monitoring as part of a package of care has been shown to be associated with improved glycaemic control.15(T) • The frequency of blood glucose monitoring should be adapted to the insulin regimen, the age of the child and the stability of the diabetes.11(C) • The use of memory-glucose meters without daily reviewing of glucose levels is not recommended as patterns of glycaemic changes may not be appreciated by the child or adolescent and the family, and appropriate changes in insulin dosage may not be made.43(C) • HbA1c is the only measure of glycaemic control that has been shown to be associated with long-term complications of diabetes and best reflects glycaemic levels over the preceding 2-3 months.15(T) • The American Diabetes Association recommends measuring the HbA1c at least twice per year in patients who are meeting treatment goals, and more frequently (quarterly) in those whose treatment has changed or who are not meeting glycaemic goals.12(C) • HbA1c results should be available at the time of the clinic visit as this may influence the outcome of the consultation.40(III-1) 11;39 • In older children and adolescents the target HbA1c should be <7.5%. (T,C) • Increased efforts to improve glycaemic control are recommended as fewer than 25% of children and adolescents in NSW had HbA1c levels <7.5%.9;10(IV) • In younger children, the HbA1c target may be set a little higher because of the dangers of hypoglycaemia to the developing brain.11(C) • HbA1c values need to be interpreted in the context of blood glucose readings and clinical parameters (eg a child with a low HbA1c may be experiencing asymptomatic hypoglycaemia).39(C) • Children whose HbA1c is rising or persistently elevated should have all aspects of their diabetes management reassessed.11(C) • Ketones should be tested for when the blood glucose is above 15 mmol/L and the child or adolescent is unwell.39(C) • Ketones should be tested for in the presence of abdominal pains, rapid breathing, flushed cheeks, high temperature, vomiting, diarrhoea or inappropriate drowsiness even when the blood glucose is <15 mmol/L.43(C) I = Evidence from a systemic review of all relevant RCT’s II = Evidence from at least one properly designed RCT Chapter 6: Glycaemic Control Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 84 III-1 = Evidence from well-designed pseudo-randomised controlled trials IV = Evidence obtained from case series, either post-test or pre-test and post-test C = Consensus statement endorsed by professional organisations Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 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Diabetes 45:1289-1298, 1996 Nathan DM, Lachin J, Cleary P, Orchard T, Brillon DJ, Backlund JY, O'Leary DH, Genuth S, Diabetes Control and Complications Trial, Epidemiology of Diabetes Interventions and Complications Research Group: Intensive diabetes therapy and carotid intimamedia thickness in type 1 diabetes mellitus. New England Journal of Medicine 348:2294-2303, 2003 White NH, Cleary PA, Dahms W, Goldstein D, Malone J, Tamborlane WV: Beneficial effects of intensive therapy of diabetes during adolescence: outcomes after the conclusion of the Diabetes Control and Complications Trial (DCCT). Journal of Pediatrics 139:804-812, 2001 Northam EA, Anderson PJ, Jacobs R, Hughes M, Warne GL, Werther GA: Neuropsychological profiles of children with type 1 diabetes 6 years after disease onset. Diabetes Care 24:1541-1546, 2001 Smith AHK: The National Paediatric Diabetes Audit. Annual Report. Diabetes UK30, 2001 Craig ME, Handelsman P, Donaghue KC, Chan A, Blades B, Laina R, Bradford D, Middlehurst A, Ambler G, Verge CF, Crock P, Moore P, Silink M: Predictors of glycaemic control and hypoglycaemia in children and adolescents with type 1 diabetes from NSW and the ACT. Medical Journal of Australia 177:235-238, 2002 Handelsman P, Craig ME, Donaghue KC, Chan A, Blades B, Laina R, Bradford D, Middlehurst A, Ambler G, Verge CF, Crock P, Moore P, Silink M: NSW/ACT HbA1c Study Group: Homogeneity of metabolic control in New South Wales and the Australian Capital Territory, Australia. Diabetes Care 24:1690-1691, 2001 National Institute for Clinical Excellence. Type 1 Diabetes (Childhood): Diagnosis and Management of Type 1 Diabetes in Children and Young People (DRAFT). 2003. American Diabetes Association: Tests of glycemia in diabetes. Diabetes Care 26:S106-S108, 2003 American Diabetes Association: ADA position statement. Urine glucose and ketone determination. Clinical practice recommendations 1995. Diabetes Care 18(suppl):20, 1995 Goldstein DE, Little RR, Lorenz RA, Malone JI, Nathan D, Peterson CM: Tests of glycemia in diabetes. Diabetes Care 18:896-909, 1995 Coster S, Gulliford MC, Seed PT, Powrie JK, Swaminathan R: Monitoring blood glucose control in diabetes mellitus: a systematic review. Health Technology Assessment 4:1-93, 2000 Lock JP, Szuts EZ, Malomo KJ, Anagnostopoulos A, Rao S.: Accuracy of alternate site testing - Comparing arm and finger blood glucose results in glucose dynamic states. Diabetes Technology and Therapeutics 4:89, 2002 Fineberg SE, Bergenstal RM, Bernstein R., Laffel LM, Schwartz SL: Use of an automated device for alternative site blood glucose monitoring. Diabetes Care 24:1217-1220, 2001 Lee DM, Weinert SE, Miller EE: A study of forearm versus finger stick glucose monitoring. Diabetes Technology and Therapeutics 4:13-23, 2002 McGarraugh G, Price D, Schwartz S, Weinstein R: Physiological influences on off-finger glucose testing. Diabetes Technology and Therapeutics 3:367-376, 2001 Peled N, Wong D, Gwalani SL: Comparison of glucose levels in capillary blood samples obtained from a variety of body sites. Diabetes Technology and Therapeutics 4:35-44, 2002 McGahan L.: Continuous glucose monitoring in the management of diabetes mellitus. Issues in Emerging Health Technologies 1-4, 2002 Gross TM, Bode BW, Einhorn D, Kayne DM, Reed JH, White NH: Performance evaluation of the MiniMed continuous glucose monitoring system during patient home use. Diabetes Technology and Therapeutics 2:49-56, 2000 Gross TM, Ter Veer A: Continuous glucose monitoring in previously unstudied population subgroups. Diabetes Technology & Therapeutics 2 Suppl 1:S27-S34, 2000 Gross TM, Mastrototaro JJ: Efficacy and reliability of the continuous glucose monitoring system. Diabetes Technology & Therapeutics 2 Suppl 1:S19-S26, 2000 Maran A, Crepaldi C, Tiengo A, GG, Vitali E, Pagano G: Continuous subcutaneous glucose monitoring in diabetic patients: a multicenter analysis. Diabetes Care 25:347-352, 2002 Schiaffini R, Ciampalini P, Fierabracci A, Spera S, Borrelli P, Bottazzo GF: The continuous glucose monitoring system (CGMS) in type 1 diabetic children is the way to reduce hypoglycemic risk. Diabetes/Metabolism Research Reviews 18:324-329, 2002 Chase HP, Kim LM, Owen SL, MacKenzie TA, Klingensmith GJ, Murtfeldt R, Garg SK: Continuous subcutaneous glucose monitoring in children with type 1 diabetes. Pediatrics 107:222-226, 2001 Ludvigsson J, Hanas R: Continuous subcutaneous glucose monitoring improved metabolic control in pediatric patients with type 1 diabetes: a controlled crossover study. Pediatrics 111:933-938, 2003 Tierney MJ, Tamada JA, Potts RO, Jovanovic L, Garg S, Cygnus Research Team.: Clinical evaluation of the GlucoWatch biographer: a continual, non-invasive glucose monitor for patients with diabetes. Biosensors & Bioelectronics 16:621-629, 2001 Garg SK, Potts RO, Ackerman NR, Fermi SJ, Tamada JA, Chase HP: Correlation of fingerstick blood glucose measurements with GlucoWatch biographer glucose results in young subjects with type 1 diabetes. Diabetes Care 22:1708-1714, 1999 Eastman RC, Chase HP, Buckingham B, Hathout EH, Fuller-Byk L, Leptien A, Van Wyhe MM, Davis TL, Fermi SJ, Pechler H, Sahyun G, Lopatin M, Wang BY, Wei C, Bartkowiak M, Ginsberg BH, Tamada JA, Pitzer KR: Use of the GlucoWatch biographer in children and adolescents with diabetes. Pediatric Diabetes 3:127-134, 2002 Gabriely I, Wozniak R, Mevorach M, Kaplan J, Aharon Y, Shamoon H: Transcutaneous glucose measurement using near-infrared spectroscopy during hypoglycemia. Diabetes Care 22:2026-2032, 1999 Chapter 6: Glycaemic Control Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 85 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. Muller UA, Mertes B, Fischbacher C, Jageman KU, Danzer K: Non-invasive blood glucose monitoring by means of near infrared spectroscopy: methods for improving the reliability of the calibration models. International Journal of Artificial Organs 20:285290, 1997 Uemura T, Nishida K, Sakakida M, Ichinose K, Shimoda S, Shichiri M: Noninvasive blood glucose measurement by Fourier transform infrared spectroscopic analysis through the mucous membrane of the lip: application of a chalcogenide optical fiber system. Frontiers of Medical and Biological Engineering 9:153, 1999 Rohlfing CL, Wiedmeyer HM, Little RR, England JD, Tennill A, Goldstein DE: Defining the Relationship Between Plasma Glucose and HbA1c: Analysis of glucose profiles and HbA1c in the Diabetes Control and Complications Trial. Diabetes Care 25:275-278, 2002 Mortensen HB.: Glycated hemoglobin. Reaction and biokinetic studies. Clinical application of hemoglobin A1c in the assessment of metabolic control in children with diabetes mellitus. Danish Medical Bulletin 32:309-328, 1985 Mortensen HB, Vestermark S, Kastrup KW: Metabolic control in children with insulin dependent diabetes mellitus assessed by hemoglobin A(1c). Acta Paediatrica Scandinavica 71:217-222, 1982 Jeppsson JO, Kobold U, Barr J, Finke A, Hoelzel W, Hoshino T, Miedema K, Mosca A, Mauri P, Paroni R, Thienpont L, Umemoto M, Weykamp C: International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). Approved IFCC reference method for the measurement of HbA1c in human blood. Clinical Chemistry & Laboratory Medicine 40:78-89, 2002 International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Grieve R, Beech R, Vincent J, Mazurkiewicz J: Near patient testing in diabetes clinics: appraising the costs and outcomes. Health Technology Assessment 3:1-74, 1999 Laffel L: Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metabolism Research and Reviews 15:412-426, 2000 Samuelsson U, Ludvigsson J: When should determination of ketonemia be recommended? Diabetes Technology & Therapeutics 4:645-650, 2002 Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Chapter 6: Glycaemic Control Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 86 Chapter 7: Nutrition Nutrition is a fundamental component in the management of diabetes.1 There are few long-term studies to support current dietary recommendations, particularly for children. Nutritional management of children and adolescents with type 1 diabetes should be by an accredited practising dietitian trained in paediatric diabetes. Nutrition Therapy The aims of nutrition therapy in type 1 diabetes are to ensure: • Adequate energy and nutritional intake for normal growth and development. • Optimal glycaemic control without severe hypoglycaemic and/or prolonged hyperglycaemic episodes. • Optimal blood lipid control. • Meeting the psychosocial needs of the individual by incorporating food and insulin regimens into usual eating habits, appetite, usual routines and exercise patterns. Nutritional Assessment Nutritional assessment on initial diagnosis should include: • Family history of diabetes, including: Parental beliefs about diabetes. Individual beliefs about diabetes. • Medical history- including conditions that may impact on dietary intake. • Social situation- family structure, cultural background and influences. • Growth (height and weight, including growth history, BMI) and development. • Diet history to establish usual dietary intake including energy intake, total and saturated fat, carbohydrate intake and distribution, variations in appetite and usual food preferences. • Usual routines and activities, including organised sport, school/pre-school timetables, after-school activities and any variations including weekend variations. • Parent/child’s learning ability and motivation to ensure appropriate nutrition intervention. Nutrition Review Ongoing nutritional monitoring of the individual with diabetes by a dietitian experienced with paediatric diabetes management is essential. The initial review should occur 2-4 weeks post-diagnosis. Ongoing reviews should occur every 12 months or more often depending on the age of the child or the needs of the child/family. Ongoing review should include: • Usual nutritional intake including appetite satisfaction. • Growth including height, weight and BMI centiles (Figures 7.1 and 7.2). • Insulin regimen including any regular insulin adjustments. • HbA1c and day to day blood glucose monitoring including patterns of hypo- or hyperglycaemia. • Method of treatment of hypoglycaemia. • Exercise regimen and carbohydrate intake pre-exercise. Chapter 7: Nutrition Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 87 • • Individual or parental concerns about dietary management. Assessment of changes in lifestyle impacting on dietary intake and quality of life (eg body image perception, alcohol, cigarettes and/or drugs depending on the age of the child). • Re-education where required, including education of the individual with diabetes as he/she becomes older and increasingly more responsible for self-care. • Consideration of new medical conditions that may impact on management (eg hypercholesterolemia, coeliac disease, bulimia, family history of newly diagnosed cardiovascular disease). Dietary Recommendations There is no research on the nutrient requirements for children and adolescents with diabetes; therefore nutrient recommendations are based on requirements for all healthy children and adolescents. These recommendations are summarised by the ‘The Dietary Guidelines for Children and Adolescents in Australia’ (Table 7.1).2 The recommended meal plan should consider the child’s usual appetite and food intake pattern. Some modification to usual intake may be necessary to reduce saturated fat intake and sugars intake and to distribute carbohydrate evenly over regular meals and snacks. Table 7.1: The Dietary Guidelines for Children and Adolescents in Australia Encourage and support breastfeeding Children and adolescents need sufficient nutritious foods to grow and develop normally • Growth should be checked regularly • Physical activity is important for all children and adolescents Enjoy a wide variety of nutritious foods Children and adolescents should be encouraged to: • Eat plenty of vegetables, legumes and fruits • Eat plenty of cereals (including breads, rice, pasta and noodles), preferably wholegrain • Include lean meat, fish, poultry and/or alternatives • Include milks, yoghurts, cheese and/or alternatives • Reduced-fat milks are not suitable for young children under 2 years, because of their high energy needs, but reduced fat varieties should be encouraged for older children and adolescents • Choose water as a drink And care should be taken to: • Limit saturated fat and moderate total fat intake (NB low fat diets are not suitable for infants) • Choose foods low in salt • Consume only moderate amounts of sugars and foods containing added sugars Care for your child’s food: prepare and store it safely Source: Dietary Guidelines for Children and Adolescents (National Health and Medical Research Council 2003) Energy Intake Many children have increased energy requirements initially to allow for regain of lost weight.3 Children and adolescents with established and stable diabetes have the same basic energy requirements as their peers. The estimates of energy requirements are made from an Chapter 7: Nutrition Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 88 individual’s food nutrition history of a typical daily intake obtained from 24 hr recall or a 3day food record. Consideration needs to be given to changing appetite and activity levels. Individual adjustment is required with regular monitoring of growth using standard height and weight charts ideally at 3-6 month intervals.3 Dietary Carbohydrate A diet providing 50-55% total energy as carbohydrate is recommended for children and adolescents with diabetes.2 Carbohydrates directly affect the blood glucose level and the amount, timing and type of carbohydrate need to be considered in relation to the insulin regimen.1;4 Practical quantification of carbohydrate intake is necessary as part of management.5 Methods of carbohydrate quantification include use of 15 gm carbohydrate exchanges or the use of the individual’s usual serving size as the basis for the meal plan.6 In practice, carbohydrate amounts are suggested for each meal and snack for those on fixed insulin doses that are based on the individual’s previous dietary intake, activity, appetite and insulin regimen. Day to day consistency in carbohydrate intake is important for those receiving fixed doses of insulin.1 Prescriptive meal plans are not recommended. Compliance is poor with rigid prescriptive meal plans and quality of life is decreased.6 The DCCT and the Dose Adjustment for Normalised Eating (DAFNE) Study which included adolescents on intensive insulin therapy demonstrated better metabolic outcomes are achieved if insulin is adjusted for carbohydrate quantity.4;7 For those on multiple daily injections or pump therapy a 1% decrease in HbA1c can be achieved by adjusting meal time insulin doses based on carbohydrate quantities.4 Glycaemic Index (GI) The GI is a ranking of foods based on their acute glycaemic impact compared to the reference standard glucose.8 The GI is one of several tools used to assist with glycaemic control. Carbohydrates with a low GI result in a slower and more gradual rise in blood glucose levels and reduce the postprandial glycaemic response compared to carbohydrates with a higher GI. Low GI food sources include wholegrain breads, legumes, pasta, temperate fruits, dairy foods. Not all low GI foods are good everyday choices (eg chocolate, fructose) (see table 7.2). Many factors may influence a food’s glycaemic response. However, the ranking of foods on the basis of their GI value is generally consistent.9 The GI is also reproducible and predictable within the context of mixed meals10;11;12 and has also been shown to have a clinically important ‘carry-over’ effect on the subsequent meal.13 It has been suggested that low-GI diets are difficult to understand, may limit food choice and variety and deteriorate overall dietary quality.14;15 However, studies have shown that low GI diets are easy to understand, and have no detrimental effect on food variety or nutritional quality.6;16 A recent meta-analysis comparing low GI diets with conventional or high GI diets, using glycaemic control (HbA1c or fructosamine) as the outcome measure concluded that low GI diets have a small but clinically useful effect on medium term glycaemic control.17 This meta-analysis analysed both adult and paediatric studies together.17 There were only two Chapter 7: Nutrition Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 89 paediatric studies which have investigated low GI diets in children and adolescents with type 1 diabetes.6;16;18 The larger study, a randomised controlled trial, showed that a flexible low-GI diet resulted in a significantly better HbA1c outcome after 12 months (8.05 ±0.95 vs. 8.61 ±1.37%, p = 0.05) and a better reported quality of life, with no decrease in number of food choices or macronutrient composition compared to a measured 15g carbohydrate exchange diabetic diet.6;16 The other study was of short duration (6 weeks) with only 7 patients enrolled, and although the glycated serum albumin was lower in the patients who received a low GI diet, these patients also had a higher daily fibre intake.18 Table 7.2: The Glycaemic Index of Some Foods (Glucose = 100)12 Low GI Foods (<55) Moderate GI Foods (55-69) High GI Foods (70) Fructose 20 Lactose 57 White bread 70 Whole milk 27 Honey 58 Watermelon 72 Apple 36 Sucrose 59 Waffles 76 Apple juice 41 Basmati rice 59 Wholemeal bread 77 Apple muffin 44 Banana 60 Puffed Wheat 80 Fruit loaf 47 Regular ice-cream 61 Jelly beans 80 Sweet potato 48 Shortbread 64 Baked potato 85 Chocolate 49 Crumpet 69 Honey-glucose enriched 87 Rolled oats 50 Pasta 50 Foster-Powell, Holt et al., 2002 Sugars The term sugars is conventionally used to describe monosaccharides (eg glucose, fructose) and disaccharides such as sucrose and lactose. These can be found naturally in foods or can be added in processing. Sugar, by contrast, is used to describe purified sucrose, as are the terms refined sugar and added sugar. The term no added sugar means no sugars have been added during the manufacturing process; it does not mean that no sugar or other sugars are present, since most foods contain sugars in some form. Australian school children consume about 50% of their daily energy intake as carbohydrates, with total sugars contributing 25% of energy intake (15% as added sugars and 10% as natural sugars).19 A recent WHO/FAO report on population nutrition strategies to reduce obesity, cardiovascular disease and diabetes recommends that added sugars be reduced to <10% of daily energy intake.20 Dietary guidelines for children and adolescents recommend the consumption of moderate amounts of sugars and foods containing added sugars.2 When sucrose is the main ingredient, such as in soft drinks and cordials, choosing the sugar-free alternative is desirable. Overall, the evidence supports moderate use of sugars (including sucrose) in the diabetes diet.21-25 Artificially sweetened products There are two main types of artificial sweeteners: • Nutritive. • Non-nutritive. Nutritive sweeteners include fructose and polyols (sugar alcohols such as sorbitol, mannitol and xylitol). Foods containing these sweeteners are often labelled as ‘carbohydrate modified’. Chapter 7: Nutrition Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 90 They are only partially absorbed from the small intestine and excessive use will cause diarrhoea in children.26 Non-nutritive sweeteners include aspartame, saccharin, sucralose and acesulfame K. All have been extensively studied for safety and their use in food products in Australia is governed by the Food Standards Code for Australia and New Zealand. Fibre The Australian Dietary Guidelines aim to ensure adequate dietary fibre intake (soluble and insoluble). High fibre diets help to prevent constipation and optimise bowel health. An adequate fibre intake is calculated using the age of the child (years) plus 5 gm.27 Controversy remains whether high fibre diets have direct effects on glycaemic control.28-30 Dietary Fat Intake The major types of dietary fats are: • Saturated (animal fats including dairy, meat and butter). • Monounsaturated (olive and canola oils). • Polyunsaturated fats (vegetable fats including margarine and vegetable oils). The Australian Dietary Guidelines for Children and Adolescents recommend limiting saturated fat intake and moderate total fat intake.2 The recommended targets for fat intakes do not differ for children with diabetes (Table 7.3). Table 7.3: Summary of the Australian Dietary Guidelines for Dietary Fat Intake during Childhood Age Group Recommendations Birth to two years • during the first 6 months fat should compromise 50% total of age energy intake by breast milk or formula. • from 6-12 months the target is 40% total energy. • skim milk and reduced fat milk should not be used in children under the age of two years. Two to five years • target is 30% total energy from fat. • no more than 10% energy from saturated fat. • reduced fat milks are suitable but not skim milk. Five to fourteen • target is 30% total energy from fat. • no more than 10% total energy from saturated fat. years Adolescence • target is 25% total energy from fat. • no more than 10% total energy from saturated fat. Source: (National Health and Medical Research Council 2003). The National Nutrition Survey (1995) reported that children and adolescents in the general population (2-18 years) had an average intake of 33% total energy from fat.31 Children with diabetes have similar high fat intakes ranging between 33%-36% total energy.16;32 International recommendations for nutrition in the population have recommended the diet contain 30% of energy from fat, with saturated fats contributing less than 10% of total energy, while polyunsaturated and monounsaturated fats each contribute more than 10% to the daily energy content.20 Chapter 7: Nutrition Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 91 Protein Protein should provide approximately 15-20% of total energy intake for children and adolescents. Lean sources of protein are recommended which include lean cuts of meat and fat-reduced dairy products as appropriate. High protein, low carbohydrate diets are not generally recommended for children and adolescents with diabetes. There are no studies that investigate the long-term effects of such diets on the growth and development in children. Restricting carbohydrate intake may impact on the nutritional adequacy of the diet and may cause hypoglycaemia. High protein diets result in ketosis, which may result in dehydration, loss of appetite, irritability, lethargy, loss of lean body mass and other abnormalities.33 Variations in Advised Meal Patterns and Insulin Regimens There are numerous variations in insulin regimens that are used to manage type 1 diabetes in children and adolescents. Expert nutritional guidance is an essential component of the overall management. Twice daily injection regimen This usually involves a combination of short/rapid-acting and intermediate-acting insulin injected twice daily, usually before breakfast and the evening meal. The meal plan should consist of three meals and three snacks a day based on carbohydrate-containing foods. Meals and snacks should not be missed or delayed (toddlers, however, tend to graze over the day). Three injections per day A mixture of short/rapid-acting and intermediate-acting insulin given before breakfast, short/rapid-acting insulin before the afternoon snack or main evening meal and intermediateacting insulin in the evening is commonly used in older children and teenagers when a 2 injection per day regimen is inadequate. Multiple daily injection regimens This usually involves a total of four injections per day with short/rapid-acting insulin given three times daily before breakfast, lunch and dinner and either intermediate- or long-acting insulin given at supper. The suggested meal plan is three main meals and an evening snack based on carbohydrate foods. Morning tea and afternoon tea snacks are not necessary but may still be eaten if desired (this may influence choice of rapid-acting versus short-acting insulin). This regimen allows some increased flexibility in meal timing and in the carbohydrate quantity for meals, and is usually better suited to the lifestyle of the older child or adolescent. For those requiring a large afternoon tea the pre dinner short/rapid-acting insulin may be given before afternoon tea. Insulin pump therapy Insulin pump therapy provides basal insulin with additional insulin bolus doses for each carbohydrate-containing meal/snack consumed (see insulin pump adjustment). It provides a greater degree of flexibility, especially in relation to the diet. Meal and snack times can be delayed or omitted and/or the carbohydrate content can be varied with the insulin bolus adjusted accordingly. Chapter 7: Nutrition Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 92 Intensified glycaemic control coupled with greater food flexibility (quality and quantity) can lead to undesirable weight gain. It is prudent to monitor closely for undesirable weight gain and to encourage healthy eating habits including 3 main meals per day. Age-group Specific Advice Approaches to the management of diabetes vary greatly at different ages and stages of development. Infants Exclusive breastfeeding for the first 6 months is recommended for all infants.2 If the mother chooses not to breastfeed, an appropriate infant formula should be used. Regular breast or bottle feeds (approx 3 hourly) will help to maintain blood glucose levels. Introduction of solids is recommended at around 6 months similar to other infants. Toddlers Tantrums, food fads and food refusal are common toddler behaviours. Such behaviours in a toddler with diabetes increase parental anxiety and accentuate problem meal behaviours.34 Toddlers eat erratically and have unpredictable activity levels. Rigid meal plans of three meals and three snacks per day are impractical and not recommended. It is normal for toddlers to ‘graze’ throughout the day. Appetite will fluctuate and toddlers generally regulate their own intakes. Practical advice includes substituting carbohydrate foods for those refused without offering excessive choices, maximising carbohydrate finger foods and monitoring blood glucose levels regularly if parents feel that there has been insufficient intake of carbohydrate foods. Toddlers are encouraged to eat the family’s usual meals. Parents should not offer too many choices, substitute carbohydrate foods with ‘junk foods’, or force feed their child as this may encourage negative food related behaviours. Primary school-aged children Children’s energy needs constantly increase as they grow and increase their activity. Weight gain is about 2.5 to 3 kg/year in boys and girls from 6 to 12 years of age, with energy intakes nearly doubling in this time. Frequent review of meal plans is essential. School-age children are encouraged to carry ‘hypo food’ and be aware of the need for extra carbohydrate for exercise. School introduces increasing peer influence and more independence, with less direct parental supervision. Issues such as lunch swapping, forgetting to eat meals, throwing away food and purchasing foods independently from school canteens need to be addressed. Adolescents In adolescence, growth patterns and nutrient requirements change rapidly. Eating habits may include large afternoon tea, skipped meals, increased snacking, more meals away from home, increased intake of high fat convenience foods and frequent consumption of sweets and soft drinks.35 There is also increased influence of peer pressure about issues such as sexuality, body weight and dieting, experimentation with alcohol, cigarettes and drugs and challenging boundaries, including those related to diabetes self-management (see Chapter 18) for discussion on insulin purging, insulin omission and eating disorders in adolescence). Many adolescents manage their diabetes on a basal-bolus insulin regimen which provides greater flexibility. However, special attention should be given to adolescents on multiple Chapter 7: Nutrition Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 93 injections because of the two-fold increased risk of obesity and increased incidence of severe hypoglycaemia.36 The Evidence The evidence for the benefits of low glycaemic index diets in the management of type 1 diabetes in children and adolescents is listed in Evidence Table 7.1. 17 6;16;18 • A recent meta-analysis (including mostly adult but some paediatric studies ) comparing low GI diets with conventional or high GI diets, using glycaemic control (HbA1c or fructosamine) as the outcome measure concluded that low GI diets have a small but clinically useful effect on medium term glycaemic control.17(I) The evidence for the benefits of adjusting insulin dose for carbohydrate quantity in the management of type 1 diabetes in children and adolescents is listed in Evidence Table 7.2. • The DCCT and the Dose Adjustment for Normalised Eating (DAFNE) Study which included adolescents on intensive insulin therapy demonstrated better metabolic outcomes are achieved if insulin is adjusted for carbohydrate quantity.4;7(II) The evidence for the effect on glycaemic control of the moderate use of sugars in children and adolescents with type 1 diabetes is listed in Evidence Table 7.3. • Five small RCTs show that moderate use of sugars (including sucrose) in the diabetes diet does not adversely affect glycaemic control.21-25(II) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence table 7.4. Recommendations and Principles • Nutrition is a fundamental component in the management of type 1 diabetes in childhood and adolescence.1;3(C) • Nutritional management of children and adolescents with type 1 diabetes should be initiated by an accredited practising dietitian trained in paediatric diabetes.37(C) • Nutritional reviews should occur 2-4 weeks post-diagnosis and ongoing at least once per year by a paediatric dietitian experienced in diabetes management.37(C) • Children and adolescents with diabetes should be encouraged to follow the NHMRC Dietary Guidelines for Children and Adolescents in Australia which recommend that:2 Carbohydrate should provide 50-55% of total energy intake. Dietary fat intake should provide between 25 and 40% of total energy intake depending on the child’s age. Saturated fat intake should be limited to <10% of total energy intake. Dietary protein intake should provide 15-20% of total energy intake.(C) • Children and adolescents with diabetes should be educated and encouraged to adjust their insulin dose depending upon carbohydrate quantity.4;7(II) • Day to day consistency in carbohydrate intake is important for those receiving fixed doses of insulin.(C) • Dietary advice should include information about low glycaemic index food as this can help to improve glycaemic control.6;16;17;18(I) • Moderate use of sucrose in the diabetes diet should be allowed as it does not significantly influence glycaemic control in type 1 diabetes.21-25(II) I = Evidence obtained from a systematic review of all relevant randomised controlled trials II = Evidence obtained from at least one properly designed randomised controlled trial C = Consensus statement endorsed by professional organisations Chapter 7: Nutrition Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 94 Figure 7.1: Body Mass Index-for-age Percentiles: Girls, 2-20 Years Chapter 7: Nutrition Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 95 Figure 7.2: Body Mass Index-for-age Percentiles: Boys, 2-20 Years Chapter 7: Nutrition Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 96 Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. American Diabetes Association: Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 26 Suppl 1:S51-S61, 2003 NHMRC. Dietary Guidelines for Children and Adolescents in Australia incorporating the Infant Feeding Guidelines for Health Workers. 2003. Ref Type: Report Franz MJ, Bantle JP, Beebe CA, Brunzell JD, Chiasson JL, Garg A, Holzmeister LA, Hoogwerf B, Mayer-Davis E, Mooradian AD, Purnell JQ, Wheeler M: Evidence-Based Nutrition Principles and Recommendations for the Treatment and Prevention of Diabetes and Related Complications. Diabetes Care 25:148, 2002 Delahanty LM, Halford BN: The role of diet behaviours in achieving improved glycemic control in intensively treated patients in the Diabetes Control and Complications Trial. Diabetes Care 16:1453-1458, 1993 International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Gilbertson HR, Brand-Miller JC, Thorburn AW, Evans S, Chondros P, Werther GA: The effect of flexible low glycemic index dietary advice versus measured carbohydrate exchange diets on glycemic control in children with type 1 diabetes. Diabetes Care 24:1137-1143, 2001 DAFNE Study Group: Training in flexible, intensive insulin management to enable dietary freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE) randomised controlled trial. British Medical Journal 325:746, 2002 Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden H, Baldwin JM, Bowling AC, Newman HC, Jenkins AL, Goff DV: Glycemic index of foods: a physiological basis for carbohydrate exchange. 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American Journal of Clinical Nutrition 48:1041-1047, 1988 Beebe C: Diets with a low glycemic index: Not ready for practice yet. Nutrition Today 34:82-86, 1999 Franz MJ: In defence of the American Diabetes Association's recommendation on the glycemic index. Nutrition Today 34:78-81, 1999 Gilbertson HR, Thorburn AW, Brand-Miller JC, Chondros P, Werther GA: Effect of low-glycemic-index dietary advice on dietary quality and food choice in children with type 1 diabetes. American Journal of Clinical Nutrition 77:83-90, 2003 Brand-Miller JH: Low-glycemic index diets in the management of diabetes: a meta-analysis of randomized controlled trials. Diabetes Care 26:2261-2267, 2003 Collier GR, Giudici S, Kalmusky J, Wolever TM, Helman G, Wesson V, Ehrlich RM, Jenkins DJ: Low glycaemic index starchy foods improve glucose control and lower serum cholesterol in diabetic children. Diabetes Nutrition and Metabolism 1:11-19, 1988 Cobiac L, Record S, Leppard P, Syrette J, and Flight I. Sugars in the Australian Diet: results from the 1995-96 National Nutrition Survey. CSIRO. 2001. Adelaide. WHO Technical Report Series. Diet, Nutrition and the Prevention of Chronic Disease. Report of a Joint WHO/FAO Expert Consultation. 2003. Ref Type: Report Loghmani E R: Glycemic response to sucrose-containing mixed meals in diets of children of with insulin-dependent diabetes mellitus. Journal of Pediatrics 119:531-537, 1991 Rickard KA, Loghmani ES, Cleveland JL, Fineberg NS, Freidenberg GR: Lower glycemic response to sucrose in the diets of children with type 1 diabetes. Journal of Pediatrics 133:429-434, 1998 Schwingshandl J: Effect of the introduction of dietary sucrose on metabolic control in children and adolescents with type I diabetes. Acta Diabetologia 31:205-209, 1994 Wang SR, Chase HP, Garg SK, Hoops SL, Harris MA: The effect of sugar cereal with and without a mixed meal on glycemic response in children with diabetes. Journal of Pediatric Gastroenterology & Nutrition 13:155-160, 1991 Wise JE, Keim KS, Huisinga JL, Willmann PA: Effect of sucrose-containing snacks on blood glucose control. Diabetes Care 12:423-426, 1989 Payne ML, Craig WJ, Williams AC: Sorbitol is a possible risk factor for diarrhoea in young children. Journal of the American Dietetic Association 97:532-534, 1997 Williams CL, Bollella M, Wynder EL: A new recommendation for dietary fiber in childhood. Pediatrics 96:t-8, 1995 Buyken AE, Toeller M, Heitkamp G, Vitelli F, Stehle P, Scherbaum WA, Fuller JH: Relation of fibre intake to HbA(1c) and the prevalence of severe ketoacidosis and severe hypoglycaemia. Diabetologia 41:882-890, 1998 Giacco R: Long-term dietary treatment with increased amounts of fiber-rich low-glycemic index natural foods improves blood glucose control and reduces the number of hypoglycemic events in type 1 diabetic patients. Diabetes Care 23:1461-1466, 2000 Lindsay AN, Hardy S, Jarrett L, Rallison ML: High-carbohydrate, high-fiber diet in children with type I diabetes mellitus. Diabetes Care 7:63-67, 1984 McLennan W, Podger A. National Nutrition Survey: nutrient intake and physical measurements. Canberra, Australian Bureau of Statistics. 1997 Wiltshire EJ, Hirte C, Couper JJ: Dietary Fats Do Not Contribute to Hyperlipidemia in Children and Adolescents With Type 1 Diabetes. Diabetes Care 26:1356, 2003 St Jeor ST, Howard BV, Prewitt TE, Bovee V, Bazzarre T: Dietary protein and weight reduction: a statement for healthcare professionals from the Nutrition Committee of the Council on Nutrition, Physical Activity, and Metabolism of the American Heart Association. Circulation 104:1869-1874, 2001 Powers SW, Byars KC, Mitchell MJ, Patton SR, Standiford DA, Dolan LM: Parent Report of Mealtime Behavior and Parenting Stress in Young Children With Type 1 Diabetes and in Healthy Control Subjects. Diabetes Care 25:313, 2002 Magrath G, Hartland BV: Dietary recommendations for children and adolescents with diabetes: an implementation paper. British Diabetic Association's Professional Advisory Committee. Diabetic Medicine 10:874-885, 1993 Chapter 7: Nutrition Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 97 36. 37. White NH, Cleary PA, Dahms W, Goldstein D, Malone J, Tamborlane WV: Beneficial effects of intensive therapy of diabetes during adolescence: outcomes after the conclusion of the Diabetes Control and Complications Trial (DCCT). Journal of Pediatrics 139:804-812, 2001 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Chapter 7: Nutrition Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 98 Chapter 8: Physical Activity Need for Physical Activity and General Recommendations The benefits of regular physical activity for people of all ages are well known and accepted.1 Physical activity is more than organised sport and includes playing at school, running, walking, dancing and other activities of daily living. The benefits of physical activity include improved insulin sensitivity, weight management, musculo-skeletal benefits, functional movement development, psychological wellbeing, social interaction and cardiovascular fitness. There is no evidence to say that these benefits are not the same for people with diabetes.2 As diabetes is associated with an increased risk of macrovascular disease, the benefit of physical activity in improving known risk factors for atherosclerosis (eg overweight/obesity, hypertension, hypercholesterolaemia) should be remembered.3 Education of the child with type 1 diabetes and their carer should include insulin administration, blood glucose control, carbohydrate intake and management of hypoglycaemia prior to undertaking any physical activity. Children and adolescents with type 1 diabetes should be encouraged to participate in sport and not be limited in their choice of activity.4 However, certain sports require special consideration and others are contraindicated in people with insulin treated diabetes. Activities should be approached with caution if they are solo in nature, take place in water or mid-air, or limit the individual’s ability to recognise and self-treat hypoglycaemia. Those involved in strenuous or water sports should have a ‘buddy’ able to offer assistance. These activities include: • Rock climbing. • Flying. • Abseiling. • Car/motorbike racing. • Cross country skiing. • Swimming in open water or snorkelling. People with insulin-treated diabetes are generally advised to avoid the following activities unless special precautions to avoid hypoglycaemia are taken and a full understanding of the possible dangers are appreciated: • Hang-gliding (except in tandem). • Scuba diving (The Australian Diabetes Society in 1994 produced a position paper stating that type 1 diabetes is an ‘absolute contra-indication’ to Entry Level SCUBA diving).5 Short-Term Effects The normal physiological response to physical activity is to decrease plasma insulin levels and increase plasma glucagon in order to increase hepatic glucose production and prevent hypoglycaemia. These normal hormonal adaptations to exercise are essentially lost in children and adolescents with type 1 diabetes. Hypoglycaemia during physical activity rarely occurs in nondiabetic individuals. High insulin levels due to exogenous insulin administration, can prevent the mobilisation of hepatic glucose, making hypoglycaemia more likely in a patient with type 1 diabetes.3 Hypoglycaemia may occur during, immediately after or many hours after physical activity. Therefore, it is recommended that: 2 • Blood glucose levels need to be measured before, during and after physical activity. Chapter 8: Physical Activity Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 99 • • • • • • Physical activity may necessitate extra carbohydrate intake and insulin reduction.2 A general recommendation is that 15 gm of easily absorbable carbohydrate or an extra serving should be taken for every 30 minutes of moderate to intensive sport or physical activity. Experience and blood glucose monitoring help determine the most appropriate strategies as the requirements vary for each individual. All children and adolescents participating in sport should have access to assistance from a person aware of the management of hypoglycaemia during physical activity. Extra carbohydrate should be consumed if blood glucose level is <7 mmol/L.2 Exercise should be delayed if blood glucose is <3.5 mmol/L. Special attention should be given to children and adolescents performing intensive sports, especially those involving endurance training, due to the association with delayed hypoglycaemic reactions which may occur in the middle of the night or before breakfast the next day. Advice should be sought from a dietitian for carbohydrate foods suitable for those undertaking endurance sports. Intensive physical activity needs to have appropriate reductions made in dosages of the insulin acting during and for the following 12-24 hours after the physical activity. In some cases decreasing insulin before physical activity reduces the need for extra food. Those who are underinsulinised may experience an excessive release of counter-regulatory hormones during physical activity. This may increase already high levels of glucose and ketones and can even precipitate ketoacidosis.3 Therefore, it is recommended that children with type 1 diabetes should avoid physical activity if blood glucose levels are >15 mmol/L especially if ketosis is present.2 Long-term Effects Regular physical activity in children and adolescents with type 1 diabetes can improve aerobic capacity6-8 and muscle strength;7 however the reported effect of physical activity on glycaemic control (measured by HbA1c) varies. One small RCT (n=9) showed an improvement in HbA1c with regular sustained physical activity compared with 30 minutes vigorous physical activity three times per week (HbA1c 11.3% versus 13.3%); however this group of patients was in very poor metabolic control.8 Another small study (n=12) found that the HbA1c in both ‘poorly’ (HbA1c >9%) and ‘well’ controlled (HbA1c <9%) diabetic patients was not affected by 12 weeks of supervised training.6 During the ensuing 12 week period of unsupervised training, any improvement in aerobic capacity decreased to pre-training levels suggesting that compliance with unsupervised training was poor.6 In a third study of a 12 week physical activity program, the HbA1c of subjects with type 1 diabetes was reduced (only in those with poor glycaemic control) by 1% (p <.05).7 The Evidence The evidence for the long term effects of physical activity in children and adolescents with type 1 diabetes is listed in Evidence Table 8.1.6-8 • Regular physical activity in children and adolescents with type 1 diabetes can improve aerobic capacity6-8 and muscle strength;7 however the reported effect of physical activity on glycaemic control (measured by HbA1c) varies. (II, IV) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 8.2. Chapter 8: Physical Activity Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 100 • The role of physical activity in health promotion and disease prevention has been emphasised by the World Health Organization.1(T) There are no published studies which indicate that these benefits are changed by having type 1 diabetes.2(T) Recommendations and Principles • Physical activity should be considered part of diabetes management. Children and adolescents with type 1 diabetes should be encouraged to participate in a variety of sport and physical activity and not be limited in their choice of activity.4(C) • Regular physical activity in children and adolescents with type 1 diabetes should be encouraged as it can improve aerobic capacity6-8 and muscle strength;7 however the reported effect of physical activity on glycaemic control (measured by HbA1c) varies.(II,IV) • Activities should be approached with caution if they are solo in nature, take place in water or mid-air, or limit the individual’s ability to recognise and self-treat hypoglycaemia and a ‘buddy’ is recommended.4(C) 2 • Blood glucose levels need to be measured before, during and after physical activity. (C) • Physical activity may necessitate extra carbohydrate intake and insulin reduction. Experience and blood glucose monitoring help determine the most appropriate strategies as the requirements vary for each individual.2(C) • All children and adolescents participating in sport should have access to assistance from a person aware of the management of hypoglycaemia.(C) • A general recommendation is that 15 gm of easily consumed and quickly absorbed carbohydrate or an extra serving should be taken for every 30 minutes of moderate to intensive sport or physical activity.(C) 2;9 • Extra carbohydrate should be consumed if blood glucose level is <7 mmol/L. (C) • Strenuous physical activity should be avoided if blood glucose levels are >15 mmol/L especially if ketones are present.9(C) C = Consensus statement endorsed by professional organisations T = Technical Report Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. WHO Technical Report Series. Diet, Nutrition and the Prevention of Chronic Disease. Report of a Joint WHO/FAO Expert Consultation. 2003. National Institute for Clinical Excellence. Type 1 Diabetes (Childhood): Diagnosis and Management of Type 1 Diabetes in Children and Young). 2004. American Diabetes Association: Physical Activity/Exercise and Diabetes Mellitus. Diabetes Care 26:73S-777, 2003 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Australian Diabetes Society. ADS Position Statements: SCUBA Diving. Hazel J. 1994. Westmead, NSW. Roberts L, Jones TW, Fournier PA: Exercise training and glycemic control in adolescents with poorly controlled type 1 diabetes mellitus. Journal of Pediatric Endocrinology & Metabolism 15:621-627, 2002 Mosher PE, Nash MS, Perry AC, LaPerriere AR, Goldberg RB: Aerobic circuit exercise training: effect on adolescents with wellcontrolled insulin-dependent diabetes mellitus. Archives of Physical Medicine & Rehabilitation 79:652-657, 1998 Campaigne BN, Gilliam TB, Spencer ML, Lampman RM, Schork MA: Effects of a physical activity program on metabolic control and cardiovascular fitness in children with insulin-dependent diabetes mellitus. Diabetes Care 7:57-62, 1984 Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Chapter 8: Physical Activity Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 101 Chapter 9: Diabetic Ketoacidosis The following guidelines for the management of diabetic ketoacidosis take into account the conclusions of a consensus statement resulting from a workshop that took place in the United Kingdom involving the European Society for Paediatric Endocrinology (ESPE) and the Lawson Wilkins Pediatric Endocrine Society (LWPES). The Consensus statement was developed with close partnership between the ESPE and LWPES and the International Society for Pediatric and Adolescent Diabetes (ISPAD), all three organisations being represented by members who participated in the writing process. The statement was also endorsed by and contributed to by related organisations; the Juvenile Diabetes Research Foundation International (JDRFI), the World Federation of Pediatric Intensive and Critical Care Societies, the European Society for Pediatric Critical Care, the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) and the Australian Pediatric Endocrine Group (APEG) were represented by invited participants.1 Definition and Aetiology Diabetic ketoacidosis is a life-threatening disorder that is due to decreased effective circulating insulin concentration,2 in association with insulin resistance3;4 and increased production of counter-regulatory hormones such as glucagon, catecholamines, cortisol and growth hormone.5-8 The hormonal changes cause: • Increased hepatic and renal glucose production and impaired peripheral glucose utilisation, leading to hyperglycaemia and hyperosmolality. • Increased lipolysis and unrestrained production of ketoacids (betahydroxybutyrate and acetoacetate),9 resulting in ketonaemia and eventual metabolic acidosis. Hyperglycaemia leads to osmotic diuresis, loss of electrolytes and dehydration, which can exacerbate the metabolic acidosis.10 The biochemical criteria for the diagnosis of diabetic ketoacidosis include: • Hyperglycaemia, defined by a blood glucose (BG) level >11 mmol/L. • Venous pH <7.3 • Bicarbonate <15 mmol/L. Rarely, young or partially treated children and pregnant adolescents may present in diabetic ketoacidosis with near-normal glucose values (‘euglycaemic ketoacidosis’).10 Diabetic ketoacidosis may be classified by the severity of the acidosis: • Mild (venous pH 7.25 to 7.30, bicarbonate concentration 10-15 mmol/L). • Moderate (pH 7.1 to 7.24, bicarbonate 5-10 mmol/L). 10 • Severe (pH <7.1, bicarbonate <5 mmol/L). Diabetic ketoacidosis is usually associated with at least 5% dehydration, vomiting and/or drowsiness. Factors associated with diabetic ketoacidosis in children with newly diagnosed type 1 diabetes include younger age (those aged less than five years are at greatest risk),11 children without a first degree relative with type 1 diabetes,12 and those from families of lower socioeconomic status.2;11;13 High dose glucocorticoids,14 antipsychotics,16 diazoxide and Chapter 9: Diabetic Ketoacidosis Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 102 immunosuppressive drugs have been reported to precipitate diabetic ketoacidosis in individuals not previously diagnosed with type 1 diabetes. Diabetic ketoacidosis has been reported in at least 25% of children with newly diagnosed type 2 diabetes.17;18 The risk of diabetic ketoacidosis in established type 1 diabetes is increased in children and young people with poor metabolic control or previous episodes of diabetic ketoacidosis.11;15 The most common precipitating factors in the development of diabetic ketoacidosis include infection,10;19 often as a result of inadequate insulin therapy during intercurrent illness and insulin omission.11;20-22 Adolescent girls,23-25 children with psychiatric disorders,25;26 such as eating disorders, and those from families of lower socio-economic status are also at increased risk.22;27 Diabetic ketoacidosis is rare in children whose insulin is administered by a responsible adult.21 Furthermore, after medical and educational interventions, metabolic control improved and diabetic ketoacidosis decreased.21 Diabetic ketoacidosis has been reported in association with continuous subcutaneous insulin infusion (CSII), as inappropriate interruption of insulin pump therapy can precipitate diabetic ketoacidosis.11;28;29 Recent studies, however, have failed to find an increased risk of diabetic ketoacidosis in patients treated with CSII.30;31 Children and adolescents are advised to have needles and syringes in reserve in case of insulin pump malfunction. Epidemiology The frequency of diabetic ketoacidosis ranges from 16%-80% of children newly diagnosed with diabetes, depending on geographic location.13;32;33 Diabetic ketoacidosis is the leading cause of morbidity and is the most common cause of diabetes-related deaths in children and adolescents with type 1 diabetes.34 Mortality is predominantly due to cerebral oedema which occurs in 0.3% to 1% of all episodes of diabetic ketoacidosis.35;36 The aetiology and pathophysiology of cerebral oedema are poorly understood. Factors associated with cerebral oedema include: 35;37;39 • Newly diagnosed type 1 diabetes. 37;38;39 • Younger age. 39 • Longer duration of symptoms. 36 • Indices of greater severity of diabetic ketoacidosis, such as dehydration and acidosis. • During treatment of diabetic ketoacidosis, a smaller rise in measured serum sodium concentration.36;40-42 Specifically, elevated blood urea at presentation of diabetic ketoacidosis has been associated with increased risk of cerebral oedema,36 which probably reflects greater dehydration. The severity of acidosis correlates with risk of cerebral oedema43 and bicarbonate treatment for correction of acidosis has also been associated with an increased risk of cerebral oedema.36;44 Furthermore, after adjusting for the degree of acidosis, more severe hypocapnia at presentation of diabetic ketoacidosis has been associated with cerebral oedema in two studies.36;45 In contrast, an association between volume or sodium content of intravenous fluids, and risk of cerebral oedema has not been found.36;39;42;45;46 Therefore, the association between sodium change and cerebral oedema may be a consequence of cerebral salt wasting rather than excessive fluid administration. Neither degree of hyperglycaemia at presentation nor rate of change in serum glucose during treatment of diabetic ketoacidosis have been associated with an increased risk of cerebral oedema.36;45 Chapter 9: Diabetic Ketoacidosis Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 103 Management Whenever possible a specialist/consultant paediatrician with training and expertise in the management of diabetic ketoacidosis should direct management. The child should also be cared for in a unit that has: • Experienced nursing staff trained in monitoring and management of diabetic ketoacidosis. • Clear written guidelines for managing diabetic ketoacidosis. • Access to laboratories that can provide frequent and accurate measurement of biochemical variables. Children with signs of severe diabetic ketoacidosis (long duration of symptoms, circulatory compromise, depressed level of consciousness) or those who may be at increased risk for cerebral oedema (<5 years of age, new onset, high blood urea, low pCO2) should be considered for immediate treatment in an intensive care unit47 (paediatric if available) or a children’s ward specialising in diabetes care with equivalent resources and supervision. It may be possible to manage children with ketosis and hyperglycaemia at home or in an ambulatory health care setting (such as an emergency ward) if they are not vomiting. The response to treatment should be evaluated frequently (2-4 hourly). If ketosis is not corrected by oral hydration and subcutaneous insulin within 12 hours, the child should be re-evaluated and the need for IV fluids, insulin and admission to hospital should be reviewed.48;73 Steps in the Assessment and Management of Diabetic Ketoacidosis The following steps are involved in the management of diabetic ketoacidosis: • Clinical assessment. • Resuscitation. • Investigation. • Monitoring. • Rehydration. • Sodium replacement. • Potassium replacement. • Insulin treatment. • Management of cerebral oedema if present. • Management of the recovery phase. Chapter 9: Diabetic Ketoacidosis Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 104 Algorithm for the Management of Diabetic Ketoacidosis IMMEDIATE ASSESSMENT Clinical History Polyuria, polydipsia Weight loss (weigh patient) Abdominal pain Tiredness Vomiting Confusion Clinical Assessment Assess hydration, perfusion, BP, GCS Deep sighing respiration (Kussmaul) Smell of ketones Lethargy/drowsiness ± vomiting Investigations Venous blood gas, FBC, electrolytes, urea, creatinine, other investigations as indicated Biochemical signs of DKA include: • Ketonuria/ketonaemia • Blood glucose level >11mol/L • pH <7.25, Bicarb <15 mmol/L CONFIRMED DIAGNOSIS OF DIABETIC KETOACIDOSIS Contact Senior Staff Shock (reduced peripheral pulses) Reduced conscious level Coma Resuscitation Airway ± insert NG tube Breathing (100% O2) Circulation (Saline 0.9% 10-20 ml/kg over 1-2 hours (may need to repeat until circulation restored) Dehydration >5% but not in shock Clinically acidotic (hyperventilation) Vomiting IV Therapy Calculate fluid requirements Correct over 48 hours Use Saline 0.9% as initial fluid Monitor ECG for elevated T-waves Add KCL 40 mmol per litre fluid Mild DKA (pH 7.25 to 7.3) Clinically well Tolerating fluids orally Therapy Start with SC insulin Continue oral hydration No improvement Low-dose continuous INSULIN INFUSION 0.1unit/kg/hour (consider 0.05 U/kg/h for young child) Critical Observations Hourly blood glucose level, RR, HR, BP Hourly accurate fluid input & output (insert urinary catheter if conscious state impaired) Neurological status at least hourly Electrolytes and blood gas 2-4 hourly after start of IV therapy Monitor ECG for T-wave changes Acidosis not improving Re-evaluate IV fluid calculations Insulin delivery systems & dose Need for additional resuscitation Consider sepsis When blood glucose < 15 mmol/L or blood glucose falls > 5 mmol/hour IV Therapy Change to Saline 0.45% + Glucose 5% Adjust insulin infusion (not <0.05 U/kg/h) Adjust sodium infusion to promote an increase in serum sodium Improvement Clinically well, tolerating oral fluids Source: adapted from ISPAD guidelines Transition to SC Insulin Start SC Insulin then Stop IV insulin 90 mins later Chapter 9: Diabetic Ketoacidosis Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Signs of neurological deterioration Headache, slowing of heart rate, irritability, decreased conscious level, incontinence, specific neurological signs Exclude Hypoglycaemia Is it cerebral oedema? Management Give Mannitol 0.25-1.0 g/kg Restrict IV fluids Call senior staff Move to Intensive Care Consider cranial CT/MRI only after patient stabilised 105 Clinical Assessment The diagnosis and clinical assessment of diabetic ketoacidosis should be confirmed with the following: • Characteristic history of polydipsia and polyuria, which may be absent in the young child. • Full physical examination, including weight (where possible), BP, assessment for evidence of acidosis (hyperventilation), assessment of conscious level (Glasgow Coma Score) and severity of dehydration. 5% (reduced skin turgor, dry mucous membranes, tachycardia, tachypnoea). 10% (capillary return 3 seconds or more, sunken eyes). >10% (shock, poor peripheral pulses, hypotension, oliguria). Note: Volume deficit is difficult to assess accurately in diabetic ketoacidosis, particularly in the young child, and may be overestimated because of the subjective criteria used.49 Shock with haemodynamic compromise is uncommon in childhood diabetic ketoacidosis. • Biochemical confirmation: glycosuria, ketonuria, capillary BG level (which may be inaccurate in the setting of circulatory compromise and acidosis) and acid-base status. Resuscitation The following aspects need to be considered in the resuscitation of a child or adolescent with diabetic ketoacidosis: • Assess and maintain airway patency and breathing. • In severely shocked patients give 100% oxygen by facial mask. • If shocked initiate IV fluid administration and volume expansion immediately with an isotonic solution (0.9% saline). The volume and rate of administration depends on circulatory status; where necessary the volume is typically 10-20 ml/kg over 1-2 hours, which may be repeated as required. • Use crystalloid and not colloid. There are no data to support the use of colloids in preference to crystalloids in the treatment of diabetic ketoacidosis. • Insert a nasogastric tube in patients with impaired consciousness or recurrent vomiting to prevent aspiration of gastric contents. Investigation The following urgent baseline laboratory measurements should be ordered: • Blood glucose. • Blood electrolytes (calculate corrected sodium) (see correction formula for sodium replacement) and osmolality (calculate by 2 [Na+ + K+] + glucose). • Venous pH and acid base status (arterial blood gas if signs of shock are present). • Full blood count and haematocrit (the white blood cell count may be elevated due to stress and cannot be interpreted as a sign of infection). • Blood urea and creatinine (creatinine measurements may be spuriously raised by assay interference from ketones). • Urine microscopy and culture. • Blood cultures and chest x-ray if indicated. • Urinalysis for ketones (and/or blood ketones). Chapter 9: Diabetic Ketoacidosis Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 106 Monitoring The management of diabetic ketoacidosis in childhood is dependent on careful clinical observation of progress. Throughout treatment, hourly clinical observations, IV and oral medication, fluids and electrolytes, and laboratory results must be documented. Signs of severe diabetic ketoacidosis (long duration of symptoms, cardiovascular compromise, depressed level of consciousness) or increased risk for cerebral oedema (including <5 years of age, new onset) should prompt immediate consideration of treatment in an intensive care unit (paediatric if available) or in a children’s ward specialising in diabetes care with equivalent resources and supervision.47 Monitoring includes: • Hourly heart rate, respiratory rate, blood pressure. • 2nd to 4th hourly temperature. • Hourly accurate fluid input and output. If the level of consciousness is impaired, a urinary catheter may be necessary. Fluid balance should be reassessed regularly (at least 2nd hourly) because continuing polyuria may worsen dehydration. • Hourly or more frequent neurological observations for warning signs and symptoms of cerebral oedema. Headache. Inappropriate slowing of heart rate. Recurrence of vomiting. Change in neurological status (restlessness, irritability, increased drowsiness, incontinence) or specific neurological signs (such as cranial nerve palsies, pupillary response). Rising blood pressure, decreased oxygen saturation. Note: it may be difficult clinically to discriminate cerebral oedema from other causes of altered mental status. • Hourly capillary BG level measurement. Laboratory confirmation with venous glucose should be performed every 2 to 4 hours because capillary methods may be inaccurate in the presence of poor peripheral circulation and acidosis. • Laboratory investigations: 2 to 4 hourly electrolytes, urea, haematocrit, venous BG level and blood gases. In severe diabetic ketoacidosis it may be necessary to monitor electrolytes hourly. • In severe diabetic ketoacidosis, ECG monitoring may be helpful to assess T-waves for evidence of hyperkalaemia or hypokalaemia. • Urinalysis for ketones until negative. Rehydration Diabetic ketoacidosis is characterised by loss of water and electrolytes. The high effective osmolality of the extracellular fluid (ECF) compartment results in a shift of water from the intracellular fluid compartment (ICF) to the ECF. Elevated serum urea nitrogen and haematocrit may be useful markers of severe ECF contraction. Dehydration is associated with a reduction in glomerular filtration rate (GFR), leading to reduced glucose and ketone clearance, which potentiate diabetic ketoacidosis. Administration of IV fluid prior to insulin results in substantial falls in blood glucose, because the resultant increase in GFR leads to increased urinary glucose excretion.50;51 The aims of fluid and sodium replacement therapy in diabetic ketoacidosis are: Chapter 9: Diabetic Ketoacidosis Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 107 • • • • Restoration of circulating volume. Replacement of sodium and water deficits over at least 36-48 hours. Restoration of GFR with enhanced clearance of glucose and ketones from the blood. Avoidance of cerebral oedema, which may be caused by fluid shifts from the ECF to the ICF compartment. Following initial resuscitation, subsequent fluid management should be with 0.9% saline. If hypernatraemia is present consider the use of 0.45% saline. • As the severity of dehydration is difficult to determine and may be overestimated, daily fluid infusion rates should rarely exceed 1.5-2 times the usual daily requirement based on age, weight, or body surface area. • IV or oral fluids that were given before the initiation of hospital management should be included in calculations of deficit and replacement. Urinary losses should not be added to the initial calculation of replacement fluids. • The patient should remain ‘nil by mouth’ except for ice to suck. • Calculation of effective osmolality may be useful to guide ongoing fluid and electrolyte therapy. Sodium Replacement Measurement of serum sodium is an unreliable measure of the degree of ECF contraction and may be depressed due to the dilutional effect of hyperglycaemia and fluid shift from the ICF to the ECF. Corrected sodium concentration can be calculated as:52 • corrected sodium = sodium + [2 x (glucose - 5.5)] / 5.5 (all values in mmol/L) The calculation can be simplified to 2 mmol/L of sodium to be added for every 5.5 mmol/L of glucose above 5.5 mmol/L. Normal saline is used as the initial rehydration fluid. Effective osmolality (2 [Na+ + K+] + glucose) at the time of presentation is frequently in the range of 300-350 mOsm/L. If the corrected sodium is greater than 150 mmol/L, a hypernatraemic as well as an independent glucose hyperosmolar state exists and correction of dehydration and electrolyte imbalances should be over 48-72 hours. Normal Saline with 40 mmol/L KCl has an osmolality of 390 mOsm/L, which may exacerbate the hyperosmolar state. The continued use of large amounts of 0.9% Saline has also been associated with the development of hyperchloraemic metabolic acidosis.53 The use of hypotonic fluids, however, is associated with greater rises in intracranial pressure compared to isotonic fluids. Therefore, the use of solutions with salt content less than 0.45% NaCl, which contain a large amount of electrolyte free water, is likely to lead to a rapid osmolar change, movement of fluid into the ICF compartment and may increase the risk of cerebral oedema. The failure of the serum sodium to rise or development of hyponatraemia during IV fluid administration has been shown to precede cerebral oedema.41;42 Potassium Replacement Diabetic ketoacidosis in adults is associated with total body potassium deficits of approximately 3-6 mmol/kg, but data are lacking in children. Hypertonicity, insulin deficiency, and buffering of hydrogen ions within the cell lead to potassium loss. Serum potassium may be reduced, normal or elevated at the time of presentation. Hypokalaemia Chapter 9: Diabetic Ketoacidosis Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 108 may be related to prolonged duration of disease, whereas hyperkalaemia is due to reduced renal function. Administration of insulin and the correction of acidosis will drive potassium back into the cells, decreasing serum levels. The following issues need to be considered in potassium replacement: • Potassium should be added after restoring normal circulation, concurrent with starting insulin therapy. • Replacement therapy should be based on serum potassium measurements. If the patient is anuric (after passage of a catheter) or hyperkalaemic, defer potassium replacement until urine output is documented and electrolytes are available. If the patient is hypokalaemic, start potassium replacement immediately. • Commence replacement at a dose of 5 mmol/kg/day (40 mmol/L IV fluid). • Do not exceed a maximal potassium infusion rate of 0.5 mmol/kg/hour without consultation/cardiac monitoring. • Potassium replacement should continue throughout intravenous fluid therapy. • Potassium phosphate salts may be used as an alternative or in combination with potassium chloride/acetate to avoid hyperchloraemia; however administration of phosphate may induce hypocalcaemia54;55 and prospective studies have failed to show significant clinical benefit from phosphate replacement.56-58 Bicarbonate Replacement Severe acidosis is reversible by fluid and insulin replacement. Insulin administration arrests further synthesis of ketoacids and allows excess ketoacids to be metabolised. The metabolism of keto-anion results in the regeneration of bicarbonate and correction of acidaemia. Furthermore, treatment of hypovolaemia improves poor tissue perfusion and renal function, leading to excretion of organic acids and reversal of lactic acidosis, which may account for up to 25% of the acidaemia. Prospective controlled trials of sodium bicarbonate in small numbers of children and adults with diabetic ketoacidosis have failed to demonstrate a clinical benefit or harm.36;59;60 Bicarbonate therapy may cause paradoxical CNS acidosis and rapid correction of acidosis may cause hypokalaemia, accentuate sodium load and contribute to serum hypertonicity. Bicarbonate therapy may also increase hepatic ketone production, thus slowing the rate of recovery from the ketosis.61 No prospective randomised studies of patients with severe diabetic ketoacidosis (pH <6.9) have been reported. Some patients may benefit from cautious bicarbonate therapy, such as those with severe acidaemia (pH <6.9 ± serum bicarbonate <5 mmol/L), which causes decreased cardiac contractility, peripheral vasodilatation and impaired tissue perfusion, and patients with potentially life-threatening hyperkalaemia. If bicarbonate is given, it should be administered at a dose of 1-2 mmol/kg by an intravenous infusion over 60 minutes. Cardiac monitoring should be performed in these patients due to the risk of inducing hypokalaemia. Insulin Rehydration alone will decrease the BG level to some extent; however insulin therapy is required to normalise the BG level and to suppress lipolysis and ketogenesis. Insulin therapy offsets insulin resistance and inhibits lipolysis and ketogenesis; causing suppression of glucose production and stimulated peripheral glucose uptake. The resolution of acidaemia usually takes longer than normalisation of blood glucose concentrations. Although different Chapter 9: Diabetic Ketoacidosis Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 109 routes (SC, IM, IV) and doses have been used, there is considerable evidence to support the use of ‘low dose’ intravenous insulin.63-67 Outline of insulin treatment: • Insulin dose: 0.1 units/kg/hour by IV infusion. Consider 0.05u/kg/hr in the younger child. • BG level should fall by approximately 4-5 mmol/L per hour, but initial rehydration alone will cause the BG level to fall, so a greater drop in BG level can be accepted in the first few hours of treatment. • The dose of insulin should remain at 0.1 U/kg/hour at least until resolution of ketoacidosis (pH >7.30, HCO3 >15 mmol/L and/or closure of anion gap). • When the BG level falls to 15 mmol/L, glucose should be added to the IV fluid to prevent an unduly rapid decrease in plasma glucose concentration and possible development of hypoglycaemia. A solution of 0.45% saline and 5% dextrose (prepared by adding 25 ml of 50% dextrose to 500 ml of 0.45% saline and 2.5% dextrose) is commonly used. • In cases of hyponatraemia, IV fluid with a higher sodium content (for example, Normal Saline) may be used with dextrose added. • The insulin infusion rate and/or the dextrose infusion rate should then be adjusted to keep the BG level between 5-10 mmol/L. • The insulin infusion rate should only be decreased if the BG level remains below the target range despite dextrose supplementation. • Do not stop insulin infusion or decrease below 0.05 units/kg/hour because continuous supplies of both insulin and glucose substrate are required to promote anabolism and reduce ketosis. • If IV fluids are required after 24 hours 0.45% saline adjusted to 5% dextrose may be used. • If biochemical parameters of ketoacidosis (pH, anion gap) do not improve, reassess the patient, review insulin therapy, and consider other possible causes of impaired response to insulin (for example infection, errors in insulin preparation, adhesion of insulin to tubing with very dilute solutions). • In circumstances where IV administration is not possible, IM or SC insulin administration has been used effectively and has been demonstrated to be safe.68 It should be noted that poor perfusion will impair insulin absorption.69 The insulin infusion can be prepared by adding 50 units of short-acting or rapid-acting insulin to 500 ml of 0.9% saline, resulting in a solution containing 1 unit of insulin per 10 ml. The infusion may be run as a sideline with the rehydrating fluid, providing a volumetric pump is used. Some intensive care units prefer to use a more concentrated solution of insulin and a step syringe pump. If a volumetric pump is not available, a separate IV site may be required for low infusion rates. The insulin infusion and the giving set should be changed every 24 hours, due to the potential for insulin to denature. The insulin infusion must be clearly labelled so that confusion with the rehydrating solution does not occur. Management of Cerebral Oedema Treatment should be initiated as soon as the condition is suspected. Management should involve: • Reduction in the rate of fluid administration. Chapter 9: Diabetic Ketoacidosis Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 110 • Intravenous mannitol should be given (0.25-1.0g/kg over 20 mins) in patients with signs of cerebral oedema before impending respiratory failure. Although mannitol has been shown to have possible beneficial effects in case reports, there has been no definite beneficial or detrimental effect in epidemiological studies.37;70 Timing of administration (delayed administration being less effective) may alter the response. 71 • Repeat mannitol administration in 2 hours if there is no initial response. • Hypertonic saline (3%) 5-10 ml/kg over 30 mins may be an alternative to mannitol. Intubation and ventilation may be necessary, but aggressive hyperventilation has been associated with poor outcome in retrospective studies of diabetic ketoacidosis-related cerebral oedema.36 • The patient should be transferred to an intensive care facility and a neurological assessment and MRI or CT scan arranged. Management of the Recovery Phase Recovery management involves: • Transition from IV fluids and ‘nil by mouth’ to oral fluids. • Transition from continuous insulin infusion to subcutaneous insulin. Oral fluids • These should be introduced when the patient is metabolically stable (BG level <12 mmol/L, pH >7.30 and HCO3 >15 mmol/L). Low joule or low calorie fluids may be given by mouth as tolerated and should be included in the fluid balance calculations. Covering snacks and meals on intravenous insulin infusion • It is useful to maintain the insulin infusion until the child or adolescent has had at least one meal. • For snacks the basal infusion rate is doubled at the commencement of the snack and continued for the duration of the snack and 30 minutes afterwards before returning to the basal rate. • For main meals the basal infusion rate should be doubled at the commencement of the meal and continued at this rate for the duration of the meal and for 60 minutes after the meal. The infusion rate can then be returned to the basal rate. • The insulin infusion can be discontinued when the patient is alert and metabolically stable and when eating has been established. Transition from intravenous to subcutaneous insulin • The most convenient time to change to subcutaneous insulin is just before a mealtime. The subcutaneous insulin should be given 30 minutes before the meal (or immediately if rapid-acting insulin analogues are used). The insulin infusion should be continued throughout the meal for a total of 30-90 minutes after the subcutaneous insulin injection depending on the type of insulin used. The half-life of intravenous insulin is only 4.5 minutes; therefore it is important that the subcutaneous insulin is given before the infusion is ceased. • Short-acting insulin should be given 4 to 6 hourly, however the dose needs to be individualised on the basis of serial blood glucose levels. • The total daily dose required is at least 1 units/kg body weight/day, however this may need to be adjusted on the basis of previous insulin dosages. • Frequent monitoring in the post diabetic ketoacidosis interval is required to avoid hypoglycaemia.62 Chapter 9: Diabetic Ketoacidosis Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 111 • Various regimens may be used: The use of intermediate and short/rapid-acting insulin as a bd, tds or basal bolus regimen will depend on the patient’s age and local practices. Typically for a bd regimen the total insulin dose is approximately 1 unit per kg per day with _ given before breakfast and _ before the evening meal, the ratio being _ intermediateacting insulin and _ short/rapid-acting (for further details, see Chapter 5). The Evidence The evidence for the definition and aetiology of diabetic ketoacidosis is listed in Evidence Table 9.1. • Diabetic ketoacidosis is due to decreased effective circulatory insulin concentration in association with insulin resistance and increased production of counter-regulatory hormones.3-8(III-2) The evidence for the frequency of diabetic ketoacidosis is listed in Evidence Table 9.1. • The frequency of diabetic ketoacidosis ranges from 16 to 80% in children newly diagnosed with diabetes, depending on geographic location.13;32;33(IV) The evidence for the factors associated with diabetic ketoacidosis is listed in Evidence Table 9.1. • Factors associated with diabetic ketoacidosis in children with newly diagnosed type 1 diabetes include younger age (those aged less than five years are at greatest risk),11 children without a first degree relative with type 1 diabetes,12 and those from families of lower socioeconomic status.2;11;13(IV) • Diabetic ketoacidosis has been reported in at least 25% of children with newly diagnosed type 2 diabetes.17;18(IV) The evidence for the most common precipitating factors of diabetic ketoacidosis in established type 1 diabetes is listed in Evidence Table 9.1. • The risk of diabetic ketoacidosis in established type 1 diabetes is increased in children and young people with poor metabolic control or previous episodes of diabetic ketoacidosis.11;15 The most common precipitating factors in the development of diabetic ketoacidosis include infection, often as a result of inadequate insulin therapy during intercurrent illness and insulin omission. 10;11;19;20-22 Adolescent girls,23-25 children with psychiatric disorders,25;26 such as eating disorders, and those from families of lower socioeconomic status are also at increased risk.22;27(IV) • Diabetic ketoacidosis has been reported in early studies in association with continuous subcutaneous insulin infusion (CSII), as inappropriate interruption of insulin pump therapy can precipitate diabetic ketoacidosis.11;28;29 However, more recent studies have not documented an increased risk of diabetic ketoacidosis in patients treated with CSII.30;31(III2) The evidence for mortality in diabetic ketoacidosis and risk factors for cerebral oedema is listed in Evidence Table 9.1. • Diabetic ketoacidosis is the most common cause of death in newly diagnosed type 1 diabetes.10;11;22;34(IV) • The greatest risk of mortality from diabetic ketoacidosis is from cerebral oedema.10;11;22;35;36(IV) • Although poorly understood, the risk factors for cerebral oedema in diabetic ketoacidosis include presentation with new onset type 1 diabetes,35;37;39 younger age,37;38;39 elevated serum urea nitrogen and/or severity of dehydration at presentation, severity of acidosis,36;43 greater hypocapnia at presentation (after adjusting for degree of acidosis), an attenuated Chapter 9: Diabetic Ketoacidosis Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 112 rise in serum sodium during treatment for diabetic ketoacidosis36;40-42; bicarbonate treatment to correct acidosis has also been associated with cerebral oedema.36;44 (III/IV) Most studies have not found an association between cerebral oedema and degree of hyperglycaemia at presentation of diabetic ketoacidosis, rate of change of serum glucose during diabetic ketoacidosis treatment or volume or sodium content of intravenous fluids have.36;45;46(III/IV) The evidence for predictors of need for admission to hospital or ICU for management of diabetic ketoacidosis or ketosis with hyperglycaemia is listed in Evidence Table 9.1. • Children with signs of severe diabetic ketoacidosis (long duration of symptoms, circulatory compromise, depressed level of consciousness) or those who may be at increased risk for cerebral oedema (<5 years of age, new onset, high blood urea, low pCO2) should be considered for immediate treatment in an intensive care unit47 (paediatric if available) or a children’s ward specialising in diabetes care with equivalent resources and supervision.(IV) • It may be possible to manage children with ketosis and hyperglycaemia at home or in an ambulatory health care setting (such as an emergency ward) if they are not vomiting.48;73(IV) The evidence for difficulties in assessing dehydration in diabetic ketoacidosis is listed in Evidence Table 9.1. • Volume deficit is difficult to assess accurately in diabetic ketoacidosis, particularly in the young child, and may be overestimated because of the subjective criteria used.49(III-3) The evidence for issues in the management of diabetic ketoacidosis is listed in Evidence Table 9.1. 53 • Hyperchloraemic acidosis and Sodium replacement. (III-2) • Potassium phosphate salts may be used as an alternative or in combination with potassium chloride/acetate to avoid hyperchloraemia; however administration of phosphate may induce hypocalcaemia54;55(IV) and prospective studies have failed to show significant clinical benefit from phosphate replacement.56-58(III-1) • Prospective controlled trials of sodium bicarbonate in small numbers of children and adults with diabetic ketoacidosis have failed to demonstrate a clinical benefit or harm. 36;59;60 Furthermore, bicarbonate therapy may cause paradoxical CNS acidosis and rapid correction of acidosis may cause hypokalaemia, accentuate sodium load and contribute to serum hypertonicity. Bicarbonate therapy may also increase hepatic ketone production, thus slowing the rate of recovery from the ketosis.61(III-1) • Although different routes (SC, IM, IV) and doses have been used, there is considerable evidence to support the use of ‘low dose’ intravenous insulin.63-67(II) • In circumstances where IV administration is not possible, IM or SC insulin administration has been used effectively and has been demonstrated to be safe.68 It should be noted that poor perfusion will impair insulin absorption.69(II) The evidence for the management of cerebral oedema in diabetic ketoacidosis is listed in Evidence Table 9.1. • Intravenous mannitol should be given (0.25-1.0g/kg over 20 mins) in patients with signs of cerebral oedema before impending respiratory failure. Although mannitol has been shown to have possible beneficial effects in case reports, there has been no definite beneficial or detrimental effect in epidemiological studies.37;70(IV) 71 • Repeat mannitol administration in 2 hours if there is no initial response. (IV) Chapter 9: Diabetic Ketoacidosis Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 113 • Hypertonic saline (3%) 5-10 ml/kg over 30 mins may be an alternative to mannitol. Intubation and ventilation may be necessary, but aggressive hyperventilation has been associated with poor outcome in retrospective studies of diabetic ketoacidosis-related cerebral oedema.36(III-3) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence table 9.2. • The guidelines for the management of diabetic ketoacidosis take into account the conclusions of a consensus statement resulting from a workshop that took place in the United Kingdom involving the European Society for Paediatric Endocrinology (ESPE) and the Lawson Wilkins Pediatric Endocrine Society (LWPES). The Consensus statement was developed with close partnership between the ESPE and LWPES and the International Society for Pediatric and Adolescent Diabetes (ISPAD), all three organisations being represented by members who participated in the writing process. The statement was also endorsed by and contributed to by related organisations; the Juvenile Diabetes Research Foundation International (JDRFI), the World Federation of Pediatric Intensive and Critical Care Societies, the European Society for Pediatric Critical Care, the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) and the Australian Pediatric Endocrine Group (APEG).1 • The American Diabetes Association has produced a position statement on hyperglycaemic crises in patients with diabetes mellitus.10 Recommendations and Principles • The guidelines for the management of diabetic ketoacidosis should take into account the conclusions of a consensus statement resulting from a workshop that took place in the United Kingdom in June 2003 involving the European Society for Paediatric Endocrinology (ESPE), the Lawson Wilkins Pediatric Endocrine Society (LWPES) and other societies including the Australasian Paediatric Endocrine group (APEG).1(C) • The most common precipitating factors in the development of diabetic ketoacidosis include infection, often as a result of inadequate insulin therapy during intercurrent illness and insulin omission.10;11;19;20-22(IV) • Diabetic ketoacidosis is the most common cause of death in newly diagnosed type 1 diabetes.10;11;22;34(IV) • The greatest risk of mortality from diabetic ketoacidosis is from cerebral oedema.10;11;22;35;36(IV) • Although poorly understood, the risk factors for cerebral oedema in diabetic ketoacidosis include presentation with new onset type 1 diabetes,35;37;39 younger age,37;38;39 elevated serum urea nitrogen and/or severity of dehydration at presentation, severity of acidosis,36;43 greater hypocapnia at presentation (after adjusting for degree of acidosis), an attenuated rise in serum sodium during treatment for diabetic ketoacidosis36;40-42; bicarbonate treatment to correct acidosis has also been associated with cerebral oedema.36;44(III,IV) • Immediate assessment for diabetic ketoacidosis should consist of clinical history, assessment and biochemical confirmation (see algorithm).72(C) • ‘Low dose’ intravenous insulin is recommended for the treatment of moderate to severe diabetic ketoacidosis. 1(C) • A specialist/consultant paediatrician with training and expertise in the management of diabetic ketoacidosis should direct management.1(C) • The child should be cared for in a unit that has experienced nursing staff trained in monitoring and management of diabetic ketoacidosis, clear written guidelines for Chapter 9: Diabetic Ketoacidosis Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 114 managing diabetic ketoacidosis and access to laboratories that can provide frequent and accurate measurement of biochemical variables.1(C) • Children with ketosis and hyperglycaemia, but who are not vomiting, may be managed at home or in an ambulatory care setting (such as an emergency ward). 48;73(IV) • Children with signs of severe diabetic ketoacidosis or those who may be at increased risk for cerebral oedema should be considered for immediate treatment in an intensive care unit (paediatric if possible) or a children’s ward specialising in diabetes care.(C) • The management of cerebral oedema in diabetic ketoacidosis is a medical emergency and treatment (fluid restriction, mannitol, neurological assessment) should be initiated in an intensive care facility as soon as the condition is suspected.37;70(IV) II = Evidence from at least one properly-designed RCT III-1 = Evidence from well-designed pseudo-randomised controlled trials (alternate allocation or some other method). III-2 = Evidence from comparative studies with concurrent controls and allocation, non-randomised (cohort studies), casecontrol studies, or interrupted time series with a control group III-3 = Evidence from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group IV = Evidence obtained from case series, either post-test or pre-test and post-test C = Consensus statement endorsed by professional organisations Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. Dunger DB, Sperling MA, Acerini CL, Bohn DJ, Daneman D, Danne TPA, Glaser NS, Hanas R, Hintz RL, Levitsky LL, Savage MO, Tasker RC, Wolfsdorf JI: ESPE / LWPES consensus statement on diabetic ketoacidosis in children and adolescents. 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Annuls of Internal Medicine 152:2472-2477, 1992 Kitabchi AE, Ayyagari V, Guerra SM: The efficacy of low-dose versus conventional therapy of insulin for treatment of diabetic ketoacidosis. Annals of Internal Medicine 84:633-638, 1976 Edwards GA, Kohaut EC, Wehring B, Hill LL: Effectiveness of low-dose continuous intravenous insulin infusion in diabetic ketoacidosis. A prospective comparative study. Journal of Pediatrics 91:701-705, 1977 Drop SL, Duval-Arnould JM, Gober AE, Hersh JH, McEnery PT, Knowles HC: Low-dose intravenous insulin infusion versus subcutaneous insulin injection: a controlled comparative study of diabetic ketoacidosis. Pediatrics 59:733-738, 1977 Baum JD, Jenkins P, Aynsley-Green A: Immediate metabolic response to a low dose of insulin in children presenting with diabetes. Archives of Disease in Childhood 50:373-378, 1975 Burghen GA, Etteldorf JN, Fisher JN, Kitabchi AQ: Comparison of high-dose and low-dose insulin by continuous intravenous infusion in the treatment of diabetic ketoacidosis in children. Diabetes Care 3:15-20, 1980 Umpierrez GE, Latif KA, Cuervo R, Karabell A, Kitabchi AE: Subcutaneous Aspart Insulin: A Safe and Cost Effective Treatment for Diabetic Ketoacidosis (Abstract). Diabetes 52:A139, 2003 Soler NG, FitzGerald MG, Wright AD, Malins JM: Comparative study of different insulin regimens in management of diabetic ketoacidosis. Lancet 2:1221-1224, 1975 Franklin B, Liu J, Ginsberg-Fellner F: Cerebral edema and ophthalmoplegia reversed by mannitol in a new case of insulindependent diabetes mellitus. Pediatrics 69:87-90, 1982 Curtis JR, Bohn D, Daneman D: Use of hypertonic saline in the treatment of cerebral edema in diabetic ketoacidosis (DKA). Pediatric Diabetes 2(4):191-4, 2001 International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Linares MY, Schunk JE, Lindsay R: Laboratory presentation in diabetic ketoacidosis and duration of therapy. Pediatric Emergency Care 12:347-351, 1996 Chapter 9: Diabetic Ketoacidosis Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 117 Chapter 10: Surgery and Fasting Surgery on children with diabetes should only be undertaken in hospitals with dedicated paediatric facilities for the care of children with diabetes and expert staff (medical, anaesthetic, surgical and nursing). Children with diabetes requiring a surgical procedure need insulin, even if fasting, to avoid ketoacidosis. They may have increased insulin requirements peri-operatively due to physiological stress and increased counter-regulatory hormones.1-3 When fasting before an anaesthetic an intravenous glucose infusion should be commenced to prevent hypoglycaemia. Paediatric patients particularly those under the age of 5 years old may be prone to hypoglycaemia during anaesthesia and surgery.4;5 Emergency Surgery Unless it is absolutely clinically indicated, emergency surgery should be delayed in any patient with ketoacidosis until diabetes control has improved and the diabetes stabilised. Diabetic ketoacidosis may by itself cause an acute abdomen, which resolves with treatment of the ketoacidosis. Elective Surgery Elective surgery should only be performed in a child or adolescent whose diabetes is under good control. If glycaemic control is uncertain or poor: • The child or adolescent should enter hospital beforehand for assessment and stabilisation of metabolic control. • If control remains poor, surgery should be cancelled and re-booked. Scheduling of Surgery Operations should be scheduled early in the morning if possible. If surgery cannot be scheduled for the morning, the patient with diabetes should be first on the afternoon list. This will allow post-operative stabilisation during the day shift. Maintaining Metabolic Control Any patient with diabetes who is undergoing prolonged fasting requires: • Continuous intravenous glucose. • Hourly blood glucose monitoring in order to maintain blood glucose levels of 5-10 mmol/L. • Adequate insulin replacement. The management of diabetes during surgery or procedures that require fasting is complex and exacting. There are different approaches and each case must be judged on its own merits. The suggested protocols below have been shown to be efficacious but do not imply that other protocols when carried out by physicians expert in the care of childhood and adolescent diabetes cannot be used or are in any way less efficacious. In children and adolescents with type 1 diabetes the optimal method of maintaining metabolic control during major surgery or prolonged post-operative fasting is by an insulin infusion,3 Chapter 10: Surgery and Fasting Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 118 which should be started in association with a maintenance saline/dextrose infusion when fasting commences. Blood glucose levels must be done hourly whilst on an insulin infusion. Other tests such as electrolytes, blood gases and additional parameters will be determined by the underlying clinical condition. Intravenous Fluids Intravenous fluid should commence at maintenance rates (see Table 9.1) when fasting begins. The intravenous fluids should contain 5 percent dextrose (50 gm/L) initially. This can be made by adding 25 ml of 50% dextrose to 500 ml of N/2 Saline + 2.5% dextrose, or by adding 12.5 ml of 50% dextrose to 500 ml of N/4 + 3.75% dextrose. The glucose concentration of the fluids can be increased if required. An alternative fluid schedule, which does not vary with age, is to use 1500 ml/m2/24 hours. Table 10.1: Maintenance Fluid Volume for Different Age Groups6 Age Group ml/kg/day Up to 9 months 120-140 12 months 90-100 2 years 80-90 4 years 70-80 8 years 60-70 12 years 50-60 Management of Short or Minor Procedures Involving Sedation or Anaesthesia Patients on twice or three times daily insulin regimens Procedure first on morning list For short procedures involving sedation or anaesthesia, it may be possible to simplify the management of the diabetes by strategies such as: Option 1: Arrange for the procedure to be performed at 8 am and delaying the morning insulin (and giving a reduced dose) until food is allowed (providing food is tolerated before 10 am). Hourly monitoring of the blood glucose levels is still required. Intravenous glucose will usually be required but may not be required if the procedure is short and the blood glucose is maintained. If food is not tolerated by 10 am, short/rapid-acting insulin will need to be started by infusion or subcutaneous injections, in addition to the glucose infusion and frequent monitoring. Option 2: Give a reduced morning insulin dose at about 7am (50-60% of the usual intermediate insulin dose, no short/rapid-acting unless blood glucose level is high).6 Commence IV fluids at the same time (N/2 Saline + 5% dextrose, or N/4 + 5% dextrose). Perform hourly blood glucose readings and increase glucose concentration of IV fluids to 7.5% or 10% if required.6 Extra mid-morning short/rapid-acting insulin may be given if required (10-25% of total daily dose).6 Chapter 10: Surgery and Fasting Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 119 Cease IV fluids once oral intake resumes. The usual doses of evening insulin can be given if eating normally.6 Procedures first on afternoon list If breakfast is not allowed follow the advice below for ‘major surgery where oral intake is not possible for prolonged period’. If breakfast is allowed give a reduced morning insulin dose prior to breakfast (30-40% of usual intermediate-acting insulin and 50% of usual short/rapid-acting insulin, depending on BG level). Commence IV fluids 2 hours after breakfast (N/2 Saline + 5% dextrose, or N/4 + 5% dextrose) at maintenance rates. Perform hourly blood glucose readings and increase glucose concentration of IV fluids to 7.5% or 10% if required.6 Extra mid-morning short/rapid-acting insulin may be given if required (10-25% of total daily dose).6 Post-operatively, IV fluids can be ceased once oral intake resumes and additional doses of short/rapid-acting insulin given if required. The usual dose of evening insulin can be given if eating normally. Otherwise a reduced dose should be given.6 Patients on basal-bolus insulin regimens Procedures first on morning list Consider the need for reduction (by 20-30%) of evening intermediate acting insulin if there is a pattern of low blood glucoses in the morning.6 At 7am give 40-50% of the usual short/rapid-acting insulin and commence IV fluids (containing 5% dextrose).6 Perform hourly blood glucose readings and increase glucose concentration of IV fluids to 7.5% or 10% if required.6 Extra mid-morning short/rapid-acting insulin may be given if required (10-25% of total daily dose).6 6 Usually resume normal food and insulin from lunch. Procedures first on afternoon list 6 The patient is usually allowed breakfast. 6 At 7am give 50-60% of the usual short/rapid-acting insulin. Commence IV fluids (containing 5% dextrose) at maintenance rates 2 hours after breakfast.6 6 At 12noon give about 10% of the total daily dose of short/rapid-acting insulin. Perform hourly blood glucose readings and increase glucose concentration of IV fluids to 7.5% or 10% if required.6 Postoperatively, additional short/rapid-acting insulin may be required (usually 10% of the total daily dose as needed 4-hourly),6 until normal eating is resumed. 6 Give the usual insulin and food at dinner and supper. Patients on insulin pumps The diabetes team will determine the approach depending on the individual patient and procedure Minor procedures: The pump can be continued at the basal rate, keeping glucose infusion to a minimum. Monitor blood glucose levels hourly. Correction doses can be given preoperatively and postoperatively as needed and carbohydrate boluses when the Chapter 10: Surgery and Fasting Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 120 patient is ready to eat. Alternatively the pump can be discontinued preoperatively and a basal-bolus regimen instituted with adjustment as above.6 Major procedures: The subcutaneous insulin pump is discontinued and an IV insulin infusion used.6 Major Surgery or Surgery where Oral Intake is not Possible for a Prolonged Period • Commence insulin infusion (see below) and intravenous fluids (containing 5% dextrose) at maintenance rate. • Hourly BG levels must be done while on an insulin infusion. • Maintain BG level between 5-10 mmol/L by adjusting the rate of the insulin infusion by 10% increments as required.6 Insulin Infusion Rates Short-acting insulin should be administered as a separate intravenous infusion and diluted in 0.9 percent Saline solution (50 units of insulin in 500 ml of 0.9 percent Saline - equivalent to 1 unit of insulin per 10 ml Saline). The insulin infusion should be run through a volumetric pump at an initial maintenance rate of 0.02 unit/kg/hr in a line separate from the hydration fluid.6 Another protocol is to infuse the insulin at a rate of 0.15 unit/gram of glucose in the maintenance fluids per hour.6 However, whatever the protocol used, the insulin dosage must be adjusted according to individual requirements. The blood glucose levels are maintained between 5-10 mmol/L by adjusting the rate of the insulin infusion by increments of 10 percent. The insulin infusion therapy is continued until oral food intake has been established and subcutaneous insulin therapy is possible. The subcutaneous insulin should be given 30 minutes before the meal (or immediately if rapid-acting insulin analogues are used). The insulin infusion should be continued throughout the meal for a total of 30-90 minutes after the subcutaneous insulin injection depending on the type of insulin used.6 The Evidence The evidence for the management of surgery and fasting in children and adolescents with type 1 diabetes is listed in Evidence Table 10.1. • Children and adolescents with type 1 diabetes have increased insulin requirements perioperatively.3(III-3) • In children and adolescents with type 1 diabetes peri-operative management with an insulin infusion results in better blood glucose control than subcutaneous insulin injection.3(III-3) Additional Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 10.2. Recommendations and Principles • Surgery on children with diabetes should only be undertaken in hospitals with dedicated paediatric facilities for the care of children with diabetes and expert staff (medical, anaesthetic, surgical and nursing).7;8(C) • When fasting before an anaesthetic an intravenous glucose infusion should be commenced to prevent hypoglycaemia.7;8(C) Chapter 10: Surgery and Fasting Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 121 • Children with type 1 diabetes requiring a surgical procedure should receive insulin, even if fasting, to avoid ketoacidosis. There may be increased insulin requirements perioperatively due to physiological stress and increased counter-regulatory hormones.3(III-3) • In children and adolescents with type 1 diabetes the optimal method of maintaining metabolic control during major surgery or prolonged post-operative fasting is by an insulin infusion.3(III-3) III-3 = Evidence obtained from comparative studies with historical control, two or more single arm studies, or interrupted time series without a parallel control group C = Consensus statement endorsed by professional organisations Reference List 1. 2. 3. 4. 5. 6. 7. 8. Raucoules-Aime M, Roussel LJ, Rossi D, Gastaud P, Dolisi C, Grimaud D: Effect of severity of surgery on metabolic control and insulin requirements in insulin-dependent diabetic patients. BJA: British Journal of Anaesthesia 74:231-233, 1995 Thomas DJ, Platt HS, Alberti KG: Insulin-dependent diabetes during the peri-operative period. An assessment of continuous glucose-insulin-potassium infusion, and traditional treatment. Anaesthesia 39:629-637, 1984 Kaufman FR, Devgan S, Roe TF, Costin G: Perioperative management with prolonged intravenous insulin infusion versus subcutaneous insulin in children with type I diabetes mellitus. Journal of Diabetes & its Complications 10:6-11, 1996 Kirschner RM: Diabetes in pediatric ambulatory surgical patients. Journal of Post Anesthesia Nursing 8:322-326, 1993 Kelly JU, Kelly TJ: Insulin-dependent diabetes. Its effect on the surgical patient. Association of Operating Room Nurses Journal 54:61-68, 1991 Endocrinology and Diabetes. In The Children's Hospital at Westmead handbook: clinical practice guidelines in paediatrics. 4th ed. Henry Kilham, David Isaacs, Eds. Sydney, McGraw-Hill Australia Pty Ltd, 186-216, 2004 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Chapter 10: Surgery and Fasting Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 122 Chapter 11: Sick Day Management Sick day management is the term used to describe the management of a child or adolescent with diabetes who develops an intercurrent illness. Diabetes and Infectious Illnesses Children and adolescents with well-controlled diabetes have no greater risk of acquiring infections than the general population, but having diabetes does introduce the need for extra caution in the management of sick days. While there are no epidemiological studies in children looking at independent risk factors for infection in diabetes, many in vitro models have suggested altered immunity affecting neutrophil function,1-3 although the exact relationship with glycaemic control remains unclear. An association with glycaemic control is suggested by studies in diabetic adults showing that more aggressive insulin therapy and blood glucose control post operatively can improve neutrophil function in vitro,4 and decrease the incidence of wound infection post operatively.5 Another study in critically ill adults (non diabetic) showed that intensive insulin therapy to maintain blood glucose (BG) between 4.4 and 6.1 mmol/L compared with conventional therapy (BG 10 – 11 mmol/L) reduced the mortality due to multi-organ failure with a proven septic focus.6 The incidence of bacteraemia was decreased by 46% in the intensive insulin therapy group. Those with poorly controlled diabetes may have decreased immune defences against infections resulting in: • Increased risk of acquiring infections. • Increased chance of infections spreading quickly. • Increased risk of unusual infections (eg tuberculosis). • Increased risk of infections from organisms that are not normally pathogenic. • Poor response to antibiotics. Diabetes may influence responses to the treatment of coexisting illnesses. Impact of Illnesses on Diabetes In general, children and adolescents with well-controlled diabetes cope with illnesses very well. Illnesses vary in their impact on the diabetes. Illnesses may cause: • Little effect on blood glucose levels. • Low blood glucose levels. • High blood glucose levels. Infections Causing Little Effect on Blood Glucose Levels The key feature of these infections seems to be the lack of systemic upset and they often cause no significant alteration in the metabolic status, eg intercurrent infections such as upper respiratory tract infections, mild infectious mononucleosis or rubella. The transient fever associated with immunisations is usually not associated with any problems with the diabetes. Chapter 11: Sick Day Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 123 Infections Causing Low Blood Glucose levels Such illnesses are usually marked by nausea, vomiting and diarrhoea, but are not accompanied by a fever or systemic features, and there is no increase in insulin resistance or requirement. The problem seems to be mainly the inability to absorb or retain food. Common causes are viral illnesses associated with mild gastritis (nausea and vomiting only) or a mild gastroenteritis (vomiting and diarrhoea). Food poisoning may lead to a similar picture and often the child may complain of abdominal discomfort or pain. Infections Causing High Blood Glucose Levels More commonly illnesses in childhood and adolescence raise blood glucose levels. Illnesses associated with fever tend to raise blood glucose because of higher levels of stress hormones and cytokines increasing gluconeogenesis and insulin resistance. In addition, ketones may appear in the urine. Many of these infections have a silent prodromal phase which may cause unexplained high glucose levels for several days before the illness declares itself. Illnesses that cause raised blood glucose levels are usually those associated with general malaise (lethargy, weakness, irritability, muscle aches, headache), fever and obvious signs of an infection. The child or adolescent may feel nauseous, not feel like eating or drinking, and may vomit. Typical infections likely to be associated with increased insulin resistance: • Viral illnesses associated with fever and systemic features, especially if associated with vomiting. Common causes are viral pharyngitis, influenza, and the childhood illnesses such as measles and varicella. • Bacterial infections, especially if associated with fever. Common causes are tonsillitis, ear infections, lower respiratory tract infections and urinary tract infections associated with fever. It is important for the child or adolescent to be seen by his/her doctor as bacterial illnesses require antibiotic therapy or other specific therapy and the sooner these are started the better. The combination of a high blood glucose level and ketones in the urine during illness is a warning sign of a serious lack of insulin action in the body and is due to development of insulin resistance. Treatment is urgent as without extra insulin this state may progress to ketoacidosis. General Principles of Sick Day Management No studies were identified addressing insulin adjustment and sick day management in children and adolescents with type 1 diabetes. However, current insulin regimens for sick day management have stood the test of time. The essential principles in sick day management are: • Treat the underlying illness The treatment of the underlying illness is no different in the child or adolescent with diabetes, the only proviso being that medical assessment should be sought earlier in case antibiotic or other therapies are required. • Symptomatic relief If a fever, headache or aches and pains are present, give regular paracetamol or ibuprofen in recommended doses and make the child or adolescent comfortable. Chapter 11: Sick Day Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 124 • Rest Encourage bedrest and keep the child or adolescent at home if unwell. • Sugar-free medications It is important for the child or adolescent to take the medications as prescribed. For young children, many syrups are available in sugar-free forms (antibiotics, paracetamol, ibuprofen) and those not sugar-free are usually satisfactory as the amount of sugar present in each dose is not large enough to cause a problem. For older children and adolescents, most medications are available in tablet or capsule form and these are sugar-free. • Hydration Encourage plenty of fluids. A child or adolescent with a fever loses more fluid due to the increased body temperature. There may be continuing losses of quite large volumes of fluid because of glycosuria causing an osmotic diuresis. It is important to remember that because of the osmotic diuresis even markedly dehydrated children or adolescents with diabetes can progress to more severe dehydration if the blood glucose remains high. If the blood glucose is >15 mmol/L water or low joule drinks should be offered so as not to raise the blood glucose further. • Preparation for sick days Each family should have a sick day kit prepared and ready to use (see Table 11.1). Table 11.1: Emergency Kit for Sick Day Management at Home • Rapid-acting insulin or short-acting insulin. • Glucose test strips, meters and lancets/finger pricking devices. • Urine test strips for glucose and ketone estimation or blood ketone meter and strips. • Doctor’s/hospital’s phone number. • Sweet cordial/fruit juice/lemonade or other soft drinks (caffeine is not recommended). • Low joule (diet drinks) or water. • Glucagon. • Diabetes manual or emergency guidelines, including sick day foods. • Thermometer. • Diary. • Paracetamol or ibuprofen - sugar-free syrup or tablets. • Education on sick day management There are several key concepts that must be taught to all families: Insulin must never be omitted. Glucose levels during illness may rise, even in the absence of any ingested food due to gluconeogenesis. Vomiting is a serious sign. The presence of ketones in the urine or blood with high blood glucose is a serious sign. Families must be aware of the signs that indicate the condition is too serious to treat at home (see Table 11.2). • General nutrition If the child or adolescent is anorexic, encourage oral intake by tempting with fluids and foods that may appeal (see Table 11.3). Chapter 11: Sick Day Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 125 Table 11.2: Indicators for Patient to be Transferred to Hospital Sick day management at home should be abandoned and transfer to hospital arranged if: • Vomiting persists, especially if it is frequent or becomes bile-stained. • Hyperventilation occurs suggestive of Kussmaul respiration. • Ketones are present and are increasing. • Blood glucose continues to rise despite treatment. • The child or adolescent becomes more unwell, drowsy, disoriented or confused. • The nature of the illness is not understood. • Abdominal pain is severe or localised. • The caregivers are uncertain about how to handle the situation. • The caregivers become exhausted. • Other diseases coexist (e.g. cystic fibrosis). • The patient is very young (e.g. under 2 years). Table 11.3: Sick Day Foods and Fluids The following quantities are approximately 1 exchange (15 gm of carbohydrate) Fluids: • _-_ cup orange, apple or pineapple juice. • tea/water with 1 tablespoon of sugar or 1_ tablespoons of honey. • _ cup of milk (170 ml) with 1 tablespoon of sweet drinking powder. • _ cup of sweet soft drink. Foods: • Slice of bread or toast. • _ cup potato or 1 medium size potato. • _ cup boiled rice. • _ English muffin. • 2-3 plain dry biscuits. • 2 scoops of ice-cream. • 200 gm unsweetened yoghurt or _ carton (100 gm) sweetened yoghurt. • _-_ cup unsweetened tinned fruit. • _ cup sweet jelly. • 1 small banana. • 1 medium orange. • 7 small jelly beans. Insulin Regimens in Infections associated with Hyperglycaemia and Ketosis Management at home Additional insulin given at home can frequently avert hospitalisation in illnesses associated with hyperglycaemia and ketosis. The additional insulin used is short-acting or rapid-acting insulin given every 2-4 hours as additional injections equal to 10-20 percent of the total insulin daily dosage. The dosage, the frequency and the route of injection will vary according to the particular circumstances for the particular patient. The factors that have to be taken into account are: • The degree of elevation of the blood glucose level. • The length of time the blood glucose levels have been elevated. • The patient’s age (extra caution in the very young). • The total insulin dosage during a normal day. Chapter 11: Sick Day Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 126 • • Presence or absence of urinary ketones. The response to the previous dose of insulin. In general, 20 percent of total daily dosage is used for the additional injections if the patient is very sick, has blood glucose in excess of 15 mmol/L and has moderate or larger amounts of ketones in the urine. An acceptable regimen is shown below in Table 11.4. Table 11.4: How to Calculate the Amount of Extra Insulin on Sick Days7;8 Blood Urine Blood glucose ketones ketones Management (mmol/L) (mmol/L)* 15 Negative <1* Do not give extra insulin. Check blood glucose and ketones again in two hours. >15 Negative <1* Re-check blood glucose in two hours. Blood glucose may fall without extra insulin. If persistently elevated consider an extra 5% of TDD (total daily dose) of insulin. >15 Trace 1.0-1.4* Give an extra 5 to 10% of TDD every 2-4 hours. or small Check blood glucose and ketones again in two hours. >15 Moderate or 1.5* Give an extra 10 to 20% of TDD every 2-4 hours. large Check blood glucose and ketones every hour. Note: Extra insulin may be given as rapid-acting insulin or short-acting insulin analogues. To calculate the Total Daily Dose (TDD) add up all the insulin given on a usual day (ie. Rapid-acting + intermediate/longacting). Do not include additional boluses given for unexpected hyperglycaemia. * Adapted from sample algorithm 8, no data available from clinical trials. If a rapid response is required, the short-acting insulin can be given intramuscularly every 2 hours (Note: syringes with 8mm needles may not reach the muscle compartment). This should be only under the direction of an endocrinologist and is outside the usual protocols supervised by diabetes educators. Normally the condition is less urgent and the injections are given subcutaneously at 4-hourly intervals until there is improvement. Once the blood glucose is less than 15 mmol/L but above 12 mmol/L, repeated doses are usually 10 percent of the total daily dose given every 4 hours (in addition to the usual insulin). Management in hospital If the patient requires transfer to hospital for any reason (see Table 11.2) the management should include the following:9 • If blood glucose level is >15 mmol/L and there are moderate or large ketones, but with no or only mild ketoacidosis (venous pH >7.20). IV fluids should be commenced (0.9% Saline initially at maintenance plus replacement of estimated deficits over 24-48 hours. Extra doses of short/rapid-acting sub-cutaneous insulin (10-20% of the total daily dose given as short/rapid acting) are given every 2-4 hours until BG level <15 mmol/L and ketones have cleared. • Once BG level falls below 15 mmol/L, dextrose should be added to the IV fluids. The recommended dextrose containing fluid is N/2 Saline + 5% dextrose. This can be made by adding 25 ml of 50% dextrose to 500 ml of N/2 Saline + 2.5% dextrose. • Grade to oral intake when possible. Chapter 11: Sick Day Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 127 Insulin Regimens in Infections Associated with Persistent Hypoglycaemia Management at home These illnesses are marked by semi-starvation due to extreme anorexia, often associated with vomiting and diarrhoea. The need is for frequent blood glucose testing, frequent sips of sugar- or glucose-containing drinks or small portions of easily absorbed carbohydrate foods. Insulin doses should be reduced but must not be suspended. In twice-daily insulin regimens the short/rapid-acting insulin can be greatly reduced or possibly even omitted. The intermediate insulin dosage may need reductions of 20-50 percent. In basal-bolus regimens the short/rapid-acting doses may need to be reduced by 20-50 percent and the intermediate insulin by 20-50 percent. Management in hospital If the blood glucose level cannot be maintained by oral intake: • IV fluids should be commenced with N/2 Saline + 5% dextrose. • The BG level should be checked every 1-2 hours. • Insulin doses should be reduced as described above. Glucagon For severe hypoglycaemia, in the hospital setting, the preferred treatment is intravenous glucose (bolus dose 2-5 ml/kg of 10% dextrose over a few minutes) followed by dextrosecontaining maintenance fluids (see also severe hypoglycaemia). Intravenous dextrose raises the blood glucose level faster than intramuscular glucagon.10;11 When intravenous access is difficult or outside the hospital setting, severe hypoglycaemia should be treated with intramuscular glucagon injection. The recommended dose is 0.5 units (or mg) for children <25kg or <8 years old and 1.0 units (mg) for older children or those weighing >25kg).12 Remember that glucagon may make the child or adolescent vomit. Minidose Glucagon Under the supervision of a doctor or diabetes educator it is possible to prevent or treat ongoing mild hypoglycaemia in a child unwilling to eat or drink in an ambulatory setting with small doses of subcutaneous glucagon.13 If hypoglycaemia is mild, ongoing or is impending (ie blood glucose <4.4 mmol/L associated with gastroenteritis or food refusal),13 an injection of a small dose of glucagon may reverse the hypoglycaemia without causing nausea and vomiting and enable oral fluids to be re-established. This may prevent hospitalisation in some cases. The recommended dose regimen is detailed below. Following the use of mini-dose glucagon continued monitoring is imperative. Table 11.5: Recommended Dose for Mini-dose Glucagon13 Quantity Age (yrs) mcg (µg) mg ml 2 2 – 15 >15 20 10 per year of age 150 0.02 0.01 per year of age 0.15 0.02 0.01 per year of age 0.15 Chapter 11: Sick Day Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Units on insulin syringe 2 1 per year of age 15 128 Insulin Pump Sick Day Management The key points in the management of sick days are the same for insulin pump users as for those on insulin injections. As people on pumps use only rapid-acting insulin and do not have any injected depot of long-acting insulin, diabetic ketoacidosis can develop rapidly and therefore hyperglycaemia must be taken very seriously. If the blood glucose level is 15 mmol/L or above, the following steps should be taken: • Immediately check for problems with the pump or delivery system. • Check for ketones in the blood or urine. • Proceed as directed in Table 11.6 depending on ketone result. • To overcome insulin resistance, the basal rate and/or correction boluses may need to be increased during the period of illness. Table 11.6: Management of Sick Days with Insulin Pump14 If urine ketones are negative or small or If urine ketones are moderate or high or blood ketones less than 0.6 mmol/L. blood ketones more than 0.6 mmol/L, or you don’t think the pump is working. • Give a correction bolus with the pump • There may be a pump delivery problem or a (see Insulin pump adjustments – Chapter significant illness developing. 5). • Liaise with diabetes pump team. • Test the BG hourly. • Use injected insulin given with a syringe or • Drink extra low joule fluids. pen to deliver the correction bolus dose (see • If BG is lower after 1 hour, recheck again Insulin pump adjustments - Chapter 5). in 1 to 2 hours and decide if another • Drink extra unsweetened (low joule) ‘diet’ correction bolus dose is needed (use the fluids. unused bolus rule, see Insulin pump • Test the BG hourly. adjustments - Chapter 5). • Replace the insulin in the pump, and the infusion set and cannula. Do not use the • If the BG is not lower after the first bolus pump again until the situation is under proceed to give an injection with a syringe control. or pen (see column 2). • If after 2 hours there is no improvement, liaise with diabetes pump team. • If after 2 hours the BG is improved, use the unused bolus rule to decide if an additional bolus is needed (see Insulin pump adjustments - Chapter 5). Pump use can be resumed. • If BG remains high, ketones persist, or nausea, vomiting or abdominal pain develop, liaise with diabetes pump team or immediate hospital assessment recommended. Table adapted from Walsh and Roberts: Pumping insulin. Everything you need for success with an insulin pump.15 When patients are eating less their meal boluses should be decreased; however as food absorption may be poor during the illness, it may be necessary to decrease insulin boluses to even less than the usual ratio. The basal insulin rate may also need to be decreased if the blood glucose still tends to be low. Hypoglycaemia should be treated in the usual way. Chapter 11: Sick Day Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 129 The Evidence No studies were identified addressing insulin adjustment and sick day management in children and adolescents with type 1 diabetes. The evidence for the management of severe hypoglycaemia (intravenous glucose versus intramuscular or intravenous glucagon) is listed in Evidence Table 11.1. • Intravenous dextrose raises the blood glucose level faster than intramuscular glucagon.10;11(II) The evidence for the management of mild or impending hypoglycaemia using minidose glucagon is listed in Evidence Table 11.1. • In a small case series, 28/33 children with type 1 diabetes who had gastroenteritis with impending hypoglycaemia, were effectively managed at home with small doses of intramuscular glucagon.13(IV) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 11.2. Recommendations and Principles • Families should be informed that intercurrent illnesses can cause high or low blood glucose levels.7;16;17(C) • All families should receive education about the management of sick days and have a sick day kit at home containing rapid-acting or short-acting insulin, glucose test strips, meters, lancets/finger pricking devices, urine test strips for glucose and ketone estimation or blood ketone meter and strips, doctor’s/hospital’s phone number, sweet cordial/fruit juice/lemonade or other soft drinks, low joule (diet drinks) or water, glucagon, diabetes manual or emergency guidelines, sick day foods, thermometer, paracetamol or ibuprofen (sugar-free syrup or tablets).7;16;17(C) 7;16;17 • Insulin should never be omitted even if unable to eat. (C) 7;16;17 • Blood glucose and ketones should be monitored frequently. (C) 7;16;17 • Any underlying illness should be treated promptly. (C) • Extra oral fluids should be encouraged especially if the blood glucose is high or ketones are present.7;16;17(C) • Additional boluses of short/rapid-acting insulin equal to 10-20 percent of the total insulin daily dosage should be given every 2-4 hours if the blood glucose is high and ketones are present.7;16;17(C) • Patients/carers should seek assistance immediately if, after extra insulin boluses, the blood glucose remains high, ketones persist, or nausea, vomiting or abdominal pain develop. 7;16;17 (C) • Severe hypoglycaemia should be treated with intravenous dextrose (in the hospital setting).10;11(II) • If venous access is difficult or outside the hospital setting, intramuscular glucagon should be used to treat severe hypoglycaemia.7;16;17(C) • Under the supervision of a doctor or diabetes educator, small doses of subcutaneous glucagon may be used to prevent or treat mild hypoglycaemia in an ambulatory setting. 13 (IV) II = Evidence from at least one properly-designed RCT IV = Evidence obtained from case series, either post-test or pre-test and post-test C = Consensus statement endorsed by professional organisations Chapter 11: Sick Day Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 130 Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Mowat A, Baum J: Chemotaxis of polymorphonuclear leukocytes from patients with diabetes mellitus. New England Journal of Medicine 284:621-627, 1971 Delamaire M, Maugendre D, Moreno M, Le Goff MC, Allannic H, Genetet B: Impaired leucocyte functions in diabetic patients. Diabetic Medicine 14:29-34, 1997 Gallacher SJ, Thomson G, Fraser WD, Fisher BM, Gemmell CG, MacCuish AC: Neutrophil bactericidal function in diabetes mellitus: evidence for association with blood glucose control. Diabetic Medicine 12:916-920, 1995 Rassias AJ, Marrin CA, Arruda J, Whalen PK, Beach M, Yeager MP: Insulin infusion improves neutrophil function in diabetic cardiac surgery patients. Anesthesia & Analgesia. 88:1011-1016, 1999 Zerr KJ, Furnary AP, Grunkemeier GL, Bookin S, Kanhere V, Starr A: Glucose control lowers the risk of wound infection in diabetics after open heart operations. Annals of Thoracic Surgery 63:356-361, 1997 van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in the critically ill patients. New England Journal of Medicine 345:1359-1367, 2001 Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parents manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Laffel L: Sick-day management in type 1 diabetes. Endocrinology & Metabolism Clinics of North America 29:707-723, 2000 Royal Alexandra Hospital for Children: Endocrinology and Diabetes. In The New Children's Hospital Handbook. Kilham H, Isaacs D, Eds. Sydney, 1999, p. 170-193 Patrick AW, Collier A, Hepburn DA, Steedman DJ, Clarke BF, Robertson C: Comparison of intramuscular glucagon and intravenous dextrose in the treatment of hypoglycaemic coma in an accident and emergency department. Archives of Emergency Medicine 7:73-77, 1990 Collier A, Steedman DJ, Patrick AW, Nimmo GR, Matthews DM, MacintyreCCA: Comparison of intravenous glucagon and dextrose in treatment of severe hypoglycemia in an accident and emergency department. Diabetes Care 10:712-715, 1987 MediMedia Australia Pty Limited: MIMS Australia. 2003 Haymond MW, Schreiner B: Mini-Dose Glucagon Rescue for Hypoglycaemia in Children With Type 1 Diabetes. Diabetes Care 24:643-645, 2001 Ambler G, Groves G: Guide to Insulin Pump Therapy. The Children's Hospital at Westmead. 2003 Walsh J and Roberts R: Pumping insulin. Everything you need for success with an insulin pump. Torrey Pines, 2000 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Chapter 11: Sick Day Management Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 131 Chapter 12: Hypoglycaemia Hypoglycaemia is the most frequent acute complication of type 1 diabetes.1 It is the major factor limiting intensified regimens aiming for near-normoglycaemia.1;2 Severe hypoglycaemia is rated as the most anxiety-promoting feature of diabetes by both children and parents and may lead to loss of self-esteem and social isolation. Hypoglycaemia does not appear to cause permanent neuro-psychological impairment in adults3-5 but may do so in younger children.6-10 Hypoglycaemia should be avoided in children, especially in those under 5 years of age.11 Definition There is no agreed definition of hypoglycaemia. The blood glucose level at which hypoglycaemic clinical features occur varies considerably between individuals and even within the same individual.12;13 Hypoglycaemia may be symptomatic or asymptomatic (hypo unawareness). The level at which hypoglycaemia is recognised by the individual is influenced by preceding hypoglycaemic episodes and also by preceding hyperglycaemia.14;15 The individual’s recognition of hypoglycaemia is predominantly due to the autonomic features (see below). Recognition of neuroglycopenic features varies considerably but may be improved in adults by specific blood glucose awareness training programmes.14;16-21 Young children may not be able to recognise the clinical features of hypoglycaemia. Counter-regulatory hormone and symptom responses to falling glucose levels develop at higher levels in children than adults and may be detected at plasma glucose values between 3.5 and 4.0 mmol/L. Children and adolescents with poor glycaemic control may experience symptoms and hormonal responses at even higher, sometimes normal, glycaemic levels.12 Whilst the precise definition of what constitutes hypoglycaemia remains controversial parents and children need to know what levels of glucose to respond to. The brain needs a constant supply of glucose, and cognitive defects in children and adolescents with diabetes have been found at glucose values between 3.3 and 3.6 mmol/L.13 As a result, it is advisable to maintain blood glucose values above 4.0 mmol/L in children with diabetes. Symptoms and Signs As in adults, symptom responses to hypoglycaemia in children or adolescents may be divided into those described as autonomic or neuroglycopenic. The autonomic symptoms and signs may be: • Cholinergic (sweating, hunger, tingling around the mouth). • Adrenergic (tremor, tachycardia, pallor, palpitations and anxiety). Neuroglycopenic symptoms and signs include: • Weakness. • Headache. • Visual disturbance. • Slurred speech. • Vertigo and dizziness. • Difficulty in thinking. • Tiredness. • Drowsiness. Chapter 12: Hypoglycaemia Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 132 • • • • Change in affect (eg depressed, angry, argumentative). Mental confusion. Coma. Convulsions. Usually autonomic responses occur before neuroglycopenic features however in hypoglycaemia unawareness, neuroglycopenic features occur before autonomic features (which may be absent). Parents and caregivers usually recognise symptoms of hypoglycaemia in younger children who show behavioural changes such as irritability or show changes in appearance such as pallor and sweatiness. The symptoms of hypoglycaemia may not always be the same for a given blood glucose level and parents and caregivers need to be aware of the protean nature of the clinical features possible during hypoglycaemia. Table 12.1: Symptoms of Hypoglycaemia in Diabetic Children and Recommendations for its Treatment Severity Clinical Features Treatment Mild Mild autonomic features (adrenergic Juice, sweet lemonade, cordial, and cholinergic) - hunger, shakiness, snack. If the hypoglycaemia is tremor, nervousness, anxiety, very mild it may be possible to sweatiness, pallor, palpitations and bring forward the scheduled tachycardia. Mild neuroglycopenia – meal if episode occurs within decreased attention and cognitive 15-30 minutes of a planned performance. meal. Moderate Moderate neuroglycopenic and 10-20 gm of easily absorbed autonomic features - headache, carbohydrate followed by a abdominal pain, behaviour changes, snack with carbohydrate foods. aggressiveness, impaired or double vision, confusion, drowsiness, weakness, difficulty in talking, tachycardia, dilated pupils, pallor, sweatiness. Severe Severe neuroglycopenic features Outside hospital: Glucagon by extreme disorientation, loss of injection (s.c., i.m. or i.v.) 0.5 consciousness, focal or generalised mg <8 years of age or <25kg, seizures. 1.0 mg >8 years of age or >25kg. If no response in 10 minutes, check blood glucose. If still low repeat once. Followup with carbohydrate foods and frequent monitoring. In hospital: intravenous dextrose (2-5 ml/kg body weight of 10% dextrose) followed by 5-10% dextrose infusion to maintain blood glucose level between 5-10 mmol/L. Chapter 12: Hypoglycaemia Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 133 Grading Hypoglycaemia may be symptomatic or asymptomatic.22 Symptomatic hypoglycaemia can usefully be divided into three grades on the following clinical criteria: • Grade 1 or mild when the child or adolescent with diabetes is able to detect and treat the hypoglycaemia himself/herself. Hypoglycaemia occurring in children under the age of 5 years can not be classified as grade 1 or mild because young children are not able to treat themselves. • Grade 2 or moderate hypoglycaemia occurs when someone else has to go to the aid of the child or adolescent with diabetes, but treatment is possible orally. • Grade 3 or severe hypoglycaemia occurs when the child or adolescent is unconscious, convulsion or unable to take oral glucose because of extreme disorientation and the only therapy is either glucagon by injection or intravenous glucose. Frequency In the Diabetes Control and Complications Trial, adolescents receiving intensive therapy had 86 episodes of hypoglycaemia per 100 patient-years requiring assistance and 27 episodes of hypoglycaemic coma or seizures per 100 patient-years. Adolescents on conventional therapy had 28 and 10 episodes per 100 patient-years respectively.23 In the UK, a national audit of children aged less than 17 years with type 1 diabetes reported that 4% experienced one or more episodes of severe hypoglycaemia per year.24 In a recent audit of glycaemic control in NSW and ACT, the prevalence of severe hypoglycaemia (coma or convulsion) was 36 episodes per 100 patient-years.25;26 In Western Australia (in 1995), the incidence of severe hypoglycaemia (coma or convulsion) was 15.6 per 100 patient-years.27 Adolescents have a higher incidence of moderate and severe hypoglycaemia despite having higher HbA1c levels than adults.23;28;29 The increased risk of hypoglycaemia in adolescence may be related to: • The need for larger insulin doses during the phase of rapid growth. • Irregular diet. • Irregular activity levels. Nocturnal Hypoglycaemia Nocturnal hypoglycaemia is frequent, often prolonged and may be asymptomatic.30 Nocturnal hypoglycaemia does not necessarily disturb sleep patterns. It may be suspected if prebreakfast blood glucose is low, confusional states, nightmares or seizures occur during the night or impaired thinking, lethargy, altered mood31 or headaches are experienced on waking. Counter-regulatory responses may be impaired during sleep.32;33 Nocturnal hypoglycaemia is not reliably predictable on the basis of a bedtime blood glucose level;34 therefore, blood glucose monitoring with regular measurements after midnight is essential to detect nocturnal hypoglycaemia. Nocturnal hypoglycaemia may be reduced by careful attention to the dose and type of insulin used. The 11pm blood glucose level does not accurately predict the 2am blood glucose level.34 Periodic early morning blood glucose levels are recommended. Chapter 12: Hypoglycaemia Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 134 Consequences The adverse consequences of hypoglycaemia include: • Injury or accident during a hypoglycaemic episode. A recent international multicentre survey of drivers with type 1 diabetes found that they are at increased risk for driving mishaps than drivers who do not have type 1 diabetes.35 • Death. Hypoglycaemia was implicated in 8% of diabetes related deaths in children <20years old.36 • Fear of hypoglycaemia by the parents of a young child. This often interferes with any attempts to improve control.37 Similarly, for an adolescent, an unexpected hypoglycaemic episode is an embarrassment that he/she may seek to avoid, even at the expense of hyperglycaemia and poorer control. • Direct effects of hypoglycaemia on the brain. Although no adverse neuropsychological effects have been demonstrated in adults following severe hypoglycaemia,3;4;38 there are greater concerns about the consequences of hypoglycaemia in young children because of the continued growth and development of the brain. Cognitive deficits have been reported in children who have developed diabetes before the age of five years, or if the child has had hypoglycaemia induced seizures.6-9;39;40 Both inadequate glycaemic control and the sensitivity of the young brain to hypoglycaemia may account for these findings. In children who have developed diabetes after the age of 5 years, this difference has not been found. • In a recent cost-of-illness study hypoglycaemia was found to have significant socioeconomic costs.41 Counter-Regulatory Responses to Hypoglycaemia and Hypoglycaemia Unawareness In non-diabetic individuals, a number of responses are generated by insulin-induced hypoglycaemia. Initially, endogenous insulin secretion is suppressed at an early stage. Secondly, glucagon and adrenaline, the rapid-acting counter-regulatory hormones, are promptly released.42 This results in glycogenolysis, but if hypoglycaemia is prolonged, gluconeogenesis is also stimulated. Adrenaline has additional effects on peripheral glucose utilisation and stimulates lipolysis. Finally, when hypoglycaemia is prolonged, growth hormone and cortisol responses increase hepatic glucose production and suppress glucose use in peripheral tissues.42 The integrity of glucose counter-regulation is disturbed by type 1 diabetes.12;43 In diabetic subjects receiving insulin by injection, insulin levels cannot therefore be suppressed and in addition glucagon responses to insulin-induced hypoglycaemia are characteristically lost. Unfortunately adrenaline responses may also be disrupted. The reduction in adrenaline responses may be: • Permanent. • Reversible and be the result of hypoglycaemia per se, ie. hypoglycaemia-associated autonomic failure. Hypoglycaemia-associated autonomic failure is often associated with loss of symptomatic responses.14;16;21 It may be reversible by prevention of hypoglycaemia. The development of hypoglycaemia unawareness in childhood should lead to suspicion of previous episodes of undiagnosed hypoglycaemia (often nocturnal).44 Chapter 12: Hypoglycaemia Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 135 Prevention Hypoglycaemia in children is largely preventable. However there is a significant proportion of severe hypoglycaemic episodes in which no obvious cause can be determined. The most common causes of hypoglycaemia are: • Inadequate or missed meals or snacks. • Physical activity (unplanned or more prolonged than usual) without appropriate food intake. • Insulin administration errors (eg inadvertent reversal of morning and evening doses or of the short/rapid- and intermediate-acting insulins). • Alcohol ingestion (resulting in impaired hepatic gluconeogenesis). • Idiopathic (no obvious cause discernible). It is likely that some of these are related to variations in insulin absorption. All children and adolescents with diabetes should carry glucose tablets or readily absorbed carbohydrate foods (preferably in waterproof sealed wrap) on their person and have glucagon available at home (and in boarding schools where there is a nurse on staff). Children and adolescents with type 1 diabetes should be encouraged to wear a MedicAlert37;45 (or similar warning information), and people rendering first aid should be made aware to look for such warning devices. Adequate parental education and support should be available so that proper insulin and dietary adjustments can be made to reduce the risk of hypoglycaemia. For example, parents and children should be taught how to deal with unusual exercise and events such as school camps. Confirmation Although it is useful to have the hypoglycaemia confirmed by a blood glucose measurement, treatment is urgent and should not be withheld if undue delay is likely. Treatment Mild to moderate hypoglycaemia Treatment involves immediate consumption of 10-20 gm of an easily absorbed form of carbohydrate, followed by a snack of carbohydrate foods to maintain normoglycaemia until the next meal or snack.45 Glucose cannot be absorbed from the oral cavity therefore massaging the outside of the cheek against the gum is not effective.46 In adults, a RCT crossover study compared the rises in blood glucose levels after various therapies for hypoglycaemia. After 10 gm oral glucose, peak BG level reached 5.4 ± 0.4 mmol/L, after 20 gm oral glucose peak BG level reached 6.8 ± 0.7 mmol/L and after 1 mg glucagon peak BG level reached 11.8 ± 0.8 mmol/L.47 Lemonade and glucose tablets (which must be easily chewable) are examples of appropriate foods for the treatment of mild to moderate hypoglycaemia. If giving a drink to a hypoglycaemic child, it is useful to put the child’s hands around the cup and to guide the cup to the mouth. This minimises the natural reaction of rejecting the drink. Insulin and dietary adjustments should be made to prevent further hypoglycaemia when appropriate. Chapter 12: Hypoglycaemia Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 136 Severe hypoglycaemia For severe hypoglycaemia therapy is urgent. People who are either unconscious or fitting are unable to swallow. Nothing should be given by mouth. The airway should be checked to ensure that respiration is unhampered, the person should be placed on their side (resuscitation position) to prevent aspiration of material into the lungs and emergency services (dial 000) called. Parents are taught to administer glucagon by injection according to the manufacturer’s instructions. The recommended dose is 0.5 units (or mg) for children who are <25kg or <8 years old, and 1.0 units (mg) for older children or those weighing >25kg. All children and adolescents with diabetes should have glucagon at home and their families shown (by ‘hands on’ practice during diabetes education sessions) how to administer it in times of severe hypoglycaemia. Following treatment with IM glucagon, further treatment with intravenous dextrose by emergency services may occasionally be required if hypoglycaemia persists. Glucagon is normally administered intramuscularly or subcutaneously but can also be given intravenously in the hospital setting. Glucagon frequently causes nausea and vomiting.48 Figure 12.1: Glucagon Kit for Treatment of Hypoglycaemia Intravenous glucose (dextrose) is more rapid at reversing hypoglycaemia than IM49 or IV50 glucagon. However, intravenous glucose can only be administered by doctors or specially trained health care professionals such a paramedics or intensive care ambulance officers. The dose is 0.2-0.5 gm/kg body weight. This can be given as 2-5 ml/kg of 10 percent dextrose. If 25 percent dextrose is used, the dose is 1.0-1.5 ml per kg body weight, but care must be taken not to exceed this because of the danger of causing severe hyperglycaemia rapidly. The dextrose should be given slowly over a few minutes. Care should be taken to avoid extravasation because its hyperosmolality may cause local tissue irritation or necrosis. 50% dextrose should not be used. Intramuscular epinephrine (0.3 mg) has been shown to be less effective than IM glucagon (1.0 mg) in raising the blood glucose at 15 minutes (2.6 ± 0.2 versus 0.5 ± 0.3 mmol/L).51 Other therapies which have been shown to have effect in adult studies include oral terbutaline (5.0 mg), subcutaneous terbutaline (0.25 mg) and oral alanine (40 gm).47 Glucagon remains the drug of choice if intravenous dextrose is not readily available. Follow-Up of Treatment of Hypoglycaemia The initial treatment for hypoglycaemia may need to be repeated if follow-up blood glucose testing indicates a recurrence or continuation of the hypoglycaemia. Chapter 12: Hypoglycaemia Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 137 Many children vomit persistently after severe hypoglycaemia, especially after glucagon. After the emergency treatment of the hypoglycaemia, it is necessary to ensure that the hypoglycaemia does not recur and hence the following actions are needed: • Frequent measurement of blood glucose levels. • Ensuring that food is tolerated (either as frequent small amounts of sugary drinks or an adequate amount of easily absorbed carbohydrate). • Supervision by a relative or friend who should accompany the person home. • Arranging an early appointment with the doctor for review of diabetes management. • If food is not tolerated, then hospitalisation for a continuous infusion of 5-10 percent dextrose and frequent monitoring is necessary. Hypoglycaemia and Physical Activity Hypoglycaemia may occur during, immediately after or many hours after physical activity. Special attention should be given to children and adolescents performing intensive sports, especially those involving endurance training, due to the association with delayed hypoglycaemic reactions which may occur in the middle of the night or before breakfast the next day. Advice should be sought from a dietitian for foods suitable for those undertaking endurance sports. Most sports days can be readily managed by increasing caloric intake during and after the sport. A general recommendation is that an extra serve of easily absorbable carbohydrate be taken for every half hour of sport. Requirements for extra carbohydrate with physical activity are very individual. Intensive sports need to have appropriate reductions made in dosages of the insulin acting during and for the following 12-24 hours after the physical activity. Blood glucose levels need to be measured before, during and after intensive sport. Experience and blood glucose monitoring help determine the most appropriate strategies. All children and adolescents participating in sport should have access to help in case of hypoglycaemia. Participating in physical activity in isolation should be discouraged. Those involved in strenuous and potentially dangerous sports should have a ‘buddy’ able to offer assistance. If weight gain is an issue, decreasing insulin before exercise lessens the need for extra food. Somogyi Phenomenon The concept of hypoglycaemia causing rebound hyperglycaemia was generally referred to as the Somogyi phenomenon or effect.52 Fasting hyperglycaemia was thought to be due to a counter-regulatory overshoot of the blood glucose following unrecognised nocturnal hypoglycaemia.52;53 Whilst the Somogyi phenomenon has been shown to exist, the dawn phenomenon and the waning of insulin levels are more likely causes of prebreakfast hyperglycaemia.53-55 Hypoglycaemia in School Teachers and carers at schools should be informed as to the symptoms of hypoglycaemia and appropriate treatment. They should also have access to advice when necessary. It may be useful for a member of the diabetes team to visit the school and provide this education to the teacher. Chapter 12: Hypoglycaemia Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 138 Children should not be restricted in activities at school but extra carbohydrate should be given prior to sports or physical education activities. Easily absorbed carbohydrate should be available at school. Foods for Management of Hypoglycaemia Examples of the foods suitable for the management of hypoglycaemia are indicated below. Easily absorbed carbohydrate should be followed within 15-20 minutes by a choice of carbohydrate foods to maintain blood glucose levels. Easily absorbed carbohydrate to begin with: • 125-200 ml ordinary soft drink or diluted cordial. • 4 large jelly beans, 7 small jelly beans. • 2-3 teaspoons of sugar. • Glucose tablets (10-20 gm). Carbohydrate foods to follow up with (equivalent to 15 gm carbohydrate or 1 exchange): • 1 slice of bread. • 1 banana or apple. • 200 gm unsweetened yoghurt or 100 gm sweetened yoghurt. • 1 glass of milk (300 ml). The Evidence The evidence for the effect of intensive diabetes management on the incidence of hypoglycaemia in type 1 diabetes is listed in Evidence Table 12.1. • In the Diabetes Control and Complications Trial, adolescents receiving intensive therapy had 86 episodes of hypoglycaemia per 100 patient-years requiring assistance and 27 episodes of hypoglycaemic coma or seizures per 100 patient-years. Adolescents on conventional therapy had 28 and 10 episodes per 100 patient-years respectively.23(II) • In NSW and ACT, the prevalence of severe hypoglycaemia (coma or convulsion) was 36 episodes per 100 patient years.25;26(IV) • A prospective study in Western Australia found that the incidence of severe hypoglycaemia (coma or convulsion) increased from 4.8 to 15.6 per 100 patient-years in parallel with a decrease in HbA1c from 10.2% in 1992 to 8.8% in 1995. This increase was particularly marked in younger children (<6 years) in whom severe hypoglycaemia increased from 14.9 to 42.1 episodes/100 patient-years.27(IV) • Adolescents have a higher incidence of moderate and severe hypoglycaemia than adults despite having higher HbA1c levels than adults.23;29(II) The evidence for the management of severe hypoglycaemia (intravenous glucose versus intramuscular or intravenous glucagon) is listed in Evidence Table 12.2. • RCT’s have found that intravenous glucose (dextrose) is more rapid at reversing hypoglycaemia than IM49 or IV50 glucagon.(II) The evidence for the effects of hypoglycaemia on cognitive function in children and adolescents with type 1 diabetes is listed in Evidence Table 12.3. • Hypoglycaemia has been associated with neurocognitive dysfunction in children especially if there is a history of hypoglycaemic seizures or if the child had early onset of diabetes.6-10;39;40(II, III, IV) Chapter 12: Hypoglycaemia Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 139 The Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 12.4. Recommendations and Principles 23;25;26;27;29 • Hypoglycaemia is the most frequent acute complication of type 1 diabetes. (II) • Hypoglycaemia is the major factor limiting intensified regimens aiming for nearnormoglycaemia.23;25;26;27;29(II) • Severe hypoglycaemia should be avoided in children, especially in those less than 5 yrs old.6-10;39;40(II, III, IV) • Blood glucose values should be maintained above 4.0 mmol/L in children and adolescents with diabetes.37;56;57(C) • Children and adolescents with diabetes should wear some form of identification or warning of their diabetes.37;56;57(C) • All children and adolescents with diabetes should carry glucose tablets or readily absorbed carbohydrate (preferably in waterproof sealed wrap) on their person and have glucagon available at home (and in boarding schools where there is a nurse on staff).37;56;57(C) • Hypoglycaemia in children is largely preventable; however there is a significant proportion of severe hypoglycaemic episodes in which no obvious cause can be determined.56;57(C) • School teachers and carers at schools should be informed of the symptoms and appropriate treatment of hypoglycaemia and should have access to advice when necessary.37;56;57(C) • In the hospital setting severe hypoglycaemia should be treated with intravenous dextrose as this is the most rapid way of treating severe hypoglycaemia.49;50(II) • The recommended dose of intravenous dextrose is 2-5ml/kg of 10% dextrose. 50% dextrose should not be used because of dangers of tissue necrosis associated with extravasation.(C) • Intramuscular or subcutaneous glucagon is an effective way of treating severe hypoglycaemia in a home-care setting or if intravenous dextrose is not possible.49;50(II) II = Evidence from at least one properly-designed RCT IV = Evidence from case series, either post-test or pre-test and post-test C = Consensus statement endorsed by professional organisations Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 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Modern standards and service models. 1-51. 2002. London, Department of Health. Jones TW, Boulware SD, Kraemer DT, Caprio S, Sherwin RS, Tamborlane WV: Independent effects of youth and poor diabetes control on responses to hypoglycemia in children. Diabetes 40:358-363, 1991 Ryan CM, Atchison J, Puczynski S, Puczynski M, Arslanian S, Becker D: Mild hypoglycemia associated with deterioration of mental efficiency in children with insulin-dependent diabetes mellitus. Journal of Pediatrics 117:32-38, 1990 Chapter 12: Hypoglycaemia Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 140 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. Fanelli C, Pampanelli S, Lalli C, Del Sindaco P, Ciofetta M, Lepore M, Porcellati F, Bottini P, Di Vincenzo A, Brunetti P, Bolli GB: Long-term intensive therapy of IDDM patients with clinically overt autonomic neuropathy: effects on hypoglycemia awareness and counterregulation. Diabetes 46:1172-1181, 1997 Jones TW, Borg WP, Borg MA, Boulware SD, McCarthy G, Silver D, Tamborlane WV, Sherwin RS: Resistance to Neuroglycopenia: An Adaptative Response during Intensive Insulin Treatment of Diabetes. Journal of Clinical Endocrinology & Metabolism 82:1713-1718, 1997 Fanelli C, Pampanelli S, Epifano L, Rambotti AM, Di Vincenzo A, Modarelli F, Ciofetta M, Lepore M, Annibale B, Torlone E: Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM.[erratum appears in Diabetologia 1995 Feb;38(2):254]. Diabetologia 37:1265-1276, 1994 Cox DJ, Gonder-Frederick L, Polonsky W, Schlundt D, Kovatchev B, Clarke W: Blood glucose awareness training (BGAT-2): long-term benefits. Diabetes Care 24:637-642, 2001 Kinsley BT, Weinger K, Bajaj M, Levy CJ, Simonson DC, Quigley M, Cox DJ, Jacobson AM: Blood glucose awareness training and epinephrine responses to hypoglycemia during intensive treatment in type 1 diabetes. Diabetes Care 22:1022-1028, 1999 Cox D, Gonder-Frederick L, Polonsky W, Schlundt D, Julian D, Clarke W: A multicenter evaluation of blood glucose awareness training-II. Diabetes Care 18:523-528, 1995 Cox DJ, Gonder-Frederick L, Julian DM, Clarke W: Long-term follow-up evaluation of blood glucose awareness training. Diabetes Care 17:1-5, 1994 Fanelli CG, Epifano L, Rambotti AM, Pampanelli S, Di Vincenzo A, Modarelli F, Lepore M, Annibale B, Ciofetta M, Bottini P: Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM. Diabetes 42:16831689, 1993 Cryer PE: Symptoms of hypoglycemia, thresholds for their occurrence, and hypoglycemia unawareness. Endocrinology & Metabolism Clinics of North America 28:495-500, 1999 DCCT Research Group: Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. Journal of Pediatrics 125:177-188, 1994 Smith AHK: The National Paediatric Diabetes Audit. Annual Report. Diabetes UK1-30, 2001 Craig ME, Handelsman P, Donaghue KC, Chan A, Blades B, Laina R, Bradford D, Middlehurst A, Ambler G, Verge CF, Crock P, Moore P, Silink M: Predictors of glycaemic control and hypoglycaemia in children and adolescents with type 1 diabetes from NSW and the ACT. Medical Journal of Australia 177:235-238, 2002 Handelsman P, Craig ME, Donaghue KC, Chan A, Blades B, Laina R, Bradford D, Middlehurst A, Ambler G, Verge CF, Crock P, Moore P, Silink M: NSW/ACT HbA1c Study Group: Homogeneity of metabolic control in New South Wales and the Australian Capital Territory, Australia. Diabetes Care 24:1690-1691, 2001 Davis EA, Keating B, Byrne GC, Russell M, Jones TW: Impact of improved glycaemic control on rates of hypoglycaemia in insulin dependent diabetes mellitus. Archives of Disease in Childhood 78:111-115, 1998 DCCT Research Group: The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial. Archives of Ophthalmology 113:36-51, 1995 DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. New England Journal of Medicine 329:977-986, 1993 Amin R, Ross K, Acerini CL, Edge JA, Warner J, Dunger DB: Hypoglycemia prevalence in prepubertal children with type 1 diabetes on standard insulin regimen: use of continuous glucose monitoring system. Diabetes Care 26:662-667, 2003 Matyka KA, Wigg L, Pramming S, Stores G, Dunger DB: Cognitive function and mood after profound nocturnal hypoglycaemia in prepubertal children with conventional insulin treatment for diabetes. Archives of Disease in Childhood 81:138-142, 1999 Porter PA, Byrne G, Stick S, Jones TW: Nocturnal hypoglycaemia and sleep disturbances in young teenagers with insulin dependent diabetes mellitus. Archives of Disease in Childhood 75:120-123, 1996 Jones TW, Porter P, Sherwin RS, Davis EA, O'Leary P, Frazer F, Byrne G, Stick S, Tamborlane WV: Decreased Epinephrine Responses to Hypoglycemia during Sleep. New England Journal of Medicine 338:1657, 1998 Porter PA, Keating B, Byrne G, Jones TW: Incidence and predictive criteria of nocturnal hypoglycemia in young children with insulin-dependent diabetes mellitus. Journal of Pediatrics 130:366-372, 1997 Cox DJ, Penberthy JK, Zrebiec J, Weinger K, Aikens JE, Frier B, Stetson B, DeGroot M, Trief P, Schaechinger H, Hermanns N, Gonder-Frederick L, Clarke W: Diabetes and driving mishaps: frequency and correlations from a multinational survey. Diabetes Care 26:2329-2334, 2003 Edge JA, Ford-Adams ME, Dunger DB: Causes of death in children with insulin dependent diabetes 1990-96. Archives of Disease in Childhood 81:318-323, 1999 International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Reichard P, Berglund A, Britz A, Levander S, Rosenqvist U: Hypoglycaemic episodes during intensified insulin treatment: increased frequency but no effect on cognitive function. Journal of Internal Medicine 229:9-16, 1991 Holmes CS, Richman L: Cognitive profiles of children with insulin-dependent diabetes. Journal of Developmental & Behavioral Pediatrics 6:326, 1985 Sansbury L: Predictors of cognitive functioning in children and adolescents with insulin-dependent diabetes mellitus: A preliminary investigation. Children's Health Care 26:210, 1997 Nordfeldt S, Jonsson D: Short-term effects of severe hypoglycaemia in children and adolescents with type 1 diabetes. A cost-ofillness study. Acta Paediatrica 90:137-142, 2001 Gale EA, Bennett T, Macdonald IA, Holst JJ, Matthews JA: The physiological effects of insulin-induced hypoglycaemia in man: responses at differing levels of blood glucose. Clinical Science 65:263-271, 1983 Bolli GB, Dimitriadis GD, Pehling GB, Baker BA, Haymond MW, Cryer PE, Gerich JE: Abnormal glucose counterregulation after subcutaneous insulin in insulin-dependent diabetes mellitus. New England Journal of Medicine 310:1706-1711, 1984 Barkai L, Vamosi I, Lukacs K: Prospective assessment of severe hypoglycaemia in diabetic children and adolescents with impaired and normal awareness of hypoglycaemia. Diabetologia 41:898-903, 1998 National Institute for Clinical Excellence. Type 1 Diabetes (Childhood): Diagnosis and Management of Type 1 Diabetes in Children and Young People. 2004. Chapter 12: Hypoglycaemia Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 141 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. Gunning RR, Garber AJ: Bioactivity of instant glucose. Failure of absorption through oral mucosa. Journal of the American Medical Association. 240:1611-1612, 1978 Wiethop BV CP: Alanine and terbutaline in treatment of hypoglycemia in IDDM. Diabetes Care 16:1131-1136, 1993 Stenninger E, Aman: Intranasal glucagon treatment relieves hypoglycaemia in children with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 36:931-935, 1993 Patrick AW, Collier A, Hepburn DA, Steedman DJ, Clarke BF, Robertson C: Comparison of intramuscular glucagon and intravenous dextrose in the treatment of hypoglycaemic coma in an accident and emergency department. Archives of Emergency Medicine 7:73-77, 1990 Collier A, Steedman DJ, Patrick AW, Nimmo GR, Matthews DM, MacintyreCCA: Comparison of intravenous glucagon and dextrose in treatment of severe hypoglycemia in an accident and emergency department. Diabetes Care 10:712-715, 1987 Monsod TP, Tamborlane WV, Coraluzzi L, Bronson M, Yong-Zhan T, Ahern JA: Epipen as an alternative to glucagon in the treatment of hypoglycemia in children with diabetes. Diabetes Care 24:701-704, 2001 Somogyi M: Exacerbation of diabetes by excess insulin action. American Journal of Medicine 26:169-191, 1959 Bolli GB, Gottesman IS, Campbell PJ, Haymond MW, Cryer PE, Gerich JE: Glucose counterregulation and waning of insulin in the Somogyi phenomenon (posthypoglycemic hyperglycemia) . New England Journal of Medicine 311:1214-1219, 1984 Holl RW, Heinze E: The dawn or Somogyi phenomenon? High morning fasting blood sugar values in young type-1 diabetics. Deutsche Medizinische Wochenschrift 117:1503-1507, 1992 Ludvigsson J, Hanas R: Continuous subcutaneous glucose monitoring improved metabolic control in pediatric patients with type 1 diabetes: a controlled crossover study. Pediatrics 111:933-938, 2003 Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Chapter 12: Hypoglycaemia Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 142 Chapter 13: Psychosocial Aspects Impact on Child Type 1 diabetes in childhood imposes a number of psychological stresses on both the child and the family. Fluctuations in blood glucose levels may contribute directly to alterations in behaviour and mood, with increased restlessness and irritability and reduced capacity to concentrate. A social worker and a clinical psychologist should be part of the multidisciplinary team involved in the management of children and adolescents with diabetes.1 Psychological morbidity is increased in children with diabetes2;3 as it is in children with other chronic illnesses.4 Initial adjustment to diabetes is characterised by sadness, anxiety, withdrawal, depression, and dependency.5-7 Such difficulties often resolve within the first year, but poor adaptation in this initial phase has been found to place children at risk for later emotional difficulties.8 Diabetes treatment routines may:9;10 • Impose a lack of spontaneity in lifestyles. • Engender passivity and inappropriate dependence upon adults for decision-making and self-care. • Foster feelings of rebellion in some young people. • Engender a loss of confidence. Treatment regimens may be difficult to accept and may lead to some children and adolescents struggling with developmentally appropriate issues of independence and autonomy. Adolescents develop an increasingly sophisticated understanding of the implications of chronic illness for future wellbeing, life opportunities, and career choices. This may cause a sense of being ‘damaged’ at a time when a strong sense of self and an unlimited future are of key importance for psychological well being. An Australian prospective study of neuropsychological and psychosocial functioning followed 133 children from diagnosis of type 1 diabetes. At ten years 36 percent of an adolescent subset met the criterion for one or more DSM-IV diagnoses,10 approximately double the prevalence reported in a recent Australian community sample of similar-aged peers.11 Impact on Family The diagnosis of type 1 diabetes itself is experienced as a significant psychological crisis in which the parents grieve the loss of the idealised child. Family adaptation to illness is not a static process, but must change to take account of the child’s developing maturity and capacity for self-management of their condition. Frequently expressed parental feelings include: • Anxiety over the ever-present possibility of hypoglycaemia. • Frustration over failure to achieve perfect glycaemic control. • Concern over long term complications. • Guilt and responsibility for transmitting the genetic components of diabetes. • Diminished enjoyment of the parental role as parents struggle to balance the psychological needs of the child with the restrictions and treatment requirements imposed by the illness. Chapter 13: Psychosocial Aspects Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 143 • • Higher parenting stress levels.7 Feeling less cohesive and more rigidly organised than control families.7 Other family members are also affected by the presence of a child with diabetes: • Siblings may resent the extra parental time directed to the child with diabetes. • Siblings may resent that family activities are curtailed to take account of the demands of the diabetes regimen. • Siblings may be fearful that they have caused the illness in their sibling. • Family members may fear that they may themselves develop diabetes. • Grandparents may be fearful of their ability to look after their grandchild. • Grandparent’s desire to compensate the child may undermine parental management, especially in regard to issues around food. Type 1 diabetes in children and adolescents is associated with higher rates of psychiatric disorders including adjustment disorders, major depression, anxiety disorders9 and eating disorders.12 Psychiatric disorders in childhood increase the risk of subsequent psychiatric disorders in adolescence and adulthood.13 Serious problems with self management in childhood diabetes tend to arise about 3.5 years after diagnosis or in early adolescence and are difficult to treat.14 The optimal time for interventions to address later problems with compliance in early adolescence appears to be in the initial period following diagnosis when compliance tends to be high.14 Mild cognitive deficits have been observed to occur more frequently in children with type 1 diabetes; especially in those children who were first diagnosed under two years of age.15 Such deficits are associated with learning difficulties which may require specialist recommendations and remediation for academic problems. Clinical psychology assessment and early intervention for psychological problems in children with type 1 diabetes and their families are essential to maximise health outcomes Psychosocial Factors and Metabolic Control Relationships between psychological factors (child adjustment, parental mental health, family functioning) and metabolic control are of great interest in type 1 diabetes. Psychological distress in siblings and adult family members may impair their relationship with the child with type 1 diabetes, reducing opportunities for effective family support. A number of studies have found an association between psychological difficulties in the child and chronic poor metabolic control.10;16-19 Causality is unproven but it is assumed that troubled children are less likely to adhere to treatment regimens, leaving them at ‘double jeopardy’ for adverse physical and mental health outcomes. In contrast, associations between mood disorders and family conflict and very ‘tight’ or good metabolic control have also been reported,20-22 raising the possibility that neurotic symptoms may either contribute to, or result from, obsessive pre-occupation with the demands of the diabetes regimen. In the Australian longitudinal study, adolescents were divided into three groups on the basis of their metabolic control history.10 Fifty percent of the mixed poor control group (HbA1c >9.5% for more than one third the time since diagnosis) had a psychiatric diagnosis compared with twenty five percent of the well controlled group (no hyper- or hypoglycaemia), with the hypoglycaemia group (no severe hypoglycaemia) falling between these two extremes.10 Chapter 13: Psychosocial Aspects Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 144 Relationships between parameters of family functioning and metabolic control in the child have shown: 23;24 • Rigidly organised, inflexible families have been associated with both better and 25 poorer metabolic control in the child. • Strict parental supervision was associated with better health outcomes but greater psychological dependency in the child.23 Metabolic control and psychological outcomes do not always coincide. Over-zealous adherence with treatment regimens may have a psychological cost for some children. Psychological dependency on parents exerting strict control may lead to failure of the child to develop age appropriate competencies and self management strategies necessary for effective metabolic control in adolescence and early adulthood. Adherence to Therapy Non-adherence to therapy should be considered in children and particularly adolescents with poor metabolic control, especially in those presenting with recurrent diabetic ketoacidosis. Medical regimens that are long-term, complex and that encroach considerably upon daily living are less likely to elicit adherence.26 Higher levels of education in parents of children with diabetes and in adolescents with type 1 diabetes are associated with improved adherence to therapy.27;28 Most children administer insulin assiduously. However, recommendations for diet, physical activity, and self-monitoring of blood glucose (and hence self-adjustment of insulin doses) are relatively neglected.29-33 Non-adherence is associated with deterioration in glycaemic control and increases the risk of complications; however, the consequences of non-adherence are not sufficient to motivate self-care behaviour.16;34 The NICE Guidelines for the Diagnosis and Management of Type 1 Diabetes in Children and Young People have systematically reviewed the literature on non-adherence in diabetes management.35 Non-adherence has typically been associated with adolescence36-39 as the responsibility for maintaining an adequate diabetic regimen in younger children is often the responsibility of parents.40 In a longitudinal study of school-age children with diabetes, serious non-adherence with the medical regimen over nine years occurred in 45%.41 The initial episode of non-adherence occurred at an average age of 14.8 years, while time spent being non-adherent was greatest when the patients were aged between 17 and 19 years.41 At a time of increasing desire for autonomy, there may be conflict between parents and an adolescent who desires independence and a sense of self-normality within peer groups.36;42 There appears to be a fine balance involved in the transfer of responsibility, with significant problems in diabetes management occurring when self-care autonomy is promoted or impeded at an inappropriate time.43 Psychiatric disorders may impact on blood glucose control by decreasing adherence with medical requirements.17;41;44 In depression, the lack of motivation, loss of interest in daily activities, and hopelessness may undermine the motivation to carry out tasks necessary to maintain good glycaemic control. Kovacs and colleagues (1992) found that 56% of children with psychiatric illnesses failed to comply with their medical regimen, as compared to 17% of those without psychiatric disorders.41 Psychological factors, such as low self-esteem, self-efficacy, and depressive symptoms, have been found to account for 50% of the variance in treatment adherence.34 Chapter 13: Psychosocial Aspects Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 145 Intentional non-adherence, as opposed to non-adherence secondary to motivational or attentional difficulties, is an area that is particularly problematic in individuals with type 1 diabetes exhibiting suicidal ideation or eating disorders. The rate of non-adherence to treatment, which may be a form of self-destructive behaviour, rises from 25% to 63.3% when suicidal ideation has been present in the past year.45 Adolescents with eating disorders are more likely to neglect the glycaemic monitoring, and diet components of their treatment,46 and have also been found to omit or reduce insulin dose in order to produce glycosuria as a method of weight control. 46;47;48 Risk Factors Not all children with type 1 diabetes develop psychological difficulties. The following factors have been studied for their impact on the development of psychological difficulties in children with diabetes: 3;10 • Some studies report that females with diabetes are at greater risk, while others have failed to identify gender as a risk factor for psychiatric disorder.2;45 9;45;49 • Socioeconomic status is not predictive of psychological difficulties. 3 50 • Maternal psychopathology, conflictual or dysfunctional family environments and 5 avoidance coping behaviours have all been associated with poor psychological adjustment to diabetes. • Poor initial adaptation to diabetes is predictive of ongoing psychological difficulties.8;9;51 • In the Australian longitudinal cohort study, children with behaviour problems at the time of diagnosis were significantly more likely to have a DSM-IV psychiatric diagnosis ten years later and to have had a history of chronic poor metabolic control.10 • A Victorian study on clinical and quality of life outcomes demonstrated lower quality of life measures in rural youth with diabetes despite glycaemic control. Treatments and Interventions Effective care of children and adolescents with diabetes involves not only optimised medical management, but also sensitive attention to psychological well being. The treatment regimen should as simple and non-disruptive to lifestyle as possible, consistent with glycaemic targets. Effective intervention with ‘at risk’ children is essential to prevent adverse physical and mental health outcomes. A Health Technology Assessment systematic review on the effects of educational and psychosocial interventions for adolescents with diabetes found an overall small but positive effect of interventions on HbA1c and psychosocial outcomes. However, as many of the studies were small and different interventions were used, the need for larger high quality RCT’s in this area is identified.52 Wysocki et al (2001)53 used Behavioral Family Systems Therapy (BFST) to teach problem-solving and communication skills to adolescents and parents. When compared to adolescents receiving standard, physician-directed treatment or those whose families had attended groups focusing on education and social support, families involved in BFST showed some improved parent-adolescent relations, and reduction in the amount and intensity of family conflict. Diabetes-specific conflict also decreased in the BFST group compared to the two control groups. Interestingly, total glycated haemoglobin values increased throughout the study but there were no significant between group or interaction effects on GHb at any measurement point.. Chapter 13: Psychosocial Aspects Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 146 Several other groups have studied interventions promoting and maintaining family involvement in diabetes management.54;55 54 • Anderson et al (1999) reported greater parental involvement in diabetes care and significantly decreased diabetes-related conflict over time but no improvement in glycaemic control. 55 • In contrast Laffel et al (2003) observed significantly improved diabetes control in the treatment group compared to controls, but no improvement in health-related quality of life or diabetes-related family conflict at one-year follow-up. Maintenance of, or an increase in family involvement in diabetes management were comparable to those found by Anderson et al (1999).54 Early research into promotion of personal and social coping skills reported promising results for children and adolescents with diabetes.56;57 In a more recent and methodologically rigorous piece of research, group Coping Skills Training (CST) was implemented as an adjunct to intensive diabetes management in adolescents.58 The treatment group used role-plays focused on social situations that are challenging for adolescents with diabetes, to develop social problem solving and conflict resolution skills using cognitive behaviour modification principles. All groups reported a decrease in HbA1c. Adolescents receiving intensive therapy plus CST reported better selfefficacy, less distress or difficulty in coping, and less impact of diabetes on quality of life in comparison to the control group. One-year later both physiological and psychological functioning had actually improved further.59 The level of distress or difficulty in coping was the only factor where between-group differences dissipated over time. Other studies also reported that diabetes-specific stress decreased over time in response to the intervention, but metabolic control, regimen adherence, coping styles, and self-efficacy about diabetes were unchanged.50;51 It is clear that no single intervention trialled to date results in improvement across all the variables of interest, nor do psychological and physical health parameters always respond in tandem. Further research is clearly needed, particularly with younger children and their families. The Evidence The evidence for the incidence and risk factors for non-adherence in children and adolescents with type 1 diabetes is listed in Evidence Table 13.1. • Non-adherence with treatment regimens is common in children and adolescents with type 1 diabetes.16;27;28;30-34;36-39;41;45(IV) 36-39 • Non-adherence with treatment regimens is common especially during teenage years, when an underlying psychiatric disorder is present,34;41;45 when the parents or child have a low level of education,27;28 when self-care autonomy is promoted or impeded at an inappropriate time,43 and when there is low level of cohesion within the family.27(IV) • Adolescents have also been found to omit or reduce insulin doses in order to produce glycosuria as a method of weight control.46;47;48(IV) The evidence for the effects of psychosocial interventions on metabolic and psychological outcomes in children and adolescents with type 1 diabetes is listed in Evidence Table 13.2. • A Health Technology Assessment systematic review on the effects of educational and psychosocial interventions for adolescents with diabetes found an overall small but positive effect on HbA1c and psychosocial outcomes. However, as many of the studies were small and different interventions were used, the need for larger high quality RCT’s in this area is identified.52(I) Chapter 13: Psychosocial Aspects Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 147 • An RCT (n=119) comparing Behavioral Family Systems Therapy (BFST) with standard treatment showed that BFST improved parent-adolescent relations and reduced family conflict, but effects on glycaemic control were mixed.53(II) • Another RCT (n=77) found the Coping Skills Training resulted in lower HbA1c and better diabetes and medical self-efficacy, and less impact of diabetes on their quality of life (P =0.005) than those receiving conventional management alone after 1 year.59(II) • An RCT comparing family focused teamwork with standard care found significantly improved diabetes control in the treatment group compared to controls, but no improvement in health-related quality of life or diabetes-related family conflict was found at one-year follow-up.55(II) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 13.3. Recommendations and Principles • Type 1 diabetes in childhood imposes a number of psychological stresses on both the child and the family.1;35;60;61(C) • Non-adherence with treatment regimens is common in children and adolescents with type 1 diabetes.16;27;28;30-34;36-39;41;45(IV) 36-39 • Non-adherence with treatment regimens is common especially during teenage years, 34;41;45 when an underlying psychiatric disorder is present, when the parents or child have a 27;28 when self-care autonomy is promoted or impeded at an low level of education, inappropriate time,43 and when there is low level of cohesion within the family.27(IV) • Health care professionals should be aware that adolescents may omit or reduce insulin doses in order to produce glycosuria as a method of weight control.46;47;48(IV) • Psychological interventions have been shown to improve HbA1c and psychosocial outcomes.52;53;55;59(I) I = Evidence from a systemic review of all relevant RCT’s II = Evidence from at least one properly-designed RCT IV = Evidence from case series, either post-test or pre-test and post-test C = Consensus statement endorsed by professional organisations Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 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Journal of Pediatrics 110:805-811, 1987 Johnson SB, Kelly M, Henretta JC, Cunningham W, Tomer A, Silverstein JH: A longitudinal analysis of adherence and health status in childhood diabetes. Journal of Pediatric Psychology 17:537-553, 1992 Johnson SB, Freund A, Silverstein J, Hansen CA, Malone J: Adherence-health status relationships in childhood diabetes. Health Psychology 9:606-631, 1990 Morris AD, Boyle DI, McMahon AD, Greene SA, MacDonald TM, Newton RW: Adherence to insulin treatment, glycaemic control, and ketoacidosis in insulin dependent diabetes mellitus. The DARTS/MEMO Collaboration. Diabetes Audit and Research in Tayside Scotland. Medicines Monitoring Unit. Lancet 350:1505-1510, 1997 Kyngas H: A theoretical model of compliance in young diabetics. Journal of Clinical Nursing 8:73-80, 1999 Kovacs M, Goldston D, Obrosky DS, Iyengar S: Prevalence and predictors of pervasive noncompliance with medical treatment among youths with insulin-dependent diabetes mellitus. Journal of the American Academy of Child & Adolescent Psychiatry 31:1112-1119, 1992 Satin W, La Greca AM, Zigo MA, Skyler JS: Diabetes in adolescence: effects of multifamily group intervention and parent simulation of diabetes. Journal of Pediatric Psychology 14:259-275, 1989 Wysocki T, Taylor A, Hough BS, Linscheid TR, Yeates KO, Naglieri JA: Deviation from developmentally appropriate self-care autonomy. Association with diabetes outcomes. Diabetes Care 19:119-125, 1996 Peyrot M, McMurry JF, Jr., Kruger DF: A biopsychosocial model of glycemic control in diabetes: stress, coping and regimen adherence. Journal of Health & Social Behavior 40:141-158, 1999 Goldston DB, Kelley AE, Reboussin DM, Daniel SS, Smith JA, Schwartz RP, Lorentz W, Hill C: Suicidal ideation and behavior and noncompliance with the medical regimen among diabetic adolescents. Journal of the American Academy of Child & Adolescent Psychiatry 36:1528-1536, 1997 Rodin G, Craven J, Littlefield C, Murray M, Daneman D: Eating disorders and intentional insulin undertreatment in adolescent females with diabetes. Psychosomatics 32:171-176, 1991 Peveler RC, Fairburn CG, Boller I, Dunger D: Eating disorders in adolescents with IDDM: A controlled study. Diabetes Care 15:1356-1360, 1992 Rydall AC, Rodin GM, Olmsted MP, Devenyi RG, Daneman D: Disordered eating behavior and microvascular complications in young women with insulin-dependent diabetes mellitus. New England Journal of Medicine 336:1849-1854, 1997 Chapter 13: Psychosocial Aspects Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 149 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. Maharaj SI, Rodin GM, Olmsted MP, Connolly JA, Daneman D: Eating disturbances in girls with diabetes: the contribution of adolescent self-concept, maternal weight and shape concerns and mother-daughter relationships. Psychological Medicine 33:525539, 2003 Wertlieb D, Hauser ST, Jacobson AM: Adaptation to diabetes: behavior symptoms and family context. Journal of Pediatric Psychology 11:463-479, 1986 Daviss WB, Coon H, Whitehead P, Ryan K, Burkley M, McMahon W: Predicting diabetic control from competence, adherence, adjustment, and psychopathology. Journal of the American Academy of Child & Adolescent Psychiatry 34:1629-1636, 1995 Hampson SE: Effects of educational and psychosocial interventions for adolescents with diabetes mellitus: a systematic review. Health Technology Assessment 5:1-79, 2001 Wysocki T, Greco P, Harris MA, Bubb J, White NH: Behavior therapy for families of adolescents with diabetes. Diabetes Care 24:441-446,2001 Anderson BJ, Brackett J, Ho J, Laffel LM: An office-based intervention to maintain parent-adolescent teamwork in diabetes management. Impact on parent involvement, family conflict, and subsequent glycemic control. Diabetes Care 22:713-721, 1999 Laffel L, Vangsness L, Connell A, Goebel-Fabbri A, Butler D, Anderson BJ: Impact of ambulatory, family-focused teamwork intervention on glycemic control in youth with type 1 diabetes. Journal of Pediatrics 142:409-416, 2003 Gross AM, Heimann L, Shapiro R, Schultz RM: Children with diabetes. Social skills training and hemoglobin A1c levels. Behavior Modification 7:151-164, 1983 Kaplan RM, Chadwick MW, Schimmel LE: Social learning intervention to promote metabolic control in type I diabetes mellitus: pilot experiment results. Diabetes Care 8:152-155, 1985 Grey M, Boland EA, Davidson M, Yu C, Sullivan-Bolyai S, Tamborlane WV: Short-term effects of coping skills training as adjunct to intensive therapy in adolescents. Diabetes Care 21:902-908, 1998 Grey M, Boland EA, Davidson M, Li J, Tamborlane WV: Coping skills training for youth with diabetes mellitus has long-lasting effects on metabolic control and quality of life. Journal of Pediatrics 137:107-113, 2000 Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Chapter 13: Psychosocial Aspects Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 150 Chapter 14: Diabetes Complications Long-term microvascular complications of diabetes can cause: • Blindness due to diabetic retinopathy. • Renal failure due to diabetic nephropathy. • Disabling pain due to diabetic neuropathy. Early microvascular changes are subclinical but can be detected by sensitive testing methods. The most important antecedents for the development of microvascular complications in children and adolescents are: • Longer duration of diabetes.1 • Older age.1 • Poor glycaemic control.2 3 • Family history of diabetes complications. The pubertal years accelerate the progression of microvascular complications of diabetes (retinopathy, nephropathy and neuropathy). Hypertension,4-9 dyslipidaemia10-13 and smoking14-19 influence the development of microvascular complications as well as macrovascular complications.20 Discussing Complications Families with a child or adolescent with diabetes should be made aware of the potential longterm complications of diabetes as part of their diabetes education. This information should also be made gradually known to the adolescent at a rate appropriate to his/her maturity and developmental stage.21 Young people need positive encouragement and education about complications during the adolescent period.21 Improvements in diabetes control, no matter how small, all reduce the risk for the development of microvascular complications.22;23 It is essential to emphasise that: • Long-term good metabolic control reduces the risk of development and progress of complications.2 • Outside of the normal range, there is no HbA1c threshold below which diabetes complications will not occur.22;23 22;23 • For every degree of improvement in diabetes control a benefit is obtained. These important facts can be used to motivate persons with diabetes to aim for gradual improvements, no matter how small, in their diabetes control. Screening for diabetes complications during adolescence reinforces this education process. The threat of complications should not be made in trying to motivate adolescents or the family to improve diabetes control. Diabetic Retinopathy Diabetic retinopathy is the fifth commonest cause of all blindness in Australia after congenital causes.24 Diabetes is estimated to be the commonest cause of new blindness in working age adults.25 Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 151 The features of background retinopathy are:26 • Microaneurysms (the only specific feature of diabetic retinopathy). • Haemorrhages (intraretinal and preretinal). • Soft exudates (microinfarctions). • Hard exudates (protein and lipid leakage). • Intra-retinal microvascular abnormalities (IRMA). • Dilatation, constriction and tortuosity of vessels. Background retinopathy is not vision-threatening and may remain stable for years. It is an almost universal finding in individuals with diabetes of over 20 years duration. Microaneurysms are specific to diabetes and are not found in nondiabetic adolescents.27 They may be transient, lasting from months to years.28 In some cases background retinopathy can progress to vision-threatening retinopathy which includes:1;26;29;30 • Pre-proliferative retinopathy. • Proliferative retinopathy. • Maculopathy. Pre-proliferative retinopathy is characterised by vascular obstruction, progressive IRMA and infarctions of the retinal nerve fibre layer causing ‘cotton wool’ spots. Proliferative retinopathy is characterised by the formation of new blood vessels (neovascularisation) in the retina and/or vitreous posterior surface and is vision-threatening. The vessels may rupture or bleed into the vitreoretinal space. Encasement in connective tissue results in adhesions, which can cause haemorrhage and retinal detachment. High-risk characteristics for visual loss are the location and extent of neovascularisation and signs of vitreous or preretinal haemorrhage.31 In diabetic maculopathy, decreased vascular competence and microaneurysm formation produce exudation and swelling in the central retina that can significantly decrease visual acuity. The most sensitive detection methods for retinopathy are: • Stereoscopic fundal photography. • Fluorescein angiography. Stereoscopic fundal photography is at least twice as sensitive as direct ophthalmoscopy for the less severe disease.32;33 Fundal photography (7-field) is comparable to two- field fluorescein angiography in detecting retinopathy,34 however the latter requires intravenous injection of fluorescein. Fluorescein commonly causes nausea and may cause anaphylactic reactions.35 Fluorescein angiography reveals functional abnormalities (vascular permeability) as well as structural abnormalities in the blood vessels whereas fundal photography reveals only structural abnormalities. Both methods produce a recording (hard copy or electronic), which can be referred to in subsequent assessments and can be shown to the adolescent. Prevalence and association studies of retinopathy The largest epidemiological study of diabetic retinopathy revealed the prevalence of any grade of retinopathy to be:6 • 17% in those with less than five years diabetes duration. • 50% after 5-6 years diabetes duration. • 98% after 15 or more years duration. Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 152 Proliferative retinopathy was present in:6 • 4% after 10 years duration. • 25% after 15 years. • 67% after 35 years. The frequency and severity of retinopathy were strongly associated with increasing diabetes duration.6 The severity of retinopathy was also independently associated with increasing age. Children less than 13 years of age had a lower prevalence of background retinopathy (9 percent) than those over 13 years (34 percent) with the same mean duration.36 In 1994, an Australian study of adolescents with type 1 diabetes showed that background retinopathy was found in 42 percent (using stereoscopic fundal photography), with highly significant associations with both total diabetes duration and glycaemic control.37 At a median follow-up of 1.3 years, progression had occurred in 11% and regression in 5%.38 High blood pressure is a risk factor for the development and progression of retinopathy4;6;8 even after controlling for microalbuminuria.4 The evidence for an association of smoking with retinopathy is inconsistent.15;17;18;19;30;39 Higher cholesterol has been correlated with hard exudates and macular oedema10 and lower HDL-cholesterol is associated with more retinopathy.12 Proliferative retinopathy is rare before 10 years of diabetes. In the Wisconsin study, proliferative retinopathy, though rare, did occur in patients less than 20 years of age and, in a few, as early as five years after diabetes.6 Screening for retinopathy There is no evidence available to determine the optimal frequency for screening for retinopathy in the paediatric and adolescent age group. One study is currently underway using 7-field stereoscopic fundal photography and thus data to answer this question may be available soon. The current ISPAD recommendation is to screen for retinopathy annually in adolescents after 2 years of diabetes and after 5 years of diabetes in those who are prepubertal.21 The Canadian Guidelines 2003 recommend annual screening in those >15 years of age and after 5 years of diabetes.40 The NICE Guidelines do not offer a recommendation for children and adolescents and recognise there is a diversity of views but indicate that for adults with type 1 diabetes screening should start at diagnosis and be performed annually.41 If stereoscopic fundal photography is used then biennial assessment may be appropriate for those with minimal background retinopathy, diabetes duration of less than 10 years and if the HbA1c is not significantly elevated. If significant retinopathy is present then more frequent review is necessary.21;42 Immediate expert ophthalmological management should be sought if any of the following are noted:42 • Progression of retinopathy to more than 10 microaneurysms. • Moderate non-proliferative or preproliferative retinopathy. • Visual change or deterioration, macular oedema or proliferative changes. The ISPAD Consensus Guidelines 2000 recommend that assessment as a minimum should be by ophthalmoscopy through dilated pupils by an observer with special expertise in diabetic eye disease21 (pupil dilation by Cyclopentilate 1% + Phenylephrine 2.5% or Tropicamide 1% ± Phenylephrine 10%). Whilst the preferred method is by stereofundal retinal photography through dilated pupils, the need for mydriasis is being investigated. Nonmydriatic retinal photography may have a place in retinal screening in type 2 diabetes in which maculopathy is Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 153 a commoner form of sight-threatening disease. However, its place is not clear in type 1 diabetes which is characterised by proliferative, often peripheral, retinopathy as a cause of sight-threatening disease. The Health Technology Board for Scotland assessment report43 states that there is no clear evidence that mydriasis or the routine use of more than one image significantly alters the sensitivity or specificity of screening for the detection of sightthreatening retinopathy in adults. Comparable screening accuracy is achieved with digital cameras, with or without mydriasis, however direct comparisons suggest that mydriasis may occasionally result in a successful image when non-mydriatic imaging fails.43 Interventions to prevent or delay progression of diabetic retinopathy The Diabetes Control and Complications Trial showed that intensive diabetes management reduced the risk and progression of background retinopathy by 53% in adolescents.2 In the adolescent cohort, vision-threatening retinopathy was too infrequent to allow comparison between the intensive and conventionally managed groups. In the subsequent four year follow-up after completion of the DCCT (EDIC-Epidemiology of Diabetes Interventions and Complications), the intensive group continued to have a reduction in significant progression despite a narrowing of the HbA1c difference between intensively and conventionally treated groups (median 6.5 years of intervention).44 Laser intervention was needed in 6% of the conventional group compared with 1% of the formerly treated intensive group.44 Improved metabolic control may initially worsen diabetic retinopathy, however within 1.5 to 3 years; definite advantages of intensive treatment in these patients are evident.45-47 Intervention to improve glycaemic control is currently the only established therapy to retard the progression of early retinopathy in adolescents. A randomised controlled trial in adults showed reduction in progression of retinopathy with lisinopril (angiotensin converting enzyme inhibitor) over a 2-year period in normotensive adults with type 1 diabetes.48 Randomised controlled trials using the older lipid-lowering drugs have shown a reduction in retinal hard exudates.49-51 Large multicentre randomised trials in adults have shown that laser therapy reduces visual loss from proliferative retinopathy.31;52 In at-risk eyes, timely laser intervention halves the risk of blindness. Focal laser photocoagulation is beneficial in eyes with macular oedema. Intervention needs to occur before clinical symptoms of visual loss. Cataracts The lens should be assessed, preferably by slit lamp examination, as specific stellate cataracts can be seen in children after relatively short diabetes duration. On close questioning these children often have symptoms suggestive of a prolonged antecedent history. The cataracts can be vision-threatening and therefore may need excision. Clinical examination of the eyes for the presence of cataracts should be performed soon after diagnosis,21 especially if there has been a slow/prolonged onset of diabetes.53;54 Refractive Errors Changes in blood glucose levels (e.g. during prolonged hyperglycaemia or more commonly following stabilisation or initiation of treatment on diagnosis) can cause transient accommodative problems. If there have been changes in glycaemic control, it is preferable to delay the prescription of spectacles for 3 months. Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 154 Diabetic Nephropathy Diabetic nephropathy is the second most common cause of end-stage renal disease in Australia (after glomerulonephritis) and the commonest in New Zealand.55 Diabetic nephropathy is also associated with premature death, generally due to associated macrovascular disease.56;57 Persistent microalbuminuria has been shown to predict the development of clinical diabetic nephropathy marked by gross proteinuria 6-14 years later.58-60 This progresses to end-stage renal failure and is associated with increased risk of macrovascular disease.56;57 Albumin excretion rate can vary by as much as 40% for an individual so more than a single sample is recommended when screening for renal disease.61 The definitions of microalbuminuria vary from centre to centre and include: • Albumin excretion rate (AER) greater than 20 ug/min but less than 200 ug/min on a minimum of two of three consecutive timed overnight urine collections.62 62 • Albumin/creatinine ratio (ACR) 2.5 - 25 mg/mmol (spot urine). • (3.5 – 25 has been proposed in females because of lower creatinine excretion) 62 • Albumin/creatinine ratio (ACR) 30-300 mg/gm (spot urine). 62 • Albumin concentration (AC) 30-300 mg/L (early morning urine). • In the DCCT microalbuminuria was defined as urinary albumin excretion greater or equal to 40 mg per 24 hours (or 27.8µg/min) and less than 300 mg per 24 hours.63 Some groups have found that elevation at even lower levels predicts progression.64 In a collaborative Australian study, a mean AER of 7.2 to 20µ g/min predicted progression to microalbuminuria (four of six overnight urine specimens greater than 20µg/min) compared with adolescents with a mean AER less than 7.2µg/min.65 Regression of microalbuminuria was documented in the DCCT and other studies. In an 8 year follow-up study of patients aged 15-44 years with microalbuminuria (defined as a mean albumin excretion rate of 30-299 ug/min determined over the first two years), the six year regression rate was 58% with progression to proteinuria only in 15%.66 Even using a definition of two of three abnormal timed collections for persistent microalbuminuria, it has been recognised that regression back to normal can occur.67;68 Although an effect of duration has not always been demonstrated,69 the Oxford Regional Prospective Study Group found that the cumulative probability for developing microalbuminuria in children was 40% after 11 years of diabetes duration.70 Hypertension is generally established by the time of overt nephropathy. It remains controversial whether blood pressure actually starts to rise during the transition from normoalbuminuria to microalbuminuria or once microalbuminuria occurs. High blood pressure is clearly associated with microalbuminuria. Mathiesen found the blood pressure to rise only after microalbuminuria had occurred.71 In contrast, others have found that blood pressure rose in parallel with the rise in AER.72 A cross sectional Australian study of adolescents showed that ambulatory blood pressure measurements were already higher during the phase of intermittent microalbuminuria compared to measurements in normoalbuminuric adolescents.73 Longitudinal studies have shown that nocturnal hypertension74 and increased ambulatory blood pressure75;76 precedes microalbuminuria. Screening for nephropathy The current ISPAD recommendation is to screen for microalbuminuria annually in:21 • Adolescents after 2 years of diabetes. • Prepubertal children after 5 years of diabetes. Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 155 Screening should be by either:21 • Timed urine collections (preferably overnight). or • A spot urinary albumin/creatinine ratio. The Canadian Guidelines 2003 recommend annual screening in postpubertal adolescents with a duration of diabetes >5years or at the commencement of puberty and having a duration of diabetes >5years.40 The NICE guidelines recognise the above diversity of views.41 Overnight timed collections are regarded as preferable as they avoid orthostatic and postexercise proteinuria. The spot or random albumin/creatinine ratios have the convenience of ease of collection but are less sensitive for detecting rises within the normal range of albumin excretion. If microalbuminuria is found then screening should be more frequent, and other renal investigations undertaken and specific focus should be placed on blood pressure measurements.21 Implications of persistent microalbuminuria should be discussed with the adolescent and the family. Other factors that can cause microalbuminuria or lead to the false diagnosis of microalbuminuria are: • Glomerulonephritis. • Urinary tract infection. • Intercurrent infections. • Menstrual bleeding. • Vaginal discharge. • Orthostatic proteinuria. • Strenuous exercise. Interventions to prevent or delay progression of diabetic nephropathy The Diabetes Control and Complications Trial showed that intensive diabetes management reduced the risk of developing microalbuminuria by 55% in adolescents in the secondary intervention arm (with diabetes duration >5 years at entry).2 In the adolescent primary prevention cohort, intensive diabetes management reduced the risk of developing microalbuminuria by 10% percent. In the EDIC Study (the subsequent 4 year follow-up after completion of the strict two treatment arms), the intensive group continued to have a reduction in significant reduction in development of microalbuminuria (53%) and proteinuria (86%).44 Effective antihypertensive therapy in patients with nephropathy (protein excretion >500 mg/ 24 hours or AER >200 ug/min) has dramatically prolonged the time to end-stage renal disease from 7 to 21 years. Angiotensin Converting Enzyme Inhibitors (ACEI) slows the decline in renal function more effectively than other antihypertensive agents.77;78 The introduction of ACEI must be combined with monitoring of serum potassium and creatinine concentrations. ACEIs are not licensed for use in pregnancy. If hypertension is not treated effectively with ACEI alone, additional antihypertensives should be considered. In normotensive patients with microalbuminuria, ACEI reduce urinary albumin excretion;79 however a delay in progression to clinically overt nephropathy has not been shown. They may in fact only mask the signs of the disease. Cessation of therapy has led to a rapid increase in albuminuria similar to those in the placebo treated group. The angiotensin II receptor antagonists are a relatively new class of drugs that are promising and have a more specific effect on renoprotection than ACEI although to date most large studies have been in adults with type 2 diabetes and nephropathy.80-82 Some reviews Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 156 indicate that they may also have a role in paediatric patients with diabetes and renal disease although published studies are still awaited.83 Close attention to improving glycaemic control,2 cessation of smoking,16 care in prescribing of OCP’s (see Chapter 18)14 and monitoring of lipids are important aspects in the management of the patient with microalbuminuria.11 Lowering of the nutritional protein intake to decrease protein excretion in growing children is not recommended, however excessive nutritional protein intake should be discouraged (recommended maximum of 1.0-1.2 gm/kg body weight/day).21 Diabetic Neuropathy Although clinical symptoms and signs of nerve disease in children and adolescents with type 1 diabetes are rare, studies have now demonstrated the presence of subclinical abnormalities. The natural history of these subclinical findings is not yet clear; in particular, which patients from this group progress to having more significant clinical abnormalities. The presence of reduced sensation in the feet places the adolescent at increased risk of foot problems and a referral for podiatric assessment is indicated. Neuropathy needs to be considered in such situations as a child with recurrent vomiting (possibly due to autonomic neuropathy) or persistent pain syndromes (possibly due to peripheral neuropathy). The prepubertal child is not necessarily protected from risk.84 Peripheral neuropathy predisposes to foot ulceration and amputation. Painful peripheral neuropathy can be disabling in young adults with childhood-onset diabetes85. Autonomic neuropathy has been associated with an increased risk of sudden death (due to hypoglycaemic unawareness or arrhythmia) and increased mortality.86 Screening for neuropathy In adults with type 1 diabetes the consensus recommendation is for annual clinical evaluation for the presence of peripheral nerve function. Clinical neuropathy is rare in children and adolescents with type 1 diabetes even though prospective nerve conduction studies and autonomic neuropathy assessment studies have demonstrated increased prevalence of abnormal findings with greater duration of diabetes.21;87-90 Persistence of such abnormalities is an inconsistent finding.87 With the exception of intensifying diabetes management no other treatment is available. In the presence of poor diabetes control the following clinical assessment should be undertaken: • History, especially of numbness, pain, paraesthesia. • Assessment of vibration sensation (by tuning fork or biothesiometer). • Assessment of ankle reflexes. • Assessment of sensation (by conventional neurologic examination or by graduated filaments). In addition, non-invasive tests of subclinical nerve function are available in some major paediatric diabetes centres. These tests include: • Autonomic nerve tests: Heart rate response to deep breathing. Heart rate response to standing. Heart rate response to Valsalva manoeuvre. Postural change in blood pressure. Pupillary responses (dark adapted pupil size, rate of constriction and dilatation following a flash of light). • Peripheral nerve tests: Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 157 Vibration sensation threshold (using a biothesiometer). Thermal discrimination thresholds. Nerve conduction. With all of the above tests of subclinical nerve function it is important that age- and genderspecific normal ranges are applied when interpreting results. The long-term implications of finding early neuropathy are not yet established and apart from recommending improved glycaemic control there is no proven specific therapy available. Interventions to prevent or delay diabetic neuropathy In the Primary Prevention Cohort of the DCCT, intensive therapy caused a 69% reduction in the development of clinical neuropathy and in the Secondary Intervention Cohort a 56% reduction.63 Clinical neuropathy was not sufficiently common for a significant effect to be seen in the combined Adolescent Cohort (7/103 in the conventional group and 3/92 in the intensive group).2 Aldose reductase inhibitors may have a place in the treatment of neuropathy91 but are not yet available for clinical use. Macrovascular Disease Cardiovascular disease is the major cause of mortality in adults with type 1 diabetes. Clinical macrovascular disease is rare under the age of 30 years. However, increased aortic and carotid intima-media thickness has been detected by ultra-sensitive ultrasound in adolescents with type 1 diabetes.92-94 Intensive therapy during the DCCT resulted in decreased progression of intima-media thickness six years after the end of the trial.95 Even though macrovascular disease is not seen in type 1 diabetes in the childhood or adolescent years, risk factors that predispose to it are frequently present, and adolescents and their families should be aware of these: • Hypertension. • Dyslipidaemia. • Smoking. • Obesity. • Microalbuminuria and diabetic nephropathy. • Hypercoagulability. • Family history of cardiovascular disease. Hypertension Blood pressure assessment in children and adolescents Due to the pivotal role that blood pressure (BP) plays in the evolution of the microvascular complications of diabetes, early and accurate diagnosis of hypertension is important to enable early initiation of treatment where indicated. Method for BP measurement Blood pressure measurement needs to be accurate and reproducible. A variety of methods exist to measure blood pressure, each of which has its strengths and weaknesses. Irrespective of the method used, standardisation of the method of measurement is important to reduce interobserver error. These include: • Position of patient: for static measurement of BP, the patient should be seated quietly for at least 5 minutes. Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 158 • Blood Pressure Cuff Size: An appropriate selection of cuff sizes is required to ensure that the bladder spans the circumference of the arm and covers at least 75% of the upper arm without obscuring the antecubital fossa. Sphygmomanometer The sphygmomanometer is the most frequently used and least expensive method of BP measurement. It is also the method most likely to result in readings with significant intraindividual and interobserver variability. To reduce this problem the method of recording BP should be standardised by: • Readings should be taken in the right arm. • The arm should be held at the level of the heart. • The manometer should be positioned at the eye level of the person performing the measurement to avoid parallax error. • Initial cuff inflation should occur while manually palpating the radial pulse to estimate systolic BP. • The stethoscope should then be placed lightly over the brachial artery (excessive pressure may create turbulence and confound results) and the cuff inflated to 20 mm Hg above systolic pressure. • Deflation should be at 2-3 mm Hg per second. • Systolic blood pressure corresponds with the onset of the audible sound (K1 - the first Korotkoff sound). • As deflation of the cuff continues, the sounds will become muffled (K4) before eventually disappearing (K5). • Diastolic BP was previously taken as K4 in children less 13 years of age, and as K5 in children greater than 13 years of age. The update on the 1987 taskforce report on high blood pressure in children and adolescents, published in 1996 recommends the use of K5 in all age groups even if Korotkoff sounds are audible down to 0 mm Hg.96 • 2 measurements should be made per visit with the mean systolic and diastolic BP taken. • Results should be interpreted in light of age, gender and height specific centiles (Table 14.1).96 Dinamap Static oscillometric blood pressure measurement devices are being used in increasing numbers in the clinical setting. Although more expensive than the sphygmomanometer, they provide reliable, reproducible readings and require minimal training. Issues of standardisation of measurement technique and appropriate equipment use are the same as for measurements with sphygmomanometer. Studies that have compared this method of measurement with conventional sphygmomanometry have obtained reasonable, although not perfect correlation97 for population. Comparison for individuals may not correlate as well, although this will be influenced by the degree of inter- and intraindividual variability that occurs with sphygmomanometer measurements. Single BP measurements with Dinamap can not differentiate ‘white coat hypertension’ (transient elevation of BP in a clinic setting) from persistent hypertension. The use of multiple supine values is more effective because BP frequently falls with repeated measurement. There are practical issues with this approach in the busy clinic setting. Paediatric reference values There are no studies that establish paediatric reference values using Dinamap. Studies that employ static oscillometric devices frequently use reference data from the second taskforce Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 159 on BP in children, which may not be valid, given that systolic BP is higher and diastolic BP lower with Dinamap measurements when compared with BP measurement using sphygmomanometer.98;99 Ambulatory blood pressure monitoring Ambulatory blood pressure monitoring provides more information than any other method of BP measurement, and correlates best with the risk of hypertension-induced target organ damage.100 Ambulatory blood pressure monitors use either an auscultatory or an oscillometric method to measure blood pressure. The auscultatory method requires the use of a microphone to detect the Korotkoff sounds. This method directly measures systolic and diastolic BP and is more prone to false positive readings due to interference from environmental noise or damage to the microphone. Oscillometric monitors are simpler, more robust, and not as prone to false positive readings. They measure systolic and mean blood pressures directly and calculate diastolic pressure. They are prone to the same variation as the Dinamap when compared with sphygmomanometer readings. Most of the studies that have developed reference ranges for ambulatory BP monitoring in children have used oscillometric monitors. Advantages of ambulatory BP monitoring over other methods of BP measurement include: • Ability to differentiate ‘white coat hypertension’, which may not pose the same risk of morbidity as persistent hypertension. • Ability to evaluate diurnal blood pressure variability - lack of nocturnal fall in BP is a predictor of progression of diabetes complications.74 • Ability to determine blood pressure burden and more effectively determine effectiveness of interventions. • Better correlation with end organ damage. • Simultaneous evaluation of heart rate variability, which may be an early marker of autonomic dysfunction. Disadvantages of ambulatory BP monitoring over other methods of BP measurement include: • Cost - average ambulatory blood pressure monitors costs $2000-$4000 to purchase. • Time consuming to staff and patient - which limits its usefulness as a screening tool. • Monitoring disturbs sleep in some adolescents. Paediatric reference values Several large studies have established paediatric reference ranges for ambulatory BP monitoring using oscillometric monitors101;102 although there are no large studies of this in an Australian paediatric population. Systolic ambulatory BP correlates with height SDS, BMI SDS, and heart rate SDS, whereas diastolic ambulatory BP correlates weakly with BMI SDS only.101 Summary of blood pressure measurement methods • Manual methods of BP measurement are most prone to measurement error although are cheapest and have the most well-established reference ranges. • Automated methods are simpler to use although values need to be interpreted carefully given that they use a different method of measuring blood pressure. • Ambulatory BP monitoring: Provides the most detail. Is useful for identifying borderline hypertension, and individuals with ‘white coat hypertension’, in addition to establishing treatment effectiveness. Is good at detecting early signs of autonomic neuropathy. Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 160 Is expensive and the time required to perform this technique mean that it is frequently not used as a primary screening tool. Age of screening for hypertension Screening for hypertension should start at 3 years of age, although if the aim is to identify hypertension resulting from non-diabetes related causes, measurement should start at diagnosis of diabetes regardless of age, and continue at least annually if BP is less than 90th centile for age and height. When blood pressure reaches the 90th-95th centile, BP should be measured at least 6 monthly. If systolic and/or diastolic BP exceeds the 95th centile, measurements should be performed at each visit, given that the diagnosis of hypertension requires persistent elevation on three consecutive occasions. Definition of hypertension The US Task Force on BP control in children has defined hypertension as the average of systolic and/or diastolic BP readings greater than or equal to the 95th percentile for age and sex based upon measurements obtained on at least three occasions96 (Table 14.1). BP readings between 90th and 95th percentiles are regarded as high normal BP and require close and repeated monitoring. In addition to height, age and gender, weight and parental hypertension are major influences of BP.103 Family studies of patients with type 1 diabetes who develop nephropathy commonly have non-diabetic parents who have essential hypertension, and also patients with diabetes who have a family history of cardiovascular disease are up to 3 times more likely to develop nephropathy.104 BP readings should be tracked longitudinally since even children without diabetes whose BP is in the upper centiles are more likely to become hypertensive as adults.96 Nomograms, based upon US data, are available for children that take into account age, gender and height.105 Obesity can also result in significant increases in blood pressure. Management of hypertension All children with type 1 diabetes who are discovered to have hypertension need investigation to establish the cause. There are frequently clinical clues that direct investigations that may include: • Clinical examination to look for evidence of cardiac murmurs (coarctation) or renal bruits (renal artery stenosis). • ECG and echocardiographic assessment of left ventricular size and thickness (looking for left ventricular hypertrophy). • Fundoscopy looking for retinal changes of hypertension. • Microscopy of urine for sediment and red cell content and morphology. • Determination of urine protein excretion. • Measurement of electrolytes, urea and creatinine. • Other investigations which may be indicated based upon clinical findings may include: Renal ultrasound. DMSA renal scan. Renin and aldosterone measurement. Urinary catecholamine measurement. • Drug treatment (see Interventions to prevent or delay progression of diabetic nephropathy). Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 161 Table 14.1: Blood Pressure Ranges for Height Centiles Boys Systolic BP by Height Centile Girls Diastolic BP by Height Centile Systolic BP by Height Centile Diastolic BP by Height Centile Age (yrs) Height centile BP Centile 1 90th 94 98 102 50 53 55 97 100 104 53 54 56 95th 98 102 106 55 57 59 101 104 107 57 58 60 90th 100 105 109 59 61 63 100 103 106 61 62 64 95th 104 109 113 63 65 67 104 107 110 65 66 68 90th 104 108 112 65 67 69 103 106 109 65 67 69 95th 108 112 116 69 71 74 107 110 113 69 71 73 90th 106 111 115 69 72 74 106 109 112 69 70 72 95th 110 115 119 74 76 78 110 113 116 73 74 76 90th 109 113 117 72 74 77 110 113 116 71 73 75 95th 113 117 121 76 79 81 114 117 121 75 77 79 90th 112 117 121 74 76 78 114 117 120 74 75 77 95th 116 121 125 78 80 83 118 121 124 78 79 81 90th 117 122 126 75 77 80 118 121 124 76 78 80 95th 121 126 130 79 82 84 121 125 128 80 82 84 90th 123 127 131 77 79 81 121 124 127 78 79 82 95th 127 131 135 81 83 86 124 128 131 82 83 86 90th 128 133 136 81 83 85 122 125 128 79 80 82 95th 132 136 140 85 87 89 126 129 132 83 84 86 3 5 7 9 11 13 15 17 5% 50% 95% 5% 50% 95% 5% 50% 95% 5% 50% 95% Adapted from: Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: A Working Group of the NHBPEP. Pediatrics. 98(4):649-658. Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 162 Dyslipidaemia There is no consensus about the optimum age at which screening for lipid abnormalities should commence in children with diabetes. The natural history of lipid disorders has not been clearly established in children with type 1 diabetes, although the adverse effects of poor glycaemic control and of puberty on the lipid profile are known. Children with diabetes have been shown to have higher levels of total and LDL cholesterol, HDL cholesterol and apolipoproteins A1 and B than their siblings106 or controls without diabetes.107 Even with good glycaemic control and normal or increased HDL-C levels, adult patients with type 1 diabetes are at increased risk of developing accelerated atherosclerosis. Type 1 diabetes is associated with a greater proportion of smaller, more atherogenic LDL particles, than controls without diabetes. Oxidation108 and non-enzymatic glycation109 increase the atherogenic risk of LDL particles, by interfering with their clearance. Hypercholesterolaemia is a risk factor for atherosclerotic vascular disease in all adult groups studied although children and adolescents have not been studied. In adults with type 1 diabetes, interventions that lower LDL cholesterol to levels <2.8 mmol/l, lower triglycerides and raise HDL cholesterol result in a reduction in the number of cardiovascular events.110 The American Diabetes Association recommends screening for lipid disorders on an annual basis in adults and 5 yearly in children >12 years of age if initial values are considered low risk.110;111 Another group recommends screening for dyslipidaemia within 6 months of diagnosis and re-testing mid-puberty.112 In most Australian tertiary paediatric diabetes clinics, screening for lipid disorders starts in: • Prepubertal children after 5 years. • Pubertal or postpubertal children after 2 years. Screening should include measurement of: • Total cholesterol. • LDL cholesterol. • HDL cholesterol. • Triglycerides. This should ideally be performed following an overnight fast, given that reference values for cholesterol subfractions have been established on fasting samples. For screening purposes, random measurement of lipid levels is acceptable, although triglyceride levels may be higher, which affects calculated LDL cholesterol levels. Interventions for dyslipidaemia There are no studies that have determined the age at which treatment should be initiated in adolescents with type 1 diabetes and dyslipidaemia. Interventions to be considered in adolescents with dyslipidaemia include: • Intensive glycaemic control. • Attempts to achieve a more normal weight if obese. • Regular exercise. • Low saturated fat intake (<10% of energy intake). Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 163 • • • • • Low cholesterol diet (step 1 cholesterol intake <300 mg/day, step 2 cholesterol intake <200 mg/day). Statins.113 Nicotinic acid.114;115 Bile acid sequestrants.115 Fibroic acid derivatives. Fibrates have been shown to lower the rate of carotid intima medial thickening in asymptomatic hyperlipidaemic adults with type 1 diabetes.116 There is limited experience with their use in children. Combination of a statin and a fibrate may increase the beneficial effects on lipids but also increases the risk of adverse events including abnormal liver function tests, rhabdomyolysis and myositis.110 Hypercoagulablity Diabetes is associated with hypercoagulability. Low dose aspirin has been recommended for adults with diabetes. However, the American Diabetes Association guidelines advise against its use in those under age 20 years because of the increased risk of Reye Syndrome.110 Cost Issues No studies were identified which addressed the costs associated with screening for and treating of microvascular or macrovascular complications of type 1 diabetes in children and adolescents. A few studies were identified that addressed these issues in adults in different health care settings. These results may not be applicable to the Australian health care setting. In 1996 the Diabetes Control and Complication Research Group (using a Monte Carlo model system) concluded that intensive therapy (compared with conventional therapy) was well within the range of cost-effectiveness considered to represent good value in the American health care system.117 This model did not include future costs. Another analysis based on the DCCT model did include future costs and concluded that intensive therapy is even more cost effective when future costs are considered.118 A computer model analysis (from the Swiss health insurance payer perspective) found that screening for microalbuminuria and retinopathy followed by appropriate treatment, were cost saving, with reduction in cumulative incidence of end stage renal disease and blindness respectively and an improvement in life expectancy for those with microalbuminuria.119 Whilst other computer model analysis agree that screening for nephropathy is cost effective,120 some disagree.121 The Evidence The evidence on the effect of intensive diabetes management on microvascular and macrovascular complications in adolescents with type 1 diabetes is listed in Evidence Table 14.1. • The Diabetes Control and Complications Trial confirmed the relationship between good glycaemic control (HbA1c) and decreased incidence of microvascular and macrovascular complications in both adults and adolescents.2;20;22;63;95(II) Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 164 No studies were identified specifically addressing the optimum frequency of screening for microvascular complications of type 1 diabetes in children and adolescents, therefore the recommendations for screening reflect current consensus guidelines.21;122(C) No studies were identified specifically addressing the optimum frequency of screening for macrovascular complications of type 1 diabetes in children and adolescents; therefore the recommendations for screening reflect current consensus guidelines.110;111;122(C) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 14.2. Recommendations and Principles • Type 1 diabetes confers the risk of long-term diabetes microvascular complications.2;20;63;95(II) • Families with a child or adolescent with diabetes should be made aware of the potential long-term complications of diabetes as part of their diabetes education. Adolescents should be made aware at a rate appropriate to their maturity.21;122(C) • Families with a child or adolescent with diabetes should be made aware that long-term good metabolic control reduces the risk of development and progress of complications.2;63(II) • Families with a child or adolescent with diabetes should be made aware that other modifiable risk factors for diabetic microvascular complications include higher blood pressure, smoking and dyslipidaemia.2;63(II) • Screening for retinopathy should be performed annually in adolescents after 2 years of diabetes and after 5 years of diabetes in those who are prepubertal.21;122(C) • Assessment for retinopathy should be by an observer with special expertise in diabetic eye disease. If stereoscopic fundal photography is used then biennial assessment may be appropriate for those with minimal background retinopathy, diabetes duration of less than 10 years and if the HbA1c is not significantly elevated. If moderately severe retinopathy is present then more frequent review is necessary.42;122(C) • Clinical examination of the eyes for cataracts should be performed soon after diagnosis, especially if there has been slow or prolonged onset of diabetes.21;122(C) • Screening for microalbuminuria should be performed annually in adolescents after 2 years of diabetes and after 5 years of diabetes in those who are prepubertal. Assessment should be either by timed overnight urine collections or a spot urinary albumin/creatinine ratio. If microalbuminuria is found then screening should be more frequent, and other renal investigations undertaken and specific focus should be placed on blood pressure measurements.21;122(C) • In the presence of poor diabetes control, clinical evaluation of peripheral nerve function should occur annually and should as a minimum include:122(C) History (especially of numbness, pain, paraesthesia). Assessment of vibration sensation (by tuning fork or biothesiometer). Assessment of ankle reflexes. Assessment of sensation. • Type 1 diabetes frequently results in accelerated atherosclerosis. Good glycaemic control can decrease this risk.20;95(II) • Blood pressure measurements should be recorded at diagnosis and, if normal, annually. Hypertension should be considered to be present if repeated blood pressure levels are >95th centile for age, gender and height specific normative data.122(C) Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 165 • Screening for lipid disorders should begin within 6-12 months of diagnosis of diabetes, and if normal should be performed every 5 years in prepubertal children and every second year in pubertal children.110;111(C) II = Evidence obtained from at least one properly designed RCT C = Consensus statement endorsed by professional organisations Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. Klein R, Klein BEK, Moss SE: The Wisconsin epidemiological study of diabetic retinopathy. IX. Four year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years. 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American Journal of Diseases of Children 144:911-914, 1990 Page SR, Manning G, Ingle AR, Hill P, Millar-Craig MW, Peacock I: Raised ambulatory blood pressure in type 1 diabetes with incipient microalbuminuria. Diabetic Medicine 11:877-882, 1994 Wuhl E, Witte: Distribution of 24-h ambulatory blood pressure in children: normalized reference values and role of body dimensions. Journal of Hypertension 20:1995-2007, 2002 Soergel M, Kirschstein M, Busch C, Danne T, Gellerman J, Holl R: Oscillometric twenty-four hour ambulatory blood pressure values in healthy children and adolescents: A multicenter trial including 1141 healthy subjects. Journal of Pediatrics 130:178-184, 1997 National Heart, Lung, and Blood Institute: Report of the Second Task Force on Blood Pressure Control in Children--1987. Task Force on Blood Pressure Control in Children. Pediatrics 79:1-25, 1987 Viberti GC, Earle K: Predisposition to essential hypertension and the development of diabetic nephropathy. Journal of the American Society of Nephrology 3:27-33, 1992 Rosner B, Prineas RJ, Loggie JM, Daniels SR: Blood pressure nomograms for children and adolescents, by height, sex, and age, in the United States. Journal of Pediatrics 123:871-886, 1993 Sosenko JM, Breslow JL, Miettinen OS, Gabbay KH: Hyperglycemia and plasma lipid levels: a prospective study of young insulindependent diabetic patients. New England Journal of Medicine 302:650-654, 1980 Lopes-Virella MF, Wohltmann HJ, Loadholt CB, Buse MG: Plasma lipids and lipoproteins in young insulin-dependent diabetic patients: relationship with control. Diabetologia 21:216-223, 1981 Lyons TJ: Oxidized low density lipoproteins: a role in the pathogenesis of atherosclerosis in diabetes? Diabetic Medicine 8:411419, 1991 Lyons TJ, Jenkins AJ: Lipoprotein glycation and its metabolic consequences. Current Opinion in Lipidology 8:174-180, 1997 American Diabetes Association: Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care 26:33S, 2003 American Diabetes Association: Management of Dyslipidemia in Children and Adolescents with Diabetes. Diabetes Care 26:21942197, 2003 Sochett E, Daneman D: Early diabetes-related complications in children and adolescents with type 1 diabetes. Implications for screening and intervention. Endocrinology & Metabolism Clinics of North America 4:865-882, 1999 de Jongh S, Ose L, Szamosi T, Gagne C, Lambert M, Scott R, Perron P, Dobbelaere D, Saborio M, Tuohy MB, Stepanavage M, Sapre A, Gumbiner B, Mercuri M, van Trotsenburg AS, Bakker HD, Kastelein JJ: Simvastatin in Children Study Group. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial with simvastatin. Circulation 106:2231-2237, 2002 Stein EA, Illingworth DR, Kwiterovich PO Jr, Liacouras CA, Siimes MA, Jacobson MS, Brewster TG, Hopkins P, Davidson M, Graham K, Arensman F, Knopp RH, DuJovne C, Williams CL, Isaacsohn JL, Jacobsen CA, Laskarzewski PM, Ames S, Gormley GJ: Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial. Journal of the American Medical Association 281:137-144, 1999 Tonstad S: Role of lipid-lowering pharmacotherapy in children. Paediatric Drugs 2:11-22, 2000 Migdalis IN, Gerolimou B, Kozanidou G, Voudouris G, Hatzigakis SM, Petropoulos A: Effect of gemfibrozil on early carotid atherosclerosis in diabetic patients with hyperlipidaemia. International Angiology 16:258-261, 1997 DCCT Research Group: Lifetime benefits and costs of intensive therapy as practiced in the diabetes control and complications trial. The Diabetes Control and Complications Trial Research Group. Journal of the American Medical Association 276:1409-1415, 1996 Meltzer D, Egleston B, Stoffel D, Dasbach E: Effect of future costs on cost-effectiveness of medical interventions among young adults: the example of intensive therapy for type 1 diabetes mellitus. Medical Care 38:679-685, 2000 Palmer AJ, Weiss C, Sendi PP, Neeser K, Brandt A, Singh G, Wenzel H, Spinas GA: The cost-effectiveness of different management strategies for type I diabetes: a Swiss perspective. Diabetologia 43:13-26, 2000 Siegel JE, Krolewski AS, Warram JH, Weinstein MC: Cost-effectiveness of screening and early treatment of nephropathy in patients with insulin-dependent diabetes mellitus. Journal of the American Society of Nephrology 3:Suppl-9, 1992 Kiberd B: Screening to prevent renal failure in insulin dependent diabetic patients: an economic evaluation. British Medical Journal 311:1595-1599, 1995 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Chapter 14: Diabetes Complications Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 169 Chapter 15: Other Complications and Associated Conditions Lipodystrophy (Lipoatrophy and Lipohypertrophy) Lipoatrophy is now seldom seen with the use of human insulin. Although recent case reports1;2 describe lipoatrophy occurring in pump patients treated with lispro insulin, it is still an uncommon side effect. Lipohypertrophy is a frequent complication of insulin therapy. It is estimated to be present in almost 30% of those with type 1 diabetes.3 Non-rotation of injection sites has been consistently reported as an independent risk factor for lipohypertrophy.3;4 Not only is it unsightly but insulin may be absorbed erratically and unpredictably from these areas.5 Necrobiosis Lipoidica Diabeticorum These are well circumscribed, raised reddish lesions sometimes progressing to central ulceration, usually seen on the pre-tibial region. The reported prevalence in children varies from 0.06% to 10%.6;7 The aetiology is not clearly understood. Necrobiosis lipoidica diabeticorum has been associated with underlying microvascular complications.8;9 A wide variety of treatments in adults have been used over the years including: topical, systemic or intra-lesional steroids, aspirin, cyclosporin, mycophenolate, becaplermin, excision and grafting, laser surgery, hyperbaric oxygen, topical granulocyte-macrophage colonystimulating factor and photochemotherapy with topical PUVA.10-17 None has been proven useful in controlled clinical trials and many of these treatments have significant side effects. Limited Joint Mobility Limited joint mobility is a common complication affecting about 30% of those with type 1 diabetes in childhood and adolescence.18;19 One study describes a decreased prevalence over the last 20 years (from 31% to 7%) which may reflect improved glycaemic control.20 Limited joint mobility is demonstrated by opposing the palms in a ‘praying position’ which demonstrates inability to straighten interphalangeal and metacarpophalangeal joints, sometimes associated with limited mobility of wrists, elbows, neck and spine. Limited joint mobility is associated with microvascular complications in children and adolescents21;22 as well as in adults.23-25 This condition is sometimes associated with thickening of the skin. Contractures are seen more often in patients with poor long-term diabetic control.21 Limited joint mobility in the feet may lead to secondary foot problems associated with abnormal pressure areas.26;27;28;29 There is no satisfactory treatment for limited joint mobility. Osteopenia Osteopenia (low bone mineral density) may occur in children and adolescents with type 1 diabetes. Decreased bone mineral density has been documented in diabetic children soon after the diagnosis of clinical diabetes30 and in those with longer diabetes duration.31;32 The underlying mechanism is not well understood and the long-term clinical significance of this is uncertain. Chapter 15: Other Complications and Associated Conditions Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 170 Impaired Growth and Development Monitoring of growth and development and the use of percentile charts is a very important part of ongoing care of children and adolescents with diabetes. Increased height at diagnosis of type 1 diabetes has been frequently reported.33-36 The precise mechanism for this and whether or not this increased height is maintained is unclear. Some studies report that poorly controlled patients show a decrease in height standard deviation score over the next few years, whilst better controlled patients maintain their height advantage.34;36 Others have not shown this relationship with diabetic control.35 In a recent Australian study, children treated with modern regimens (diagnosed after 1990) maintained their increased height better than children diagnosis before 1991.33 Although the median HbA1c did not differ significantly, those diagnosed after 1990 had a significantly higher number of insulin injections per day. Poor gain of height and weight and late pubertal development (Mauriac syndrome) are often seen in children with persistently poorly controlled diabetes. Insulin insufficiency, coeliac disease and other gastrointestinal disorders should be considered in this setting. There is no role for human growth hormone therapy in the poorly growing child with diabetes, unless it is associated with documented growth hormone deficiency. Once the child or adolescent has reached a satisfactory weight after diagnosis, excessive weight gain may indicate excessive energy intake and this may be related to excessive insulin. Excessive weight gain is more common during and after puberty.37 The Diabetes Control and Complications Trial and other studies have described greater weight gain as a side effect of intensive insulin therapy.38-40 As obesity is a modifiable cardiovascular risk factor, careful monitoring and management of weight gain in diabetes should not be overlooked. As large doses of insulin are required during the adolescent growth spurt, it is important to remember to reduce the dose, if possible, as adult height is approached. Associated Autoimmune Conditions Hypothyroidism Primary hypothyroidism due to autoimmune thyroiditis occurs in approximately 3-5 percent of children and adolescents with diabetes. Antithyroid antibodies have been shown to occur in up to 25% of individuals with diabetes,41-44 but are not necessarily associated with hypothyroidism. Screening of thyroid function by Thyroid Stimulating Hormone (TSH) every two years is recommended in asymptomatic individuals without a goitre or in the absence of autoantibodies.45;46 More frequent assessment is indicated otherwise. Clinical features may include the presence of a painless goitre, increased weight gain, decreased growth, tiredness, lethargy, cold intolerance and bradycardia. Diabetic control may not be significantly affected. Hypothyroidism is confirmed by demonstrating a low free thyroxine and a raised TSH. Compensated hypothyroidism may be detected in an asymptomatic individual with a normal thyroxine level and a modestly raised TSH. The treatment is oral L-thyroxine (T4) replacement sufficient to normalise TSH levels and usually this allows regression of the goitre if present. Hyperthyroidism Hyperthyroidism is less common than hypothyroidism in association with diabetes,43;47 but still more common than in the general population. It may be due to Grave’s disease or the hyperthyroid phase of Hashimoto’s thyroiditis. Chapter 15: Other Complications and Associated Conditions Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 171 Hyperthyroidism should be considered if there is unexplained difficulty in maintaining glycaemic control, weight loss without loss of appetite, agitation, tachycardia, tremor, heat intolerance, thyroid enlargement or characteristic eye signs. Treatment is anti-thyroid drugs such as carbimazole or propylthiouracil. Beta-adrenergic blocking drugs are helpful during the acute phase of thyrotoxicosis to control tachycardia and agitation. Treatment options for persistent or recurrent hyperthyroidism include surgery or radio-active iodine. Coeliac disease Coeliac disease occurs in 1-10% of children and adolescents with diabetes.48-54 Recent Australian paediatric studies have shown prevalence rates of 2.6-5.7% in diabetes clinic populations.55;56 Coeliac disease is often asymptomatic52;54;57 and not necessarily associated with poor growth or poor diabetes control (although it should be considered in these situations). Any child with gastrointestinal signs or symptoms including diarrhoea, abdominal pain, flatulence, dyspeptic symptoms, recurrent aphthous ulceration, unexplained poor growth or anaemia should be investigated. Undiagnosed coeliac disease has also been associated with increased frequency of hypoglycaemic episodes and a progressive reduction of insulin requirement over the 12 months prior to diagnosis.58 Screening by immunological tests At present there are no clear data regarding how frequently coeliac disease should be screened for. Current consensus recommendations suggesting screening (by looking for the presence of antiendomysial antibodies (EMA) or antigliadin antibodies when EMA is not available) should be carried out around the time of diagnosis and every 2-3 years thereafter46;59;60 or if the clinical situation suggests the possibility of coeliac disease.45 This may need to be revised when more data are available. IgA deficiency (which is present in 1: 500 people) should be excluded when screening for coeliac disease by measuring the total IgA level. EMA IgA may not be detected in IgA deficiency, resulting in a false negative test. If the child is IgA deficient, then IgG antigliadin should be used for screening. It is important to remember that coeliac disease is more common in those with IgA deficiency than in the general population (1.7% compared with 0.25%).61 Although experience with a recently introduced assay for tissue transglutaminase (tTG) antibodies suggests that tTG may be more sensitive than EMA (91% vs 86%), the latter is slightly more specific for coeliac disease (100% vs 96%).62 If EMA or tissue transglutaminase antibodies are not available, then IgA antigliadin or IgG antigliadin (in the <2-year-old child) antibodies are sensitive but less specific screening tests (than EMA) for coeliac disease. Follow up of positive antibody tests In the presence of an elevated antibody level, a small bowel biopsy is needed to confirm the diagnosis of coeliac disease (by demonstrating subtotal villus atrophy). Treatment A gluten-free diet normalises the bowel mucosa and frequently leads to disappearance of EMA but may not lead to improved diabetic control. In an asymptomatic child with proven coeliac disease the justifications for a gluten-free diet are to reduce the risk of subsequent gastrointestinal malignancy and conditions associated with subclinical malabsorption (osteoporosis and iron deficiency). Whilst this is a prudent recommendation, there is no literature documenting the long-term benefit of a gluten-free diet in asymptomatic children Chapter 15: Other Complications and Associated Conditions Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 172 diagnosed with coeliac disease by routine screening. One paediatric case series has shown an increase in height-for-weight following the introduction of a gluten-free diet.57 Another demonstrated a non-significant increase in BMI and a non-significant reduction in HbA1c.63 Some studies have demonstrated short term benefits in other patient groups in terms of improved wellbeing and increased bone mineral density.64-66 Another study demonstrated that bone mineral density was already significantly decreased at the time of diagnosis of coeliac disease in truly asymptomatic adults.67 A Swiss population based study found the risk of enteropathy associated T-cell lymphoma to be low (0.07/100,000 per year). None of the 10 patients identified suffered from type 1 diabetes.68 Children with proven coeliac disease should be referred to a paediatric gastroenterologist and receive support from a paediatric dietitian with experience in gluten-free diets. Vitiligo Vitiligo is an acquired, pigmentary disorder characterised by a loss of melanocytes resulting in white spots or leukoderma.69 It is a common autoimmune condition associated with type 1 diabetes and is present in about 6% of diabetic children.7 Treatment is difficult and multiple therapies have been tried with little success. Oedema Generalised oedema due to water retention is a rare complication of insulin therapy. Oedema may be seen during establishment of glycaemic control after prolonged periods of poor glycaemic control, particularly if there has been significant omission of insulin.70;71 The oedema spontaneously resolves over a period of days to weeks with continued good glycaemic control. Primary adrenal insufficiency (Addison's disease) Up to 2% of patients with type 1 diabetes have detectable antiadrenal autoantibodies.41;72;73 Addison’s disease is occasionally associated with type 1 diabetes (Autoimmune Polyglandular Syndrome, APS I or II). The condition is suggested by the clinical picture of: • Frequent hypoglycaemia. • Unexplained decrease in insulin requirements. • Increased skin pigmentation. • Lassitude. • Weight loss. • Hyponatraemia and hyperkalaemia. Diagnosis is by demonstrating a low cortisol response to a Synacthen test. Treatment with glucocorticoid and mineralocorticoid is urgent and lifelong. In asymptomatic children with positive adrenal antibodies detected on routine screening, methods of follow up vary. A rising ACTH level suggest a failing adrenal cortex and the development of primary adrenal insufficiency. The Evidence No studies were identified addressing the optimal frequency of screening for thyroid disease and coeliac disease in children and adolescents with type 1 diabetes. Therefore the recommendations for screening are based on current consensus guidelines.45;59 Chapter 15: Other Complications and Associated Conditions Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 173 The evidence for the effect of a gluten-free diet in children and adolescents with type 1 diabetes detected to have coeliac disease on routine screening is listed in Evidence Table 15.1. • Only two short-term studies were identified describing the effect of a gluten-free diet in asymptomatic children and adolescents with type 1 diabetes who have been detected to have coeliac disease on routine screening. One case series has shown an increase in height-for-weight following the introduction of a gluten-free diet.57 Another case series demonstrated a non-significant increase in body mass index and a non-significant reduction in HbA1c following a gluten-free diet.63(IV) • No long-term studies were identified showing the benefits of a gluten-free diet in children and adolescents with type 1 diabetes who do not have symptoms of coeliac disease when detected by routine screening. Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 15.2. Recommendations and Principles • Monitoring of growth and development and the use of growth charts is a very important part of ongoing care of children and adolescents with type 1 diabetes.45;59(C) • Screening of thyroid function by Thyroid Stimulating Hormone (TSH) every 2 years is recommended in asymptomatic individuals without a goitre or in the absence of thyroid autoantibodies. More frequent assessment is indicated otherwise.45(C) • Screening for coeliac disease should be carried out around the time of diagnosis and every 2-3 years thereafter. More frequent assessment is indicated if the clinical situation suggests the possibility of coeliac disease.46;59;60(C) • Although the benefits of a gluten-free diet have not been proven in those with type 1 diabetes detected to have coeliac disease on routine screening,57;63 these children should be referred to a paediatric gastroenterologist and on confirmation of the diagnosis receive support from a paediatric dietitian with experience in gluten-free diets.59;74(C) C = Consensus statement endorsed by professional organisations Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Ampudia-Blasco FJ, Hasbum B, Carmena R: A New Case Of Lipoatrophy With Lispro Insulin In Insulin Pump Therapy: Is there any insulin preparation free of complications? Diabetes Care 26:953, 2003 Griffin ME, Feder A, Tamborlane WV: Lipoatrophy Associated With Lispro Insulin in Insulin Pump Therapy: An old complication, a new cause? 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Prevalence of IgA-antiendomysium and IgA-antigliadin autoantibodies at diagnosis of insulin-dependent diabetes mellitus in Swedish children and adolescents. Pediatrics 103:1248-1252, 1999 Crone J, Rami B, Huber WD, Granditsch G, Schober E: Prevalence of Coeliac Disease and Follow-up of EMA in Children and Adolescents With Type 1 Diabetes Mellitus. Journal of Pediatric Gastroenterology & Nutrition 37:67-71, 2003 De VI, Ghirlanda G, Gasbarrini G: Prevalence of coeliac disease in type I diabetes: a multicentre study. Acta Paediatrica Supplement. 412:56-57, 1996 Hansen D, Bennedbaek FN, Hansen LK, Hoier-Madsen M, Hegedu LS, Jacobsen BB, Husby S: High prevalence of coeliac disease in Danish children with type I diabetes mellitus. Acta Paediatrica 90:1238-1243, 2001 Not T, Tommasini A, Tonini G, Buratti E, Pocecco M, Tortul C, Valussi M, Crichiutti G, Berti I, Trevisiol C, Azzoni E, Neri E, Torre G, Martelossi S, Soban M, Lenhardt A, Cattin L, Ventura A: Undiagnosed coeliac disease and risk of autoimmune disorders in subjects with Type I diabetes mellitus. Diabetologia 44:151-155, 2001 Westman E, Ambler GR, Royle M, Peat J, Chan A: Children with coeliac disease and insulin dependent diabetes mellitus--growth, diabetes control and dietary intake. Journal of Pediatric Endocrinology & Metabolism 12:433-442, 1999 Smith CM, Clarke CF, Porteous LE, Elsori H, Cameron DJ: Prevalence of coeliac disease and longitudinal follow-up of antigliadin antibody status in children and adolescents with type 1 diabetes mellitus. Pediatric Diabetes 1(4):199-203, 2000 Saukkonen T, Vaisanen S, Akerblom HK, Savilahti E, Childhood Diabetes in Finland Study Group.: Coeliac disease in children and adolescents with type 1 diabetes: a study of growth, glycaemic control, and experiences of families. Acta Paediatrica 91:297-302, 2002 Mohn A, Cerruto M, Lafusco D, Prisco F, Tumini S, Stoppoloni O, Chiarelli F: Coeliac disease in children and adolescents with type I diabetes: importance of hypoglycemia. Journal of Pediatric Gastroenterology & Nutrition 32:37-40, 2001 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 National Institute for Clinical Excellence. Type 1 Diabetes (Childhood): Diagnosis and Management of Type 1 Diabetes in Children and Young People. 2004. Cataldo F, Marino V, Bottaro G, Greco P, Ventura A: Coeliac disease and selective immunoglobulin A deficiency. Journal of Pediatrics 131:306-308, 1997 Tesei N, Sugai E, Vazquez H, Smecuol E, Niveloni S, Mazure R, Moreno ML, Gomez JC, Maurino E, Bai JC: Antibodies to human recombinant tissue transglutaminase may detect coeliac disease patients undiagnosed by endomysial antibodies. Alimentary Pharmacology & Therapeutics 17:1415-1423, 2003 Acerini CL, Ahmed ML, Ross KM, Sullivan PB, Bird G, Dunger DB: Coeliac disease in children and adolescents with IDDM: clinical characteristics and response to gluten-free diet. Diabetic Medicine 15:38-44, 1998 Corazza GR, Di Sario A, Cecchetti L, Jorizzo RA, Di Stefano M, Minguzzi L, Brusco G, Bernardi M, Gasbarrini G: Influence of pattern of clinical presentation and of gluten-free diet on bone mass and metabolism in adult coeliac disease. Bone 18:525-530, 1996 Fabiani E, Catassi C, Villari A, Gismondi P, Pierdomenico R, Ratsch IM, Coppa GV, Giorgi PL: Dietary compliance in screeningdetected coeliac disease adolescents. Acta Paediatrica Supplement 412:65-67, 1996 Mustalahti K, Collin P, Sievanen H, Salmi J, Maki M: Osteopenia in patients with clinically silent coeliac disease warrants screening. Lancet 354:744-745, 1999 Mazure R, Vazquez H, Gonzalez D, Mautalen C, Pedreira S, Boerr L, Bai JC: Bone mineral affection in asymptomatic adult patients with coeliac disease. American Journal of Gastroenterology 89:2130-2134, 1994 Lang-Muritano M, Molinari L, Dommann-Scherrer C, Schueler G, Schoenle EJ: Incidence of enteropathy-associated T-cell lymphoma in celiac disease: Implications for children and adolescents with type 1 diabetes. Pediatric Diabetes 3:42-45, 2002 Handa S, Dogra S: Epidemiology of childhood vitiligo: a study of 625 patients from north India. Pediatric Dermatology 20:207210, 2003 Hirshberg B, Muszkat M, Marom T, Shalit M.: Natural course of insulin edema. Journal of Endocrinological Investigation 23:187188, 2000 Wheatley T, Edwards OM.: Insulin oedema and its clinical significance: metabolic studies in three cases. Diabetic Medicine 2:400404, 1985 Falorni A, Laureti S, Nikoshkov A, Picchio ML, Hallengren B, Vandewalle CL, Gorus FK, Tortoioli C, Luthman H, Brunetti P, Santeusanio F: 21-hydroxylase autoantibodies in adult patients with endocrine autoimmune diseases are highly specific for Addison's disease. Belgian Diabetes Registry. Clinical & Experimental Immunology 107:341-346, 1997 Peterson P, Salmi H, Hyoty H, Miettinen A, Ilonen J, Reijonen H, Knip M, Akerblom HK, Krohn K: Steroid 21-hydroxylase autoantibodies in insulin-dependent diabetes mellitus. Childhood Diabetes in Finland (DiMe) Study Group. Clinical Immunology & Immunopathology 82:37-42, 1997 Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Chapter 15: Other Complications and Associated Conditions Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 176 Chapter 16: Foot Care Children and adolescents with diabetes do not display the devastating foot problems seen in older people with diabetes. However, structural and functional abnormalities known to predispose adults with diabetes to plantar ulceration are already present in young people with diabetes. Young people with diabetes may present with potentially destructive foot changes include deformity, plantar callus and high plantar pressure. Although these abnormalities are not unique to diabetes they have been shown to contribute to soft tissue breakdown, ulceration and even amputation in adults. Other structural changes such as soft tissue thickening and limited joint mobility in the foot are specific complications of diabetes and have been found to alter the mechanics of the foot leading to high plantar pressure and ulceration. When any of these abnormalities is associated with the macrovascular and/or neuropathic complications of diabetes their effect is potentially devastating. The identification of potentially destructive foot problems in young people with diabetes is not always simple for the clinician. General foot deformities such as hammer toes, hallux abductovalgus and plantar callus are simple to detect clinically. Superficial skin lesions such as interdigital maceration, heloma durum (corns), onychocryptosis (ingrown toenails) or verrucae (warts) are also simple to detect clinically. However less obvious structural abnormalities require closer inspection by the clinician. The clinical assessment process should include checking for abnormalities, which may indicate that the individual has some form of mechanical imbalance. Deformity Any of the following abnormalities may indicate a functional imbalance, which can result in abnormal pressure changes on the plantar surface of the foot or abnormal pressure from footwear: • A significant leg length discrepancy - greater than 1cm. • Genuvarum or genuvalgum - genuvarum is normal up to the age of 2, genuvalgum is normal between 2 to 7 year olds. • Internal or external knee position. • Varus or valgus foot position - a small degree of valgus alignment is normal up to 7 years old. • In-toeing or out-toeing. • Abnormal shoe wear patterns – the heel should wear to the centre or slightly laterally, the sole should show even wear and the upper of the shoe should not be deformed. • Inadequate shoe fit – either too small or too large. Studies by Barnett et al1 and Larsen2 found that the incidence of foot deformities and skin lesions (including plantar callus) in young people with diabetes is higher than that found in those without diabetes. Both these studies also found that young people with diabetes were more likely to wear shoes that were too small. Some of the lower limb abnormalities outlined above should lead to examination by a podiatrist, orthopaedic surgeon, paediatrician or physiotherapist with experience in biomechanical evaluation of children. Chapter 16: Foot Care Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 177 Plantar Callus Two studies have shown that the incidence of plantar callus is higher in the young diabetic population.1;2 A more recent study3 found that there was no significant difference in the number of diabetic subjects who presented with callus compared to age and sex matched controls. Although, in this study, the number of subjects affected with plantar callus was no different, those with callus had significantly higher plantar pressure than those without. Plantar callus and high plantar pressure have been strongly linked to plantar ulceration in adults with diabetes. Young people presenting with plantar callus should be monitored closely for any indication of soft tissue damage. They should also be advised to see a podiatrist for general foot care and/or possibly some form of orthotic device because: • Plantar callus may indicate structural or functional abnormality in the foot. • Plantar callus can increase plantar pressure. • People with plantar callus should always be regularly monitored for soft tissue change. High Plantar Pressure In adults high plantar pressure is a reliable predictor of subsequent ulceration in diabetic people. Although neuropathy is an essential part, it is now believed that high plantar pressures are a major determinant for the development of these lesions.4-8 No significant difference in plantar pressure between young people with diabetes and nondiabetic controls has been detected.3 However those with plantar pressures two standard deviations above the non-diabetic control mean may be at risk of future foot pathology. Treatment should be instigated when high plantar pressure is detected. Treatment should be instigated when high plantar pressure is detected. Effective and non-invasive pressure reducing treatments have also been investigated. These include simple cushioning insoles, orthoses or both in conjunction.3 Plantar callus may be present in some individuals but there are no clinical signs of high plantar pressure. The only method of evaluating plantar pressure is by using pressure analysis equipment. This equipment should be available at most high-risk foot clinics and diabetes complications assessment clinics. Plantar pressure is assessed using pressure analysis equipment. High plantar pressure may damage underlying soft tissue. People with diabetes who have high plantar pressure should be encouraged to have regular foot examinations. Soft Tissue Changes Skin changes in diabetes are similar to those found in scleroderma and the aging process.9;10 In essence these changes result in the loss of elasticity and anchoring fibrils and thickening of the dermis.11;12 This predisposes plantar skin to injury from minor trauma.12 Qualitative and quantitative examination of the skin has been undertaken in young people with diabetes. Rosenbloom et al13 found that the skin on the dorsum of the hands appeared thick, tight and waxy in some young people with diabetes. This prompted investigation of the skin on the sole of the foot using ultrasonography but no thickening of plantar skin was noted when diabetic subjects were compared to non-diabetic controls.14 Thickening of the plantar aponeurosis has been found to be associated with increased forefoot plantar pressure and limited joint mobility in adults with diabetes.15;16 Chapter 16: Foot Care Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 178 Plantar aponeurosis thickening (greater than two standard deviations above the nondiabetic control mean) has been detected by ultrasound in thirty-two per cent of young people with diabetes.14 In this study, thickening of the aponeurosis was associated with limited subtalar joint mobility, but not with high plantar pressure in these younger individuals. It is possible that the soft tissue changes found in these younger patients may not have progressed sufficiently to alter plantar pressure. However, these young people should be closely monitored for any increase in plantar pressure. Features to note include: • Changes in skin tone which may predispose the foot to damage from minor trauma. • Reduced adipose tissue on the plantar surface of the foot which increases mechanical stress on plantar skin. • Increased thickness of the plantar aponeurosis which may be associated with higher plantar pressure. Limited Joint Mobility Limited joint mobility in the feet of adults with diabetes increases plantar pressure, which in turn leads to tissue breakdown and ulceration.4-6;17;18 High plantar pressures in adults with neuropathy are uncommon when joint mobility is within normal range.7 The primary determinant of high plantar pressures is limited joint mobility, and neuropathy is a secondary phenomenon.4-6 Limited joint mobility has also been detected in the feet of young people with diabetes.1;14;19 The foot joints affected include the ankle, subtalar, 1st metatarsophalangeal and interphalangeal joints. Joint limitation particularly at the 1st metatarsophalangeal joints has been shown to increase plantar pressure under the hallux, an area at great risk of developing a plantar ulcer.3 Limited joint mobility at the 1st metatarsophalangeal joint is relatively simple to detect clinically. Young people with less than 60° of dorsiflexion (in a weightbearing position) should be suspected of having limited joint mobility and more in-depth investigations of other foot joint motion and plantar pressure should be undertaken. The Evidence The evidence for the effect of type 1 diabetes on joint mobility in the feet of young people is listed in Evidence Table 16.1. 1;14;19 • Reduced joint mobility in the feet has been found in young people with diabetes. ( IV) The evidence data for the management of high plantar pressure in adolescents with type 1 diabetes is listed in Evidence Table 16.2. • The effects of orthosis, cushioning or both in combination were monitored in 17 diabetic subjects with high peak plantar pressure and in 17 diabetic subjects with plantar callus; reductions of up to 63% were achieved. Diabetic subjects who had not received any interventions showed no significant change in peak plantar pressure.3(IV) No studies were identified addressing the optimal frequency of screening for foot complications in children and adolescents with type 1 diabetes. Therefore the recommendations for screening are based on current consensus guidelines.20(C) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 16.3. Chapter 16: Foot Care Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 179 Recommendations and Principles • Health care professionals should be aware that the structural and functional abnormalities known to predispose adults with diabetes to plantar ulceration are already present in young people with diabetes.1;14;19(IV) • Young people presenting with plantar callus, or detected to have high plantar pressures or limited joint mobility need to be monitored closely for foot complications.20(C) • Orthosis, cushioning or both in combination may be used to treat high peak plantar pressure.3(IV) IV = Evidence obtained from case series, either post-test or pre-test and post test C = Consensus statement endorsed by professional organisations Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. Barnett SJ, Shield JPH, Potter MJ, Baum JD: Foot pathology in insulin dependent diabetes. Archives of Disease in Childhood 73:151-153, 1995 Larsen K, Katz L, Nielsen B: Footwear and deformity in diabetic children's feet. The chiropodist 11:435-437, 1980 Duffin A, Kidd R, Chan A, Donaghue K: High plantar pressure and callus in diabetic adolescents. Journal of the American Podiatric Medical Association 93:214-220, 2003 Cavanagh PR, Fernando DJS, Masson EA, Veves A, Boulton AJM: Limited joint mobility (LJM) and loss of vibration sensation are predictors of elevated plantar pressure in diabetes. Diabetes 40:513 A, 1991 Cavanagh PR, Ulbrect JS: Clinical plantar pressure measurements in diabetes: rational and methodology. The Foot 4:123-135, 1994 Fernando DJS, Masson EA, Veves A, Boulton AJM: Relationship of limited joint mobility (LJM) to abnormal foot pressures and diabetic foot ulceration. Diabetes Care 14:8-11, 1991 Masson EA: What causes high foot pressures in diabetes: how can they be relieved. The Foot 2:212-217, 1992 Veves A, Murray H, Young M, Boulton A: The risk of foot ulceration in diabetic patients with high foot pressure: a prospective study. Diabetologia 35:660-663, 1992 Brik R, Berant M, Vardi P: The Scleroderma-Like Syndrome of Insulin Dependent Diabetes Mellitus. Diabetes/ Metabolism Reviews 7:121-128, 1991 Goodfield M, Millard L: The skin in diabetes mellitus. Diabetologica 31:567-575, 1988 Braveman I, Yen A: Ultrastructural abnormalities of the microvasculature and elastic fibres in the skin of juvenile diabetics. Journal of Invesigative Dermatology 82:270-274, 1984 Dowd P, Gaywood I, Kurtz A, Shipley M: Diabetic Sclerodactyly. British Journal of Dermatology 116:21, 1986 Rosenbloom A, Silverstein J: Connective tissue and joint disease in diabetes mellitus. Endocrinology and metabolism clinics of North America 25:473-481, 1996 Duffin AC, Lam A, Kidd R, Chan AKF, Donaghue KC: Ultrasonography of plantar soft tissues thickness in young people with diabetes. Diabetic Medicine 19:1009-1013, 2002 D'Ambrogi E, Giurato L, D'Agostino MA, Giacomozzi C, Macellari V, Caselli A, Uccioli L: Contribution of plantar fascia to the increased forefoot pressures in diabetic patients. Diabetes Care 26:1525-1529, 2003 Kidd R, Kidd R: The role of abnormal collagen synthesis in the pathomechnics of the diabetic foot: A re-evaluation of the paradism of neuropathy in podiatric practice. Australian Podiatrist 97-101, 1993 Delbridge L, Perry P, Marr S, Arnold N, Yue DK, Turtle JR, Reeve TS: Limited joint mobility in the diabetic foot: relationship to neuropathic ulceration. Diabetic Medicine 5:333-337, 1988 Mueller MJ, Diamond JE, Delitto A, Sinacore D: Insensitivity, limited joint mobility and plantar ulcers in patients with diabetes mellitus. Physical Therapy 69:453-462, 1989 Duffin AC, Donaghue KC, Potter M, McInnes A, Chan AK, King J, Howard NJ, Silink M: Limited joint mobility in the hands and feet of adolescents with Type 1 diabetes mellitus. Diabetic Medicine 16:125-130, 1999 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Chapter 16: Foot Care Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 180 Chapter 17: Dental Health The maintenance of dental health and the prevention of dental disease is important for children and adolescents with diabetes mellitus. The assessment of dental health should be a part of the regular medical follow-up. The overall dental management for children and adolescents with diabetes includes: • Maintaining oral hygiene using all available cleaning techniques (brushing, flossing, and using toothpastes and antibacterial rinses). • Regular cleaning and scaling of teeth by the dentist. • Dietary advice. • In some cases, chlorhexidine rinses. • In some cases, antibiotics. Children and adolescents with diabetes should be referred early to a dental specialist, such as a periodontist or paediatric dentist, if there are special periodontal or decay problems. Assessment of dental health includes not just the teeth, but the whole mouth cavity. It should be remembered that patients with type 1 diabetes, especially those with poor metabolic control, have an increased risk of oral candida carriage.1;2 This may also be associated with dryness of the mouth, a burning sensation and painful fissures in the mouth and lips.1 Dental Caries Sugary foods and poor toothbrushing promote formation of dental plaque on the surface of the tooth. Acids made by plaque bacteria become trapped under the plaque and cause tooth decay. Substances released from the surface of the dental plaque (eg bacterial lipopolysaccharides) activate a destructive inflammatory response in the gingivae. For the child and adolescent with good glycaemic control, dental caries is no more likely than for those without diabetes.3 However, dental decay is increased in those with poor glycaemic control and this has been attributed to:4 5 • Reduced amount of saliva in the mouth. • High glucose content in the saliva. Periodontal Disease Diabetes is a risk factor for periodontal disease especially when metabolic control is poor or when diabetes duration is long.6-9 Periodontal disease is a chronic, potentially progressive bacterial infection resulting in inflammation and destruction of tooth-supporting tissues. Diabetes is associated with increased incidence, greater progression and severity of periodontal disease. The periodontal tissues are made up of the: • Gingivae (gums). • Ligament holding the tooth into the bone (periodontal ligament). • Bone itself. Chapter 17: Dental Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 181 The point of attachment of the gingival tissues to the tooth is a shallow groove around the neck of the tooth (gingival crevice). The gingival crevice needs to be kept clean if it is to stay healthy. If dental plaque is left on the surface of the teeth adjacent to the dental crevice, inflammation of the gingivae will occur (periodontal disease). In diabetes there are changes in the small blood vessels of the gingiva and changes in the local immune response to plaque, particularly the neutrophil response. These changes can increase the risk of periodontal disease. Periodontal disease includes: • Gingivitis. • Periodontitis. In gingivitis: • The gingivae become red, swollen and bleed easily. • The infection damages the attachment between the teeth. • The infection is typically painless and little attention is usually paid to it. 10 • Associated smoking is a major risk factor for periodontal disease and can accelerate the onset of periodontitis in teenagers. In periodontitis: • Periodontitis is unusual in children and adolescents; gingivitis is far more common. • Progression to periodontitis occurs when the gum margins lose their tight seal against the surface of the tooth and a pocket is formed between the gum and the tooth. Such pockets provide an ideal spot for the growth of bacteria and are hard to clean out. The bacteria are typically gram-negative anaerobes including Porphyromonas gingivalis, Prevotella intermedia, spirochaetes and occasionally the micro-aerophilic organism Actinobacillus actinomycetemcomitans.11 • Periodontitis is characterised by destruction of the gingiva, periodontal ligament, alveolar bone, cementum and loss of connective tissue attachment. • The gingivae may recede and the teeth begin to look longer (the recession may become so severe that the teeth get very loose and need to be removed). Gingivitis or more severe problems can be recognised just by looking and by gently probing the gum margins to see if there is any bleeding or pocketing around the necks of the teeth. Those with poor glycaemic control are more liable to gingivitis. If more detailed assessment of the bone around the teeth is required then dental x-rays are used. Prevention and Treatment of Dental Caries and Gingivitis Tooth decay and gingivitis can be both prevented and/or reversed by: • Using low fluoride or ‘Junior’ toothpaste (until 8 years of age), and daily use of a low dose fluoride mouthwash to help repair any surface damage to the teeth. • Regularly examining (twice yearly) for the presence of gingivitis or periodontal disease. • Taking extra care with dental hygiene in adolescents with orthodontic bands and wires which make the cleaning of teeth very difficult and can exaggerate the gum response. In this situation, the routine dental team should review more frequently for caries. • Brushing and flossing teeth at least twice a day to remove the plaque from the surfaces of the teeth and gingivae. Important points to note are: Chapter 17: Dental Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 182 The best brush is one with soft bristles and a small head and to use small circular movements or short backward and forward vibration strokes. Children seldom have the ability to perform efficient cleaning before the age 10 years and often the duration of their brushing is too brief. Children also forget to clean the backs of their teeth and for these reasons parents should brush young children’s teeth routinely. With older children ‘parental brushing’ as often as possible is important. The use of a battery-powered automatic toothbrush often improves a child’s acceptance of this and increases the duration of brushing. The Evidence The evidence for the effect of type 1 diabetes on dental health in children and adolescents is listed in Evidence Table 17.1. 4 • Dental decay is increased in those with poor glycaemic control. (IV) • Diabetes is a risk factor for periodontal disease especially when metabolic control is poor or when diabetes duration is long.6-9( IV) No studies were identified specifically addressing the optimum frequency of screening for dental pathology in children and adolescents with type 1 diabetes; therefore the recommendations for screening reflect current consensus guidelines.12(C) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 17.2. Recommendations and Principles • Children and adolescents with type 1 diabetes should be informed that dental decay is increased when glycaemic control is poor.4(IV) • Health care professionals should be aware that diabetes is a risk factor for periodontal disease especially when metabolic control is poor or when diabetes duration is long.6-9(IV) • Children and adolescents with type 1 diabetes should be informed that tooth decay and gingivitis can be prevented and/or reversed by brushing and flossing teeth at least twice a day to remove plaque from the surfaces of the teeth and gingivae.12(C) • The mouth should be examined regularly (twice a year) for the presence of gingivitis or periodontitis.12(C) IV = Evidence obtained from case series, either post-test or pre-test and post test. C = Consensus statement endorsed by professional organisations Reference List 1. 2. 3. 4. 5. 6. 7. 8. Bai KY, Reddy CD, Abu-Talib SH: Oral candidal carriage in young insulin dependent diabetics. Journal of the Indian Society of Pedodontics & Preventive Dentistry 13:20-23, 1995 Hill LV, Tan MH, Pereira LH, Embil JA: Association of oral candidiasis with diabetic control. Journal of Clinical Pathology 42:502-505, 1989 Iughetti L, Marino R, Bertolani MF, Bernasconi S: Oral health in children and adolescents with IDDM--a review. Journal of Pediatric Endocrinology & Metabolism 12:603-610, 1999 Twetman S, Johansson I, Birkhed D, Nederfors T: Caries incidence in young type 1 diabetes mellitus patients in relation to metabolic control and caries-associated risk factors. Caries Research 36:31-35, 2002 Moore PA, Guggenheimer J, Etzel KR, Weyant RJ, Orchard T: Type 1 diabetes mellitus, xerostomia, and salivary flow rates. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, & Endodontics 92:281-291, 2001 Miralles-Jorda L, Silvestre-Donat FJ, Grau Garcia-Moreno DM, Hernandez-Mijares A: Buccodental pathology in patients with insulin-dependent diabetes mellitus: a clinical study. Medicina Oral 7:298-302, 2002 Pinson M, Hoffman WH, Garnick JJ, Litaker MS: Periodontal disease and type I diabetes mellitus in children and adolescents. Journal of Clinical Periodontology 22:118-123, 1995 Marin N, Loyola-Rodriguez JP, Valadez-Castillo FJ, Hernandez-Sierra JF, Jesus Pozos-Guillen A: Effect of metabolic control in diabetes mellitus type 1 patients and its association with periodontal disease. Revista de Investigacion Clinica 54:218-225, 2002 Chapter 17: Dental Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 183 9. 10. 11. 12. Takahashi K, Nishimura F, Kurihara M, Iwamoto Y, Takashiba S, Miyata T, Murayama Y: Subgingival microflora and antibody responses against periodontal bacteria of young Japanese patients with type 1 diabetes mellitus. Journal of the International Academy of Periodontology 3:104-111, 2001 Grossi SG, Zambon JJ, Ho AW, Koch G, Dunford RG, Machtei EE, Norderyd OM, Genco RJ: Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. Journal of Periodontology 65:260-267, 1994 Sakamoto M, Takeuchi Y, Umeda M, Ishikawa I, Benno Y: Application of terminal RFLP analysis to characterize oral bacterial flora in saliva of healthy subjects and patients with periodontitis. Journal of Medical Microbiology January 52:79-89, 2003 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Chapter 17: Dental Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 184 Chapter 18: Adolescent Health Introduction Adolescents often struggle to cope with the demands of diabetes care. Adolescence is a time when major physiological changes occur leading to increased insulin resistance. Insulin dosages are typically higher during adolescence and most teenagers need to switch to a multiple injection regimen.1 The DCCT demonstrated that HbA1c levels were generally 1% higher in adolescents, both in the intensively treated and in the conventionally treated groups but despite this had a higher prevalence of severe hypoglycaemia.2;3. Young people with type 1diabetes need to maintain and develop self-esteem and independence at a time when diabetes care itself is at its most challenging. The major risks faced by adolescents with type 1 diabetes include:4 • Deterioration of glycaemic control (see chapter 6). • Risk-taking behaviour. • Hypoglycaemia (see chapter 12) • Recurrent diabetic ketoacidosis (see chapter 9). • Accelerated microvascular complications (see chapter 14). When managing adolescents with type 1 diabetes the aim is to achieve: • Normal growth. • Normal pubertal development. • Normal psychological development. 1 • Maintenance of glycaemic control. 2;3 • Prevention of acute complications of diabetes (hypoglycaemia, diabetic ketoacidosis5;6) 7 • Prevention or minimisation of microvascular complications. • Normal lifestyle. • Normal education opportunities. • Avoidance of risk taking behaviours (smoking, substance abuse). • Regular attendance to medical supervision. • Comprehensive preparation for and transition to adult care. An Approach to the Assessment of Adolescents The HEADSS technique may be used (along with the routine medical history taking) to guide the assessment of any adolescent.8 This comprehensive technique includes questions about: • Home • Education (or employment) • Activities • Drugs (also including alcohol and smoking) • Sexuality (including contraception) • Suicide (including other mental health issues) Transition to Adult Care Adolescents with diabetes have specific health needs relating to the physical, emotional, psychological and socio-cultural stages of adolescence.9 Adolescents are less likely to adhere to prescribed care and have poor glycaemic control.10-13 The transition from a paediatric to an Chapter 18: Adolescent Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 185 adult service for the adolescent with diabetes is often difficult. The position paper on transition prepared by the Society for Adolescent Medicine outlines principles for successful transition including:14 • The need for services to be appropriate for both chronological age and developmental attainment. • Transitional programmes to be flexible enough to meet the needs of a wide range of young people, health conditions and circumstances. • Transitional programmes to be prepared to address common concerns of young people including growth and development, sexuality, mood and other mental health disorders and damaging behaviours. • Transfer of care to be individualised to meet specific needs. If the transition is not carefully managed the following consequences may occur: 13 • Non-adherence to insulin regimens. • Lack of follow-up. • Prolonged period of poor glycaemic control resulting in suboptimal health. • Acceleration of microvascular complications. • Loss of access to emergency advice. Of the 7 studies identified which addressed the issue of transition to adult services for adolescents with type 1 diabetes, 6 were surveys of the patient15-19 or their paediatrician,20 and one was a case series.21 An Australian survey of young people with type 1 diabetes found that 5.7% felt the transfer should occur before the age of 17 years, 48.6% between 17-20 years, and 44.8% at any stage up to 25 years of age.15 Overseas surveys reported the mean ages for transition were: 18 • Canada 18.5 years. 21 • Finland 17.5 years. 16 • United Kingdom (Exeter) 15.9 years. A study of transition processes in the Oxford region, UK, showed that the 2 year clinic attendance (at least 6 monthly) fell from 98% pre-transfer to 61% post-transfer (p<0.0005) and the attendance rate for the first appointment on transfer was only 79%.17 A Canadian survey of transition mean age 18.5 years) revealed 21% would have preferred earlier transfer whereas 65% felt they would have liked transfer later.18 After transfer 13% had no regular contact with the adult service, 3% maintained contact with a family practitioner only while the remainder had regular contact with either an endocrinologist in private practice or an adult clinic.18 Thirty-three percent reported problems with the transition process. A delay of more than 6 months between the last visit to the paediatric service and the first visit to the adult service occurred in 27% and in 17% the transition process took more than a year.18 As none of the studies compared different models of transition, the following recommendations for transition are largely consensus based. The formal transition phase should occur at a time of relative stability in the adolescent’s health and may be coordinated with other life transitions. A useful age at which transition should take place is the end of high school or when the adolescent leaves school to join the workforce, however the following factors need to be taken into account: • The admission policy of the hospital if care is managed through a hospital-based diabetes service (many now incorporate adolescent services allowing care to the age of 18 years, while others have an age limit of 13-14 years). • The wishes of the adolescent. Chapter 18: Adolescent Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 186 • • • Emotional maturity. Physical maturity. Presence of any coexisting medical, surgical or psychiatric disorders that may be more appropriately managed through the paediatric service. Ideally the transfer to an adult service should involve: • A preparation phase (from 12 years) which should be: Planned well in advance. Organised by a special transition service. Discussed with the adolescent and family progressively over several years and supplemented with written information outlining the transition process and the available options. • A formal transition phase (16-18 years) which should be: Directed to an adult diabetes specialist or a clinic with a special interest in young adults with type 1 diabetes. Facilitated by a visit to the adult service or by having the adult physician attend the adolescent clinic if care is provided through a paediatric hospital-based diabetes service. Formally arranged with appropriate letters of referral and details of past history. Accompanied by clear directions on which emergency service to contact in the transition period. • An evaluation phase (18-19 years) to follow-up and confirm that the transition has taken place in a timely fashion and that continuing appointments have been arranged. Career Options In previous times, there were a number of career paths which people with diabetes were discouraged from pursuing. However, with improved understanding and management of diabetes there are now few occupations from which people with diabetes are excluded. In recent years a number of cases of workplace discrimination against people with diabetes mellitus have been successfully challenged in the courts. However, it is still prohibited to enter professions in: • The Australian defence forces. • The full-time or volunteer fire brigade. • The police force (currently under challenge). • The aviation industry - commercial or private pilot licences. (Note: An individual already employed in one of the above listed services prior to a diagnosis of diabetes mellitus may be removed from active duties following diagnosis and placed in a more administrative role within the service). It is not advisable for people with type 1 diabetes to work at heights (because of the risk to themselves and others if they are affected by hypoglycaemia. Driving In the first instance, adolescents with diabetes should discuss with their parents and medical team the issue of driving. The importance of having a good knowledge about hypoglycaemia, its treatment and prevention cannot be overemphasised. The adolescent must be made aware that the combination of alcohol, with its potential to cause hypoglycaemia, and diabetes can result in fatal accidents. The main hazard to driving is unexpected hypoglycaemia. Chapter 18: Adolescent Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 187 Results from a recent American survey of drivers revealed an increased incidence of driving mishaps in drivers with type 1 diabetes.22 Driving performance is significantly disrupted at relatively mild hypoglycaemia.23 A responsible attitude towards driving is therefore essential. Adolescents should be taught to do a blood glucose estimation immediately before driving a car and to have rapidly absorbed carbohydrate (eg glucose tablets) readily accessible and to take these at the first indication of hypoglycaemia. When considering hypoglycaemia for licensing purposes the Road and Traffic Authorities are concerned with severe episodes which may impair consciousness, awareness, motor skills or result in abnormal behaviour. Each State and Territory has its own set of regulations governing the issue of licences to people with diabetes and health care professionals should acquaint themselves with the regulations applying in their State or Territory. The second edition of ‘Assessing fitness to drive: Guidelines and standards for health care professionals in Australia’ produced by Austroads Inc. in 2001, and approved by all Australian Driver Licensing Authorities makes the following statements in relation to suitability of people with diabetes to drive:24 • If there is poor management of a diabetic condition, or poor compliance by a patient to their specified treatment, then the patient with diabetes should be advised not to drive. • Patients with diabetic retinopathy may drive if their vision meets the specified criteria; regular review by an eye practitioner is required. • Patients with type 1 diabetes may drive providing they meet the other criteria in the book. Two yearly review is required but the physician may recommend a shorter review period. • Patients newly starting on insulin therapy should be advised to notify the driving licensing authority of the condition and the treatment. • Patients should not drive after admission to hospital for stabilisation of diabetes until cleared by their primary health physician. • Patients should not drive after a major hypoglycaemic episode or hypoglycaemic episode whilst driving until cleared by a physician. Patients should be made aware about the effects of their condition on driving and advised of their legal obligation to notify the driver licensing authority where driving is likely to be affected. As a last resort, practitioners may themselves advise the driver licensing authority.24 Individuals who wish to pursue licences other than for cars, light trucks (up to 8 tonnes gross vehicle mass) and motor cycles, should make enquires to their nearest driver licensing authority. Risk Taking Behaviour Smoking Smoking should be actively discouraged in diabetes25 and the education process should be commenced in paediatric services. The risk of morbidity and mortality among smokers with type 1 diabetes is increased.26 Clinicians working with adolescents should use outpatient office visits as an important ‘teachable moment’ to prevent tobacco use.27 Brief interventions (taking 1-2 minutes to ask about smoking and make some recommendations) can be effective and should involve the following stages: • Ask about smoking habit. • Advise to consider quitting. Chapter 18: Adolescent Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 188 • • • Assess level of addiction and what ‘stage of change’ they are at. Assist by providing quitting strategies and supports. Arrange follow-up. Approximately 30 percent of teenagers show evidence of recent nicotine exposure (from screening surveys using urinary cotinine) and the prevalence in adolescents with diabetes does not differ. Diabetes education needs to address the following issues: 28 • Smoking is deleterious to the health of all persons at any age. • Medical evidence indicates that smoking has been implicated is an additional risk factor for the appearance and progression of microvascular disease (retinopathy, nephropathy and neuropathy) and of macrovascular disease.29 • Smoking is also associated with: Hypertension. Poorer glycaemic control. Excess general morbidity. Additional risks in pregnancy. Increased risk of periodontal disease. Alcohol It is illegal for alcohol to be sold to or served to young people under the age of 18 years in Australia. Proof-of-age identity cards are needed by young people wishing to purchase or be served alcohol. No studies have been reported on the effects of alcohol ingestion on adolescents with type 1 diabetes. Several small studies have reported the effects of moderate amounts of alcohol consumed in the evening in adults with type 1 diabetes (0.5-1.0 gm per kg body weight, equivalent to 3.5-7 standard (10gm alcohol) drinks for a 70 kg person).30-32 One study (0.75 gm/kg alcohol) reported lower post-prandial and morning fasting blood glucose to the point of requiring treatment of hypoglycaemia in 5 out of 6 patients,32 while the other two studies showed no effect.30;31 The effects of drinking larger quantities (‘binge drinking’) have not been studied. However, this pattern of drinking is emerging as the dominant form especially for young females. Alcoholic drinks provide extra kilojoules (important if weight control is a problem) and the potential to cause the following effects: • May initially increase blood glucose. • May increase plasma lipids. • May increase ketone levels. • May inhibit gluconeogenesis resulting in delayed hypoglycaemia. The combination of alcohol-induced confusion and hypoglycaemia is a particularly dangerous one. Reaction times during hypoglycaemia have been shown to be reduced during hypoglycaemia.33 Adolescents with diabetes need to be warned about the dangers of alcohol as part of their diabetes education. Consensus guidelines4;34 relating to alcohol consumption have advised the following: • Drink in moderation. • Do not exceed recommended safe intakes (2 standard drinks for adult males, 1 standard drinks for adult females (1 standard drink is equivalent to approx 10gm alcohol)). Chapter 18: Adolescent Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 189 • • • • • • • Avoid binge drinking. Avoid consuming alcohol on an ‘empty stomach’. Drink low-alcohol beers or wine rather than spirits, fortified wines or spirits/soft drink mixes. Measure blood glucose levels regularly during and after consuming alcohol. Eat carbohydrate foods while consuming alcohol. Eat prescribed snacks/meals on time. Measure blood glucose before going to bed, eat a bedtime snack and ensure BG is greater than 8 mmol/L. Drugs The most commonly used substances with the potential for abuse are still tobacco and alcohol. From the limited information available it would appear that adolescents with diabetes are no more likely to experiment with or use drugs. A survey of adolescents (age 1020 years) in the US found that 10% had used a drug in the past (8% in the previous year).35 There is little published information on substance misuse and their effects in adolescents with type 1 diabetes. In general substance use has the capacity to: • Alter perception. • Alter cognitive ability. • Alter consciousness. • Alter sensation. • Decrease capacity to achieve glycaemic control. • Decrease interest in achieving glycaemic control. • Decrease interest in routines, injection and meal schedules. • Increase risk of hypoglycaemia being ignored or misinterpreted. • Reduce appetite and interest in food that may potentiate hypoglycaemia. • In the case of marijuana, stimulate appetite (the ‘munchies’) with a craving for carbohydrate. A significant percent of adolescent drug use is likely to be intermittent, experimental or recreational, and effects on diabetes and its management may be few. Regular drug use has the potential of causing deterioration in diabetes control. Regular drug use does not generally occur in isolation but in the context of other risk-taking behaviours, psychosocial distress and peer group or family drug usage. Sexuality Impotence Fear of impotence may be a concern for adolescent boys with diabetes. Impotence may be caused by psychological or organic conditions. Impotence due to organic reasons may occur in adults with diabetes of long duration as a result of autonomic neuropathy affecting the nerve supply to the corpora cavernosa or as a result of macrovascular disease of the aorta affecting the blood supply to the penis. Increasing age, duration of diabetes and poor glycaemic control are risk factors for erectile dysfunction.36 Impotence is rare in the adolescent age group and may well be minimised or prevented by good glycaemic control. Impotence due to psychological reasons needs to be treated by counselling and reassurance. Chapter 18: Adolescent Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 190 Contraceptives Assessment of sexual activity and the need for contraception should be a routine part of adolescent diabetes care, as young persons may not actively seek contraceptive advice. The clinician should reassure the adolescent that confidentiality will be maintained. Ensuring confidentiality, along with establishing empathy will create a more suitable environment to explore contraception and related issues. Oral contraceptive pill (OCP) Low dose oestrogen-containing OCP preparations are not contra-indicated in adolescents with type 1 diabetes but should be used with caution if there is: • Uncontrolled hypertension. • Dyslipidaemia (particularly hypertriglyceridaemia). • Evidence of microvascular disease. • Evidence of macrovascular disease. In general OCP use is not advised in young women with micro- or macro-vascular disease. The best choice of oral contraceptive pill for adolescents with type 1 diabetes is a low dose oestrogenic-containing monophasic or triphasic preparations.37 The new gestodenecontaining OCPs may have some advantages in patients with type 1 diabetes as they have less effect on lipid profiles and carbohydrate metabolism, as well as being less androgenic. Young women with type 1 diabetes using OCPs should have an annual gynaecological review that should incorporate expert advice on the most appropriate method of contraception. Intrauterine devices (IUDs) Although IUDs are not ideal, particularly in a nulliparous female with type 1 diabetes, if this is the only form of contraception that is suitable or tolerated, it is preferable to an unplanned pregnancy. The newer IUDs appear to be effective and well tolerated in diabetic women.38;39 The risk of pelvic infection, while probably low with newer devices, is highest in: • New users. • Younger age groups. • Those at risk of sexually transmitted disease. • Women with poorly controlled diabetes. Barrier methods (condom, diaphragm) Condoms may be used both as a primary contraceptive method and, importantly, should always be advised for additional protection against the risk of sexually transmitted disease even when other contraceptive methods are employed. Barrier methods may appear to be well suited to young women with diabetes due to their lack of side effects. However, a high degree of motivation and compliance is required as these methods may have higher failure rates. Progestogen depot/implant These are extremely effective forms of contraception. Their use is limited in all women by their side effects. Although they are suitable for use in women with diabetes they should be used with caution as lipid profiles may be altered.40 Chapter 18: Adolescent Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 191 Diabetes and Pregnancy Pregnancy in all women with type 1 diabetes should be monitored from the pre-conception stage by an experienced multidisciplinary team of obstetrician, diabetologist, diabetes educator and dietitian. Adolescent girls with diabetes should be made aware of the extreme importance of a planned pregnancy. Education should address effective contraception to avoid an unplanned pregnancy. Pregnancy should only occur when the HbA1c is within or close to the nondiabetic range because poor glycaemic control increases the risk of large babies as well as increasing the risk of foetal malformations 2-10 fold with progressive elevation of the HbA1c.41-43 Furthermore pregnancy may accelerate the progression of microvascular complications44 and the risk of hypertensive disease in pregnancy is increased.45;46 Eating Disorders A systematic review of case-control studies in children and adults showed that the incidence of anorexia nervosa in people with type 1 diabetes is not increased.47 However, adolescent females with type 1 diabetes and anorexia nervosa have a significantly increased mortality rate compared to patients with type 1 diabetes alone.48 A systematic review of case-control studies has shown that the incidence of bulimia nervosa, ED-NOS (Eating Disorder - Not Otherwise Specified) and sub-threshold disorders are significantly increased in female adults and children with type 1 diabetes. 47 Eating disorders in males with diabetes have been less extensively investigated, but some studies suggest that they may display high levels of unhealthy weight control behaviours and high drives for thinness.49;50 Studies have found an increased level of retinopathy in patients with type 1 diabetes and sub-clinical and clinical eating disorders.47;51;52 The diagnostic criterion of the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders criteria) recognises medication manipulation for the purpose of weight loss as a behavioural disturbance associated with eating disorders.53 Intensive glycaemic control is associated with weight gain,2 and this may be unacceptable to many adolescents. Intentional reduction or omission of insulin induces glycosuria and ketonuria, and hence weight loss (socalled insulin purging).56 The incidence of insulin omission or misuse in females with type 1 diabetes is 12-15%.54;55 Insulin purging leads to poor glycaemic control and increased risk of medical complications.57 Predictive signs of disordered eating include:58 • Poor glycaemic control. • Frequent hospital presentations with diabetic ketoacidosis. • Weight loss or weight cycling. • Unhealthy attitudes toward weight and/or food. • Falsification of blood glucose levels. The co-existence of type 1 diabetes and eating disorders presents difficulties for the management of the diabetes as well as for psychological treatment. One of the goals of cognitive behavioural therapy for bulimia nervosa is to relax control over eating and this can conflict with the nutritional aspect of diabetes management.57 Treatment of eating disorders depends on the type and severity of the disorder, but should include medical, nutritional and psychological therapy by an experienced multi-disciplinary team.58 Chapter 18: Adolescent Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 192 The Evidence The evidence comparing glycaemic control in adolescents and adults is listed in Evidence Table 18.1. • The DCCT demonstrated that HbA1c levels were generally 1% higher in adolescents, both in the intensively treated and in the conventionally treated groups.2;3(II) The evidence for current transition processes and outcomes for adolescents with type 1 diabetes moving to the adult care system is listed in Evidence Table 18.2. • Seven studies addressing the issues of transition to adult services identified poor or delayed post-transfer clinic attendance and frequent dissatisfaction with the transition process.15-21(IV) • A study of transition processes in the Oxford region, UK, showed that the 2 year clinic attendance (at least 6 monthly) fell from 98% pre-transfer to 61% post-transfer (p<0.0005) and the attendance rate for the first appointment on transfer was only 79%.17(IV) The evidence for the effect of type 1 diabetes on driving performance is listed in Evidence Table 18.3. • Results from a recent American survey of drivers revealed an increased incidence of driving mishaps in drivers with type 1 diabetes.22(IV) • Simulated driving performance is significantly disrupted at relatively mild hypoglycaemia.23(IV) The evidence for eating disorders in type 1 diabetes is listed in Evidence Table 18.4. • A systematic review of case-control studies has shown that the incidence of Anorexia Nervosa in females with type 1 diabetes is not increased, however the incidence of bulimia nervosa, ED-NOS (Eating Disorder - Not Otherwise Specified) and sub-threshold disorders are significantly increased in female adults and children with type 1 diabetes.47 Adolescent females with type 1 diabetes and anorexia nervosa have a significantly increased mortality rate compared to patients with type 1 diabetes alone.48(IV) • Males with diabetes have high levels of unhealthy weight control behaviours and higher drives for thinness than non diabetic controls.49;50 • The incidence of insulin omission or misuse in females with type 1 diabetes is 1215%.54;55(IV) • Studies have found an increased level of retinopathy in patients with type 1 diabetes and sub-clinical and clinical eating disorders.47;51;52(IV) Additional Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 18.5. Recommendations and Principles • Health care professionals should be aware that glycaemic control is more difficult in adolescents with type 1 diabetes.2;3(II) • Adolescents with diabetes have specific health needs relating to physical, emotional, psychological and socio-cultural stages of adolescence.4;9(C) • The major risks faced by adolescents with diabetes include deterioration of glycaemic control, risk-taking behaviour, hypoglycaemia, recurrent diabetic ketoacidosis and accelerated microvascular complications.4(C) • The transition from a paediatric to an adult service for the adolescent with diabetes is often difficult.15-21(IV) 14 • Ideally the transfer to an adult service should be comprehensive and should involve: (C) Chapter 18: Adolescent Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 193 A preparation phase which is planned well in advance by a special transition service and the adolescent and family. A formal transition phase to an adult clinic, with appropriate referral and clear directions for the patient and family (eg in case of emergencies). An evaluation phase. Adolescents should be taught to do a blood glucose estimation immediately before driving a car and to have rapidly absorbed carbohydrate (eg glucose tablets) readily accessible and to take these at the first indication of hypoglycaemia.22;23(IV) Smoking should be actively discouraged in diabetes.25(C) Adolescents with diabetes need to be warned about the dangers of alcohol as part of their diabetes education.59;60(C) Issues surrounding sexuality should be approached with confidentiality and empathy.4(C) Assessment of sexual activity and the need for contraception should be a routine part of adolescent diabetes care.4;59(C) Health care professionals should be aware that the incidence of eating disorders is increased in males and females with type 1 diabetes47;49;50 and that adolescent females with type 1 diabetes and anorexia nervosa have a significantly increased mortality rate compared to patients with type 1 diabetes alone.48(IV) Health care professionals should be aware that intentional reduction or omission of insulin to achieve weight loss is common (so-called insulin purging).54;55(IV) Health care professionals should be aware that increased levels of retinopathy have been found in patients with type 1 diabetes and sub-clinical and clinical eating disorders.47;51;52(IV) Treatment of eating disorders should include medical, nutritional and psychological therapy by an experienced multidisciplinary team.57;58(C) • • • • • • • • • II = Evidence obtained from at least one properly designed randomised controlled trial IV = Evidence obtained from case series, either post-test or pre-test and post-test C = Consensus statement endorsed by professional organisations Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 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Journal of Pediatric Psychology 17:537-553, 1992 Chapter 18: Adolescent Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 194 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. Morris AD, Boyle DI, McMahon AD, Greene SA, MacDonald TM, Newton RW: Adherence to insulin treatment, glycaemic control, and ketoacidosis in insulin-dependent diabetes mellitus. The DARTS/MEMO Collaboration. Diabetes Audit and Research in Tayside Scotland. Medicines Monitoring Unit. Lancet 350:1505-1510, 1997 Rosen DS, Blum RW, Britto M, Sawyer SM, Siegel DM, Society for Adolescent Medicine: Transition to adult health care for adolescents and young adults with chronic conditions: position paper of the Society for Adolescent Medicine. Journal of Adolescent Health 33:309-311, 2003 Court JM: Issues of transition to adult care. 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Archives of Disease in Childhood 88:53-56, 2003 Salmi J, Huupponen T, Oksa H: Metabolic control in adolescent insulin-dependent diabetics referred from pediatric to adult clinic. Annals of Clinical Research 18:84-87, 1986 Cox DJ, Penberthy JK, Zrebiec J, Weinger K, Aikens JE, Frier B, Stetson B, DeGroot M, Trief P, Schaechinger H, Hermanns N, Gonder-Frederick L, Clarke W: Diabetes and driving mishaps: frequency and correlations from a multinational survey. Diabetes Care 26:2329-2334, 2003 Cox DJ, Gonder-Frederick LA, Kovatchev BP, Julian DM, Clarke WL: Progressive hypoglycemia's impact on driving simulation performance. Occurrence, awareness and correction. Diabetes Care 23:163-170, 2000 Austroads: Assessing Fitness to Drive. Guidelines and Standards for Health Professionals in Australia. Sydney, Austroads Incorporated, 2001 International Diabetes Federation. Position Statement. Diabetes and tobacco use: a harmful combination . 2003. Gay EC, Cai Y, Gale SM, Baron A, Cruickshanks KJ, Kostraba JN, Hamman RF: Smokers with IDDM experience excess morbidity. The Colorado IDDM Registry. Diabetes Care 15:947-952, 1992 Vickers KS, Thomas JL, Patten CA, Mrazek DA: Prevention of tobacco use in adolescents: review of current findings and implications for healthcare providers. Current Opinion in Pediatrics 14:708-712, 2002 Doll R, Peto R, Wheatley K, Gray R, Sutherland I: Mortality in relation to smoking: 40 years' observations on male British doctors. British Medical Journal 309:901-911, 1994 Sinha RN, Patrick AW, Richardson L, Wallymahmed M, MacFarlane IA: A six-year follow-up study of smoking habits and microvascular complications in young adults with type 1 diabetes. Postgraduate Medical Journal 73:293-294, 1997 Koivisto VA, Tulokas S, Toivonen M, Haapa E, Pelkonen R: Alcohol with a meal has no adverse effects on postprandial glucose homeostasis in diabetic patients. Diabetes Care 16:1612-1614, 1993 Moriarty KT, Maggs DG, Macdonald IA, Tattersall RB: Does ethanol cause hypoglycaemia in overnight fasted patients with Type 1 diabetes? Diabetic Medicine Vol.10(1):61-65, 1993 Turner BC, Jenkins E, Kerr D, Sherwin RS, Cavan DA: The effect of evening alcohol consumption on next-morning glucose control in type 1 diabetes. Diabetes Care 24:1888-1893, 2001 Kerr D, Macdonald IA, Heller SR, Tattersall RB: Alcohol causes hypoglycaemic unawareness in healthy volunteers and patients with type 1 (insulin-dependent) diabetes. Diabetologia 33:216-221, 1990 Diabetes UK. Information. Alcohol and Diabetes. 2003. London, Diabetes UK. Prey MA, Guthrie B, Loveland-Cherry C, Pil SP, Foster CM: Risky behavior and risk in adolescents with IDDM. Journal of Adolescent Health 20:38-45, 1997 Fedele D, Coscelli C, Cucinotta D, Forti G, Santeusanio F, Viaggi S, Fiori G, Velona T, Lavezzari M, Diade Study Group: Incidence of erectile dysfunction in Italian men with diabetes. Journal of Urology 166:1368-1371, 2001 Alison Nankervis: Sexual Function and Pregnancy. In Diabetes and the Adolescent. 1 ed. George A Werther, John M Court, Eds. Melbourne, Miranova Publishers, 113-136, 1998 Kimmerle R, Weiss R, Berger M, Kurz KH: Effectiveness, safety, and acceptability of a copper intrauterine device (CU Safe 300) in type I diabetic women. Diabetes Care 16:1227-1230, 1993 Petersen KR, Skouby SO, Jespersen J: Contraception guidance in women with pre-existing disturbances in carbohydrate metabolism. European Journal of Contraception & Reproductive Health Care 1:53-59, 1996 Diab KM, Zaki MM: Contraception in diabetic women: comparative metabolic study of Norplant, depot medroxyprogesterone acetate, low dose oral contraceptive pill and CuT380A. Journal of Obstetrics & Gynaecology Research 26:17-26, 2000 Rosenn B, Miodovnik M, Dignan PS, Siddiqi TA, Khoury J, Mimouni F: Minor congenital malformations in infants of insulindependent diabetic women: association with poor glycemic control. Obstetrics & Gynecology 76:745-749, 1990 Ray JG, O'Brien TE, Chan WS: Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. Quarterly Journal of Medicine 94:435-444, 2001 Small M, Cassidy L, Leiper JM, Paterson KR, Lunan CB, MacCuish AC: Outcome of pregnancy in insulin-dependent (type 1) diabetic women between 1971 and 1984. Quarterly Journal of Medicine 61:1159-1169, 1986 The Diabetes Control and Complications Trial Research Group.: Effect of pregnancy on microvascular complications in the diabetes control and complications trial. The Diabetes Control and Complications Trial Research Group. Diabetes Care 23:10841091, 2000 Roach VJ, Hin LY, Tam WH, Ng KB, Rogers MS: The incidence of pregnancy-induced hypertension among patients with carbohydrate intolerance. Hypertension in Pregnancy 19:183-189, 2000 Hanson U, Persson B: Epidemiology of pregnancy-induced hypertension and preeclampsia in type 1 (insulin-dependent) diabetic pregnancies in Sweden. Acta Obstetricia et Gynecologica Scandinavica 77:620-624, 1998 Nielsen S: Eating disorders in females with type 1 diabetes: An update of a meta-analysis. European Eating Disorders Review 10:241-254, 2002 Nielsen S, Emborg C, Molbak AG: Mortality in concurrent type 1 diabetes and anorexia nervosa. Diabetes Care 25:309-312, 2002 Neumark-Sztainer D, Patterson J, Mellin A, Ackard DM, Utter J, Story M, Sockalosky J: Weight Control Practices and Disordered Eating Behaviors Among Adolescent Females and Males With Type 1 Diabetes: Associations with sociodemographics, weight concerns, familial factors, and metabolic outcomes. Diabetes Care 25:1289, 2002 Chapter 18: Adolescent Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 195 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. Svensson M, Engstrom I, Aman J: Higher drive for thinness in adolescent males with insulin-dependent diabetes mellitus compared with healthy controls. Acta Paediatrica 92:114-117, 2003 Affenito SG, Backstrand JR, Welch GW, Lammi-Keffe CJ, Rodriguez NR, Adams CH: Subclinical and clinical eating disorders in IDDM negatively affect metabolic control. Diabetes Care 20:182-184, 1997 Rydall AC, Rodin GM, Olmsted MP, Devenyi RG, Daneman D: Disordered eating behavior and microvascular complications in young women with insulin-dependent diabetes mellitus. New England Journal of Medicine 336:1849-1854, 1997 American Psychiatric Association: Diagnostic and statistical manual of mental disorders - Fourth Edition (DSM - IV). Washington DC, American Psychiatric Association, 1994 Peveler RC, Fairburn CG, Boller I, Dunger D: Eating disorders in adolescents with IDDM: A controlled study. Diabetes Care 15:1356-1360, 1992 Rodin G, Craven J, Littlefield C, Murray M, Daneman D: Eating disorders and intentional insulin undertreatment in adolescent females with diabetes. Psychosomatics 32:171-176, 1991 Crow SJ, Keel PK, Kendall MD: Eating Disorders and Insulin-Dependant Diabetes Mellitus. Psychosomatics 39:233-243, 1998 National Institute for Clinical Excellence. Eating Disorders: Core interventions in the treatment and management of anorexia nervosa, bulimia nervosa, and related eating disorders. 2003. London. Daneman D, Olmsted M, Rydall A, Maharaj S, Rodin G: Eating disorders in young women with type 1 diabetes. Prevalence, problems and prevention. Hormone Research 50:79-86, 1998 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 National Institute for Clinical Excellence. Type 1 Diabetes (Childhood): Diagnosis and Management of Type 1 Diabetes in Children and Young People. 2004. Chapter 18: Adolescent Health Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 196 Chapter 19: School School attendance is compulsory for children from 6 to 15 years unless: • Families lack access to an educational facility if geographically isolated. • A medical condition or religious conviction prevents attendance. All children and adolescents with type 1 diabetes should attend school and participate in normal school activities. Diabetes should not be the cause of a child or adolescent being excluded from any school activity. Full participation in all academic, social and sporting activities is possible and should be encouraged. Any discrimination or stigmatisation is unacceptable. School is a major part of a child’s life and needs to be a rewarding experience. It is important for children to enjoy school and to function well at school because during the school term they spend approximately 40 percent of their waking hours there.1 School achievement and adjustment to school are important indicators of the child’s general wellbeing. Furthermore, development of self-esteem and confidence in school activities is likely to have positive effects on diabetes management. Conversely, school difficulties are likely to impact negatively on diabetes control. Behavioural problems at school may be totally unrelated to the child’s diabetes and should not be dismissed as due to diabetes alone. Children with chronic illness are more at risk for school absenteeism and dysfunction than their healthy peers.2;3 School personnel need to be provided with sufficient information to enable them to provide a classroom environment which facilitates the child’s full integration by ensuring or facilitating: • Safety at all times. • Attainment of developmental goals (by exposure to normal life experiences). • Development of self-esteem. • Freedom from discrimination from staff and students. • Peer acceptance and understanding. It is a legal requirement that schools provide a safe environment conducive to learning and social development in all children, including those with special health needs. Students with diabetes may require additional care. The school has a duty of care to all children including those with special needs. Parents and caregivers of children and adolescents with diabetes should work cooperatively with the school system to ensure mutual understanding of the extent of care provided. With appropriate training some teachers may volunteer to supervise or carry out blood glucose testing, insulin administration or glucagon administration. It is important that all staff, including relief staff, have sufficient knowledge about diabetes to ensure the safety of students with diabetes (especially in regard to hypoglycaemia and safety in sport). An individualised Diabetes Health Care Plan, especially for the younger child with diabetes, should be developed by the parents/care-givers, the student’s health care team and the school.4 Specific responsibilities in the Care Plan need to be understood and accepted by parents/care-givers as well as the school. In some states, for very young children with unstable diabetes, an application can be made to the Department of Education for additional supervision (‘integration support’) in the school setting. Chapter 19: School Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 197 The diabetes management should cause as little disruption as possible, provided that metabolic control and avoidance of hypoglycaemia are not compromised. General Considerations in the Development of the Care Plan Many children’s diabetes centres and some diabetes associations provide school visits by diabetes educators to inform the staff of the details they need to know about diabetes and to answer any specific questions. The value of these visits cannot be over-estimated and all teaching and office staff should attend. Priority should be given to younger children especially those attending long day care and pre-school. Diabetes Australia in some States provides a ‘Schools Care Line’. This is a telephone service, manned by a paediatric diabetes educator, available to teachers, parents and students. Essential information (for example the IDF School Pack, accessible from www.diabetesnsw.com.au) for school personnel is available from diabetes centres, Diabetes Australia, Juvenile Diabetes Research Foundation (JDRF) and community health centres. All school personnel (including relief staff and after-school care staff) should be informed if a child in their care has type 1 diabetes. It may be helpful for relief staff to have photographic identification of any child with diabetes in their care. Background information on diabetes provided to schools should include: • Differences between type 1 and 2 diabetes. • Provision of basic information on hypoglycaemia including: Recognition of hypoglycaemia symptoms. Treatment protocols for mild to moderate hypoglycaemia. Awareness that repeat treatment may be necessary. Awareness of the transient deterioration in the child’s brain function and behaviour during and following a hypoglycaemic episode. Basic first aid treatment eg coma position. • Provision of information on hyperglycaemia including: Polyuria and polydipsia. Need for extra toilet privileges and access to water. • Awareness that infection control protocols must be adhered to during blood glucose monitoring. • Provision of a suitable environment for glucose monitoring or insulin injections if required during school hours. • Awareness that some children now use a continuous subcutaneous insulin pump. • Emergency contact details. It is useful to have a photo of the child with important contact numbers in the staff room and in each classroom to alert all staff including relief and part time staff. A medical alert information card should be kept in the child’s records. The child should wear a medical identification bracelet or necklace at all times. Issues to be Considered in the Individual Care Plan Parents/care-givers should meet with the relevant school personnel as soon as practicable to discuss the issues involved in the care of their child at school. An individual care plan should be developed and reviewed regularly. In general, the younger the child, the greater is the supervision required at school. The extent of the individual care plan will vary greatly and Chapter 19: School Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 198 will be influenced by the consideration of the following issues by the school and the parents/care-givers: • Child’s level of understanding and knowledge of diabetes. • Child’s developmental stage and ability to accept responsibility. • Current treatment recommendations for the individual child. • Any additional medical problems (eg coeliac disease). • Child’s usual hypoglycaemic symptoms. • Avoiding delays in meals, snacks. • Treating hypoglycaemia immediately. • Providing the school with an emergency supply of rapidly absorbed carbohydrate (eg jellybeans) in the classroom or wherever the school activity is undertaken. • Providing extra snacks before, during and possibly following exercise. • Knowing which foods are easily accessible and easy to consume (eg fruit that does not require peeling). • Not leaving a child unaccompanied during or after a hypoglycaemic episode (eg in sick bay). • Knowing that the child should not be sent away unaccompanied by an adult from the classroom to test his/her blood glucose during a suspected hypoglycaemic episode. • Informing parents/care-givers of the time and nature of the hypoglycaemia (a communication book noting unusual occurrences is helpful for teachers and parents). • Encouraging the child to eat all of his/her meal (mealtime supervision may be necessary for primary school children. Parents need to be informed if meals are not eaten). • Being aware that birthday parties at preschool and primary school should not exclude the child with diabetes, as this is a ‘special treat’ occasion and should be so for all the children. Any special considerations (eg provision of diet drinks) should be discussed with the child’s parents or caregivers. • Providing access to the canteen, recognising that this may need some restrictions. • Encouraging the child to report hypoglycaemia to school personnel. Teachers need to be cognisant of the child’s personality and feelings, and encourage communication. • Knowing that following a hypoglycaemic episode children usually recover sufficiently to rejoin the class, although cognitive function may be impaired for several hours.5;6 However, if the episode occurred during a sports activity, the child should rest for 10 15 minutes before recommencing the activity. • Helping to fit diabetes into the school routine to prevent the child from feeling different (eg they should eat at the same time as the other children, be given privacy to give injections or do blood tests). • Determining exactly the physical location where in the school glucose testing and insulin injections will take place. • Assisting and encouraging the child gradually to take on some responsibility for the diabetes tasks eg negotiating how much reminding the child would like in order to remember to eat on time and how much he/she would like to be left alone. • Allowing extra access to toilets and drinks when blood glucose levels are high. • Notifying parents in advance of special events, eg excursions, swimming carnivals, changes to meal times. • Knowing the impact which diabetes may have on the functioning of the child and family (awareness and acknowledgment of parental concerns inspires confidence, reduces anxiety and their tendency to be over-protective). • Knowing how blood glucose levels can affect concentration and behaviour. • Knowing that diabetes should not alter the child’s academic potential. Chapter 19: School Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 199 • Encouraging full participation in all school social, sporting and academic activities, including excursions and camps. Detentions Teachers should be aware of the need for regular carbohydrate intake and that eating may be necessary during detention to avoid hypoglycaemia. Travel to and from School by Bus Students with type 1 diabetes should be allowed to eat on the bus to avoid hypoglycaemia. A ‘bus’ card approved by transport authorities is available for such special provision in some States. Emergencies at School If severe hypoglycaemia causes a child to have a seizure, be unconscious or so disorientated that oral treatment is not possible or is dangerous, the school personnel should lay the child in the coma position and call an ambulance, stating that it is a diabetic emergency (dial 000). School Examinations If an examination coincides with the child’s or adolescent’s usual meal or snack time, it is advisable for the child to nibble small amounts of bite-sized carbohydrate food, eg nuts and raisins, throughout, rather than risk having hypoglycaemia by waiting to eat until after the examination. Examination candidates need to be aware that their food should not be wrapped in ‘noisy’ packaging. High School Examinations The school is required to send an ‘Application for Candidates with Disabilities’ form, accompanied by a medical certificate, to the ‘Special Provisions for Students’ programmes provided by the individual State or Territory authorities responsible for senior examinations some months prior to the examination. Parents in each State or Territory should enquire about the procedures available to children and adolescents who may experience difficulties with their diabetes during examinations from their diabetes centres, schools or Diabetes Australia. Most States allow the student to: • Take in bite-sized starchy food. • Have easy access to leave the room as necessary. • Take in a glucose meter and test strips. • Have extra time to do an initial blood glucose test, to correct a blood glucose reading under 5 mmol/L and to re-test it. The provisions may be made on an individual basis depending on the recommendations of the medical practitioner. It is advised that the student receives a copy of the provisions made for him or her. It should be noted that students experiencing hypoglycaemia during the Higher School Certificate examinations (or equivalent in other States) should apply to be treated as an ‘illness/misadventure case’. Giving extra time to compensate for the occurrence of a hypoglycaemic episode may not compensate accurately for the time lost nor allow for the Chapter 19: School Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 200 effect of hypoglycaemia on the child’s concentration Students treated as an illness/misadventure case usually receive a mark based on a school assessment in place of their actual examination mark. School Camps Students with diabetes can participate fully in school camp programs. Usually students attend camps when they are reliably independent in the care of their diabetes. This includes the ability to:7 • Inject. • Do blood glucose tests. • Recognise/treat hypos. • Understand the importance of timed meals. • Understand a food plan, dietary carbohydrate portions or serves and the need for extra food before, during and after physical activity. Parents/guardians should meet with the organisers before the camping event.7 Each camper should have a standardised medical information sheet completed prior to the camp.8 All members of staff must be aware of the child with diabetes. The student’s friends and room mates should also be aware. Staff must know about:7 • Food planning and the need for carbohydrate with all meals and snacks. • Blood glucose testing. • Prevention of hypos. • Recognition and treatment of hypos. • Sick-days. • When to call for medical help and how to arrange medical evacuation. The extra exercise at camps increases the risk of hypos. The insulin dose may need to be reduced by up to _ of the usual insulin dose. Carbohydrate should be served regularly with every meal and snack. Additional carbohydrate should be available for prevention and treatment of hypos. Short-term Effects of Fluctuations in Glycaemia on Cognitive Function In a case series of 47 children with type 1 diabetes cognitive function was found to remain impaired for a variable period of time following a mild hypoglycaemic episode (despite complete resolution of the hypoglycaemic symptoms) therefore confirming that there is a time lag between recovery rate of physical symptoms and cognitive function in children following a mild hypoglycaemic episode.5 Decreased cognitive function was also found during hyperglycaemia in an RCT in 8 out of 12 subjects.9 Mood disturbances have been documented the day after nocturnal hypoglycaemia.10 Long-term Effects of Fluctuations in Glycaemia on Cognitive Function Studies have shown that cognitive function is decreased among some children with early onset (<7yrs)11;12 and longer duration (>5yrs duration)11;13 of diabetes. Chapter 19: School Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 201 Children who had experienced hypoglycaemic seizures were significantly more likely to have a decline in verbal IQ score and other cognitive aspects of perception, fine motor, visuomotor, visual memory and attention.12;14;15 Two longitudinal studies found that the expected cognitive developmental gains (especially verbal skills) were smaller than expected when children were followed from diagnosis of type 1 diabetes to one year,16 two years17 and 6 years post diagnosis.18 A prospective study in Switzerland found cognitive impairment was associated with male gender, young age at diagnosis (before age 6 years), more severe metabolic disturbance at diagnosis and chronic poor metabolic control.19 The Evidence The evidence for the effect of type 1 diabetes on cognitive function in children and adolescents with type 1 diabetes is listed in Evidence Table 19.1. • A case series showed that cognitive function remained impaired for a variable period of time following a mild hypoglycaemic episode despite complete resolution of the hypoglycaemic symptoms.5(IV) 10 • Mood disturbances have been documented the day after nocturnal hypoglycaemia. (III-2) • In an RCT decreased cognitive function was found during hyperglycaemia in 8 out of 12 subjects.9(II) • Studies have shown that cognitive function is decreased in some children who have a history of hypoglycaemic seizures.12;14;15(IV) • Early age of onset, longer duration of diabetes and prolonged hyperglycaemia and poor metabolic control are also associated with a higher risk of cognitive dysfunction.11-13;19(IV) • Two longitudinal studies found that the expected cognitive developmental gains (especially verbal skills) were smaller than expected when children were followed one to six years from diagnosis of type 1 diabetes.16;17;18 (IV) Additional Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 19.2. Recommendations and Principles • Parents/care-givers and teachers should be aware that discrimination or stigmatisation is unacceptable.20(C) • Parents/care-givers and teachers should be aware that diabetes should not be the cause non-participation in any school activity.20;21(C) • Parents/care-givers should meet with the relevant school personnel as soon as practicable to discuss the issues involved in the care of their child at school.20(C) 4 • An individual care plan should be developed and reviewed regularly. (C) • Parents/care-givers and teachers should be aware how to recognise and treat hypoglycaemia.20;21(C) • An emergency supply of rapidly absorbed carbohydrate should be readily available in the classroom or wherever the school activity is undertaken.20;21(C) • During or following hypoglycaemia or suspected hypoglycaemia, a child must not be expected to walk to a ‘medical room’ nor left unaccompanied.20;21(C) • Parents/care-givers and teachers should be aware that cognitive function and mood may be affected for some hours after hypoglycaemia.5;10 (III-2, IV) • Parents/care-givers and teachers should be aware that decreased cognitive function may occur when hyperglycaemia is present.9(II) Chapter 19: School Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 202 • Parents/care-givers and teachers should be aware that risk factors for cognitive dysfunction include a history of hypoglycaemic seizures,12;14;15 early age of onset and longer duration of diabetes.11-13;16;17;18(IV) • Parents/care-givers, teachers and students should be aware that students with diabetes sitting for the higher examinations may apply for special provisions.21(C) II = Evidence obtained from at least one properly designed RCT IV = Evidence obtained from case series, either post-test or pre-test and post test C = Consensus statement endorsed by professional organisations Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. Canadian Diabetes Association: Standards of care for students with type 1 diabetes in school. Canadian Journal of Diabetes Care 23:66-70, 1999 Gallant RD: School achievement and absence in children with chronic health conditions. Journal of Pediatrics 106:683-687, 1985 Ryan C, Longstreet C, Morrow L: The effects of diabetes mellitus on the school attendance and school achievement of adolescents. Child: Care, Health & Development 11:229-240, 1985 American Diabetes Association: Care of children with diabetes in the school and day care setting. American Diabetes Association. Diabetes Care 26:131-135, 2003 Puczynski MS, Puczynski SS, Reich J, Kaspar JC, Emanuele MA: Mental efficiency and hypoglycemia. Journal of Developmental & Behavioral Pediatrics 11:170-174, 1990 Strachan MWJ, Deary IJ, Ewing FME, Frier BM: Recovery of cognitive function and mood after severe hypoglycemia in adults with insulin-treated diabetes. Diabetes Care 23:305-312, 2000 Silink M, Mellor L, Mc Gill M, Middlehurst A, Jackson L, Phelan H, and Harris G. Diabetes information - Camps. 2003. Ref Type: Pamphlet American Diabetes Association: Management of diabetes at diabetes camps. Diabetes Care 26 Suppl 1:S136-S138, 2003 Davis EA, Soong SA, Byrne GC, Jones TW: Acute hyperglycaemia impairs cognitive function in children with IDDM. Journal of Pediatric Endocrinology & Metabolism 9:455-461, 1996 Matyka KA, Wigg L, Pramming S, Stores G, Dunger DB: Cognitive function and mood after profound nocturnal hypoglycaemia in prepubertal children with conventional insulin treatment for diabetes. Archives of Disease in Childhood 81:138-142, 1999 Holmes CS, Richman L: Cognitive profiles of children with insulin-dependent diabetes. Journal of Developmental & Behavioral Pediatrics 6:326, 1985 Rovet J, Alvarez M: Attentional functioning in children and adolescents with IDDM. Diabetes Care 20:803-810, 1997 Sansbury L: Predictors of cognitive functioning in children and adolescents with insulin-dependent diabetes mellitus: A preliminary investigation. Children's Health Care 26:210, 1997 Rovet JF, Ehrlich RM: The effect of hypoglycemic seizures on cognitive function in children with diabetes: a 7-year prospective study. Journal of Pediatrics 134:503-506, 1999 Hannonen R, Tupola S, Ahonen T, Riikonen R: Neurocognitive functioning in children with type-1 diabetes with and without episodes of severe hypoglycaemia. Developmental Medicine & Child Neurology 45:262-268, 2003 Rovet JF, Ehrlich RM, Czuchta D: Intellectual characteristics of diabetic children at diagnosis and one year later. Journal of Pediatric Psychology 15:775-788, 1990 Northam EA, Anderson PJ, Werther GA, Warne GL, Adler RG, Andrewes D: Neuropsychological complications of IDDM in children 2 years after disease onset. Diabetes Care 21:379-384, 1998 Northam EA, Anderson PJ, Jacobs R, Hughes M, Warne GL, Werther GA: Neuropsychological profiles of children with type 1 diabetes 6 years after disease onset. Diabetes Care 24:1541-1546, 2001 Schoenle EJ, Schoenle D, Molinari L, Largo RH: Impaired intellectual development in children with Type I diabetes: association with HbA(1c), age at diagnosis and sex. Diabetologia 45:108-114, 2002 International Society for Pediatric and Adolescent Diabetes: Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Chapter 19: School Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 203 Chapter 20: Diabetes Camps Diabetes camps are an integral component of overall care and support for diabetic children and adolescents in Australia. Diabetes camps are held annually in most states in a variety of settings. Despite the varying nature of different diabetes camps all have several features in common. These are: • Camps are primarily recreational and enjoyable. • Camps provide both overt and subliminal peer support. • Camps provide a safe environment for children and adolescents to pursue more challenging activities (physical or social) than they would previously have undertaken. • Camps provide education and assistance in managing type 1 diabetes. Background Diabetes camps have been a part of diabetes care for almost as long as insulin therapy has been available. The first diabetes camp was held in Detroit in the US in 1925.1 In Australia diabetes camps have been held since 1947.2 Participation in diabetes camps is now recognised as an important aspect of care for children and adolescents with diabetes.3 Guidelines and standards for diabetes camps have been published for most countries including Australia.4;5 The Need for Diabetes Camps in Australia Australian and international research has shown that many children and adolescents with diabetes have needs that are inadequately met in the context of traditional clinical encounters with either a medical practitioner or diabetes nurse specialist. These needs include: • Poor quality of life and functional health (particularly in children and adolescents from regional Australia).6;7 8;9 • High rates of depression, anxiety, behavioural, cognitive and mood disorders. 10 • Feeling isolated. 11 • Feeling disempowered and helpless. 12 • Lacking meaningful age-specific diabetes information. 7 • Significant negative impact on family function. Meeting these needs is important both in terms of overall outcomes for individuals and also for the associated potential benefits with regard to specific clinical outcomes. Deteriorating metabolic control through adolescence is well documented in young people with diabetes13 despite the application of substantial health-care resources.14 Peer-based and role model support, fundamental aspects of diabetes camps, have the potential to improve outcomes in these areas.15 Benefits Diabetes camps provide an environment where having diabetes is the ‘norm’ rather than something that sets children and adolescents apart from their peers. Given that camps are organised around diabetic routines (meal-times, injection times, finger-prick testing times etc) many campers report that being on camp is ‘…like having a holiday from their diabetes’, in that they don’t have to worry about routine- ‘…it just happens’. In most camps not only the campers but also the leaders have diabetes, thus providing a mini-society where both the members (campers) and elders (leaders) all have one common bond. This creates an Chapter 20: Diabetes Camps Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 204 environment where there is both peer support and aspirational motivation. Camps often provide the impetus for establishing ongoing social groups, pen pals, internet chat-room groups etc that can provide ongoing, year-round support. Camp staff who also have diabetes can be valuable mentors and role models to the camp participants. Goals The goals of diabetes camps are: • To be enjoyable. • To allow campers to compare experiences with each other and feel less isolated. • To increase the confidence of campers in both social and physical activities. • To allow campers to feel less depressed and anxious, and more positive about their future lives. • To allow campers to feel less depressed and anxious, and more positive about their future lives. • To allow campers to gain perspective on their own family dynamics. • To motivate campers to undertake aspects of their own diabetes care (such as selfinjecting and finger prick testing) when there has been child or parental resistance preventing this from occurring. • Improve diabetes-related knowledge of campers. In short, diabetes camps are about individual empowerment through increased confidence, understanding and motivation. Other Benefits Diabetes camps also have other non-camper benefits. These include: • Parental respite. • Establishment of ongoing peer-support networks. • Useful postgraduate, reality-based education for training diabetes health care professionals (medical staff, nurse educators dietitians etc). Prerequisites Above all else diabetes camps must provide a safe environment for both campers and camp staff. This entails subscribing to an agreed set of standards and protocols prior to the establishment of camps. Standards and protocols should specify leader to camper ratios, levels of medical and paramedical support, dietary routines, injection routines, hierarchy and responsibility of camp organisers, leader and camper application processes, emergency and evacuation protocols and indemnity arrangements. Many of these issues are broadly covered in the Diabetes Australia camping standards.4 However, some issues are regional and need to be specifically organised for individual camps. Diabetes camps require a high level of support from both medical and paramedical staff in order to provide an adequate level of health safety for campers. Camp leaders, however, are the key component to successful diabetes camps. Camp leaders should: • Be suitable role models for young people with diabetes. • Be mature, enthusiastic and positive in their interaction with campers. • Have a basic knowledge of diabetes. • Have knowledge of hypoglycaemia prevention, recognition and treatment. Chapter 20: Diabetes Camps Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 205 • Know how to use, maintain and adjust the insulin dose as well as doses of pumps (if campers using an insulin pump are attending). • Have the ability to arrange prompt medical aid when appropriate. • Have a knowledge of appropriate age-related sports and activities for children and adolescents with diabetes. • Have a solid grasp of risk-minimisation principles and how these apply to supervision of the various camping activities. Medical Management A written plan including camp policies and medical management procedures should be available at camp.5 A standardised medical information form should be completed for each camper (by his/her family and the managing physician) prior to attending diabetes camp. Multiple blood glucose determinations should be made throughout each 24-hour period. These should be done before meals and at bedtime. Extra test should be done (throughout the day and also overnight if required) following prolonged strenuous activity, prior hypoglycaemia, after extra insulin doses, or if the child has symptoms of hypo/hyperglycaemia or other physical complaints. All blood glucose levels and insulin dosages should be recorded in a format that allows for review and insulin dose alteration if required. Due to increased physical activity it may be necessary to decrease the home insulin dosage by 10-30% (occasionally more), especially in those children with good control who were not active before the camp. Three meals and three snacks should be given at set times each day. Additional food should be available for the treatment of hypoglycaemia at all times. Universal precautions for procedures involving blood draws should be followed. Appropriate containers for disposal of sharps should be available. Conclusion Diabetes camps are a valuable aspect of care for children and adolescents with diabetes. They are highly popular with both campers and leaders (as is evidenced by high camper and leader return rates). Whilst diabetic peer group interventions have been shown to be more effective than traditional clinical encounters in improving outcomes for adolescents,16 it is difficult to quantify the clinical and psychological benefits of camping per se for young people with diabetes. The anecdotal experience from diabetes health care professionals however is highly positive.17;18 The recent adoption of Australian national standards for diabetes camps should further improve the safety and quality of the diabetes camping experience. Information on diabetes camps Further information regarding diabetes camps may be obtained from Diabetes Australia and major diabetes education centres. The Evidence No studies were identified specifically demonstrating the benefits of diabetes camps on glycaemic control for children and adolescents with type 1 diabetes. Additional Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 20.1. Chapter 20: Diabetes Camps Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 206 Recommendations and Principles • Diabetes camps should be an integral component of overall care and support for diabetic children and adolescents in Australia.19;20(C) 3 • Diabetes camps must provide a safe environment for both campers and camp staff. (C) • Camps should be organised using an agreed set of standards and protocols. Standards and protocols should specify leader to camper ratios, levels of medical and paramedical support, dietary routines, injection routines, hierarchy and responsibility of camp organisers, leader and camper application processes, emergency and evacuation protocols and indemnity arrangements.5(C) • A standardised medical information form should be completed for each camper (by his/her family and the managing physician) prior to attending diabetes camp.5(C) C = Consensus statement endorsed by professional organisations Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. Travis LB, Schreiner B: Camps for children with diabetes: a philosophy and its application. Diabetes Educator13-20, 1984 Court JM: A holiday camp for diabetic children. Medical Journal of Australia 334-337, 1962 International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Medical Forum International, 2000 Diabetes Australia. Camping Standards: Guidelines for the conduct of educational camps for children and teenagers with diabetes. 2003. American Diabetes Association: Management of diabetes at diabetes camps. Diabetes Care 26 Suppl 1:S136-S138, 2003 Cameron FJ, Clarke C, Hesketh K, White EL, Boyce DF, Dalton VL, Cross J, Brown M, Thies NH, Pallas G, Goss PW, Werther GA: Regional and urban Victorian diabetic youth: clinical and quality-of-life outcomes. Journal of Paediatrics & Child Health 38:593-596, 2002 Wake M, Hesketh K, Cameron FJ: The functional health status of children with diabetes. Diabetic Medicine 17:700-717, 2000 Northam EA, Matthews LK, Anderson PJ, Cameron FJ, and Werther GA. Psychological morbidity and health outcome in type 1 diabetes - perspectives from a prospective longitudinal study (submitted to Diabetic Medicine). 2003. Northam EA, Anderson PJ, Jacobs R, Hughes M, Warne GL, Werther GA: Neuropsychological profiles of children with type 1 diabetes 6 years after disease onset. Diabetes Care 24:1541-1546, 2001 Hauser ST, Jacobson AM, Lavori P, Wolfsdorf JI, Herskowitz RD, Milley JE, Bliss R, Wertlieb D, Stein J: Adherence among children and adolescents with insulin-dependent diabetes mellitus over a four-year longitudinal follow-up: II. Immediate and longterm linkages with the family milieu. Journal of Pediatric Psychology 15:527-542, 1990 Kuttner MJ, Delamater AM, Santiago JV: Learned helplessness in diabetic youths. Journal of Pediatric Psychology 15:581-594, 1990 Fox C: The wasted resource: helping young people with diabetes to help each other. Diabetic Medicine 3:475-476, 1986 Dabadghao P, Vidmar S, Cameron FJ: Deteriorating diabetic control through adolescence-do the origins lie in childhood? Diabetic Medicine 18:889-894, 2001 Cameron FJ, Widdison J, Boyce D, and Gerbert R. Comparison between optimal and actuarial health care costs of adolescents with diabetes. Journal of Paediatrics and Child Health . 2003. Olsson C, Toumbourou J, Bowes G, Walsh B: Therapeutic Peer Support. In Diabetes and the Adolescent. 1 ed. Werther GA, Court JM, Eds. Melbourne, Miranova Publishers, 1998, p. 217-230 Anderson BJ, Wolf FM, Burkhart MT, Cornell RG, Bacon GE: Effects of peer-group intervention on metabolic control of adolescents with IDDM. Randomized outpatient study. Diabetes Care 12:179-183, 1989 Court JM: Camping for Youth with Diabetes. In Diabetes and the Adolescent. 1 ed. Werther GA, Court JM, Eds. Melbourne, Miranova Publishers, 271-281, 1998 Rosenbloom AL: Why diabetes camp? Clinical Pediatrics 40:511-516, 2001 Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Chapter 20: Diabetes Camps Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 207 Chapter 21: Travelling and Holidays Families are encouraged not to restrict their travel plans because of diabetes in the family. However, to make the holiday safe and enjoyable, families do need to consider: • The length of the journey. • The possibility of delays. • The timing between insulin injections and meals. • The availability of carbohydrate food. • Access to medical services and diabetes supplies. • Changes of climate. • Changes of types of food. • Changes in activity levels (increases in physical activity may require reduction of insulin dosage). • Changes in meal and sleep routines (especially when crossing time zones). • The management of sickness away from home. Preparation The child or adolescent with diabetes should have a medical visit and see the diabetes educator a minimum of 4-6 weeks prior to departure in order to:1-3 • Arrange necessary immunisations e.g. tetanus booster, malaria prophylaxis. • Assess glycaemic control and diabetes management. • Arrange scripts and medications to take (insulin, glucagon, gastrolyte). • Organise appropriate identity/Medic-Alert bracelet. • Discuss necessary adjustments to be made to the diabetes regimen for the flight/long coach trip, and holiday activities with the main aim being avoidance of hypoglycaemia (consider notifying the airline of the child’s special needs). • Learn how to use short-acting insulin. • Prepare an emergency kit for sick day management. • Discuss management of illness away from home. • Arrange a card with emergency commands (eg ‘I need sugar quickly’) in the appropriate language. • Prepare the following documentation: Introductory letter for an overseas doctor, ie a summary letter of the child’s medical history and current treatment outline (check with the consulate of the country to be visited if they wish to sight these letters prior to departure). Letter for customs stating the need to carry syringes, insulin and other medical supplies. Translated letters in the appropriate language(s). Travel insurance documents. Contact telephone, fax numbers and addresses of diabetes services in area to be visited. Contact details of the child’s physician or diabetes educator in Australia. Supplies Families need to arrange: • Enough insulin, syringes, pen needles, glucometer, blood and urine test strips for duration of the anticipated stay plus an extra supply. The insulin, glucagon, glucometer Chapter 21: Travelling and Holidays Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 208 • • • • • • • need to be protected from extremes of temperature if these are anticipated on the trip (use wide necked thermos/other insulated container or packing). Insulin, glucagon and testing equipment to be readily available in hand luggage, and be divided between two bags to avoid complete loss in case one bag is lost. Insulin should only be carried in hand luggage and not placed in luggage in the hold. Readily available food for treating hypoglycaemia. Enough extra carbohydrate food, the equivalent of two meals, in case of unexpected delays or unsuitable food being provided by airline or restaurant (insulin should be given when it is certain that food is about to be served or is readily available). Airlines tend to give diets for type 2 diabetes if contact is made regarding dietary needs. This is usually not appropriate for children with type 1 diabetes as there is little carbohydrate provided. Families should also take food with them when leaving the aircraft as unexpected delays may occur at any time, even at transit stops or the destination itself. Readily available bottled drinks and water. Loperamide for diarrhoeal illnesses. This medication should not be used in the very young and in general is over-prescribed. If travelling overseas, loperamide may be a useful stand-by in case of severe diarrhoea. Antiemetics. These medications are in general not usually used in children but may be of use if adolescents with diabetes are travelling overseas. Management of Diabetes on Long Flights The detailed management of the diabetes during flights that are long and involve many time zones should be discussed with the diabetes educator or the physician well before the departure date. The best way of managing the insulin replacement will vary from individual to individual and will depend on the insulin regimen being used. Generally, no adjustment is required when travelling north or south. Adjustments may be necessary if travelling east or west, especially if six or more time zones are being crossed.2 For westward travel the shift in time zone means that the day will be much longer therefore extra meals will require extra doses of insulin.3;4 For eastward travel the day will be cut short and the time between injections decreases, therefore requiring a lower insulin dose.3;4 For some, it is easiest to have a watch that remains on the time of the place of origin and to keep to the routines that would have been given for those times. This is possible providing the families have their own food supply and do not rely on airline meal times. Following arrival, adjustments need to be made to the insulin regimen to bring it into line with local times. For others, especially if there is a major variance in the morning and evening doses (eg patients taking twice-daily insulin) an acceptable regimen is to change to using pre-meal (approximately 6-hourly) injections of short-acting insulin during the flight.5 The need to have an independent source of food and perform frequent blood glucose monitoring is still essential. The Evidence The evidence on insulin adjustment during travel when crossing time zones is listed in Evidence Table 21.1. • There are no paediatric studies addressing the issue of glycaemic control and insulin adjustment while travelling. • During westward travel the day will be much longer therefore extra meals will require extra doses of insulin. A case series of 27 adults with type 1 diabetes found that for Chapter 21: Travelling and Holidays Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 209 westward travel extra insulin was required (3.1% of total daily insulin dose per time shift hour).4(IV) • The same study found that less insulin was required during eastward travel (total daily insulin dose reduced by 2.6% per time shift hour). During eastward travel the day is cut short and the time between injections decreases therefore requiring a lower insulin dose.4(IV) • A case series (which included some children) found that patients were generally satisfied with a simplified regimen using pre-meal injections of short-acting insulin (approximately 6-hourly) during long haul flights.5(IV) Additional Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 21.2. Recommendations and Principles • The detailed management of diabetes during visits to distant locations or foreign countries should be discussed with the diabetes educator or the physician well before the departure date.1;6(C) • The detailed management of diabetes on long flights crossing many time zones should be discussed with the diabetes educator or the physician well before the departure date.1;6(C) • The family should be advised to arrange enough insulin, syringes, pen needles, glucometer, blood and urine test strips for the duration of the anticipated stay plus an extra supply.1;6(C) • The family should be advised to have insulin, glucagon and testing equipment readily available in hand luggage, and to have essential supplies divided between two bags to avoid complete loss in case one bag is lost.1;6(C) • The child or adolescent with diabetes should be advised to have his/her own food supply and not rely on airline meal times.1;6(C) • The family should be advised that no major change to the insulin regimen is required for north-south travel.1(C) • The family should be advised that extra insulin may be required for westward travel as the day will be much longer and extra meals will require extra doses of insulin.4(IV) • The family should be advised that less insulin may be required during eastward travel as the day is cut short and the time between injections decreases therefore requiring a lower insulin dose.4(IV) • Switching to a simplified regimen of pre-meal injections of short-acting insulin during long haul flights should be considered as an option.5(IV) IV = Evidence obtained from case series, either post-test or pre-test and post-test C = Consensus statement endorsed by professional organisations Reference List 1. 2. 3. 4. 5. Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parents manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Dewey CM, Riley WJ: Have diabetes, will travel. How to help patients avoid diabetic emergencies away from home. Postgraduate Medicine 105:111-126, 1999 Gustaitis J: Taking to the air with diabetes. Diabetes Self-Management 19:36-37, 2002 Sane T, Koivisto VA, Nikkanen P, Pelkonen R: Adjustment of insulin doses of diabetic patients during long distance flights. British Medical Journal 301:421-422, 1990 Jones H, Platts J, Harvey JN, Child DF: An effective insulin regimen for long distance air travel. Practical Diabetes 11:157-158, 1994 6. Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Chapter 21: Travelling and Holidays Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 210 Chapter 22: Complementary and Alternative Medicine The National Center for Complementary and Alternative Medicine at the National Institutes of Health (USA) defines CAM as ‘a broad domain of healing resources that encompasses all health systems, modalities, and practices and their accompanying theories and beliefs, other than those intrinsic to the politically dominant health system of a particular society or culture in a given historical period’.1;2 It is generally understood to be health care practices that are outside of those used by conventional medicine; however, there may be some overlap. There is some evidence to support the use of some complementary and alternative medicine therapies for particular conditions. However, for the majority of such therapies there is limited or no information to support their use and there is a lack of information about their safety. Like any other medications, complementary and alternative medicine therapies have the potential for adverse effects and for interactions with conventional treatments or other complementary and alternative medicine therapies.3 Complementary and alternative medicine may include medicinal (herbal remedies, dietary supplements, vitamins and minerals, naturopathic and homeopathic remedies), or nonmedicinal remedies (such as chiropractic, osteopathy and naturopathy). Complementary and Alternative Medicine use in Diabetes The amount and nature of complementary and alternative medicine used over a twelve-month period in children attending a diabetes clinic at a tertiary referral hospital in Australia was estimated to be:4 • 49% (44% medicinal and 16% non-medicinal). • 18% medicinal, if the use of vitamins and minerals were excluded. The most commonly used medicinal remedies were multivitamins and minerals, vitamin C, echinacea, other herbal treatments and homeopathic remedies. There are many complementary and alternative medicine treatments that have been recommended for use in diabetes, but there appears to be little consensus between authors and little evidence to support these recommendations.5 • There are no complementary and alternative medicine therapies that have been shown in controlled trials to cure diabetes or improve control. It is important to remember that many complementary and alternative medicine therapies used by children with diabetes may be for treatment of other conditions or for general health reasons. Children with chronic illnesses are, in general, more likely to use complementary and alternative medicine.6 A systematic review of all published prevalence studies (n=10) reporting the use of complementary and alternative medicine in the paediatric population found that the reported prevalence varied from 9% to 70%.6(IV) Ketoacidosis and death have been described when insulin has been omitted as part of an alternative treatment.7 Parents should be warned that insulin should never be significantly reduced or omitted as part of an alternative treatment. Clinicians and Complementary and Alternative Medicine Clinicians have a responsibility to ensure that they are aware of all the forms of therapies that patients are using. In addition, it is important to try to understand different approaches to health and help parents in making informed and safe choices. Chapter 22: Complementary and Alternative Medicine Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 211 Studies consistently show that families rarely tell their treating doctors about complementary and alternative medicine use.8;9 Thus asking about their use should always be a part of the routine history taking process. In order to discuss complementary and alternative medicine effectively, it is important for clinicians to:4;10;11 • Ask about their use. Specific questions about different types of complementary and alternative medicine may be required; for example: Naturopathic or natural treatments. Herbal remedies. Dietary supplements. Vitamins and minerals. Homeopathic treatments. • Avoid dismissal of complementary and alternative medicine, which may discourage families from discussing their actual use. Patients may be concerned about a clinician’s response to their use. • Be prepared to discuss complementary and alternative medicine use and discuss the risks and benefits of different therapies. • Understand the reasons and motivations for the health care choices that families make. • Be aware of and explain to patients that the quality of advice available on the Internet is variable and inconsistent. A recent study looking at complementary and alternative medicine websites for treatment of diabetes found that out of 13 websites, one gave definitely harmful advice (by actively discouraging conventional diabetes therapy) and a further five websites were deemed to be potentially harmful.12 Discussing complementary and alternative medicine with families may involve trying to obtain appropriate information about the particular treatment, and like other treatments weighing up the potential benefits and risks with the family. Management of a Patient using Complementary and Alternative Medicine When a child taking complementary and alternative medicine is admitted to hospital the following steps should be taken:13 • Consider the possible effects and interactions of the particular substance. • Phone the local drug or poisons line for information if necessary. • If the parent wishes for the child to continue taking the remedy whilst in hospital, the drug should have an AUST R or AUST L number (phone drug information to find out). AUST R medicines are assessed for safety, quality and effectiveness. They include all prescription-only medicines and many over-the-counter products such as those for pain relief, coughs and colds and antiseptic creams.14 AUST L medicines are used for minor health problems and are reviewed for safety and quality. They include sunscreens over SPF4 and many vitamin, mineral, herbal and homoeopathic products.14 • If the drug has a valid AUST L or AUST R number, and the admitting consultant approves the use of that particular complementary and alternative medicine in the patient, then this should be documented in the patient notes. The parents may then supply, administer and record the administration of the complementary and alternative medicine whilst in hospital. • If the drug does not have an AUST L or AUST R number it should not be administered in hospital.13 If the parents insist on its use, they should be counselled and advised that they cannot administer the drug whilst in hospital. If they still choose to use the drug Chapter 22: Complementary and Alternative Medicine Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 212 they should sign an ‘Against Medical Advice’ statement and supply, administer and record any further administration of the complementary and alternative medicine. Issues to consider when assessing the risks and benefits of complementary and alternative medicine use include: • A common misconception that, by being ‘natural’, they are therefore safe. Like all medical treatments, however, complementary and alternative medicine therapies may have beneficial effects but may also have side effects. • The type of therapies being used – medicinal treatments versus non-medicinal treatments. • Available information about a particular therapy regarding efficacy, safety and potential harmful effects. • The source of the complementary and alternative medicine (eg whether purchased overthe-counter, from a naturopath, etc). • Where the product was manufactured. Products manufactured and registered with the Australian regulatory authority, the Therapeutic Goods Administration (TGA), will have an AUST L or an AUST R number. The ingredients of products without these are less reliably identified. • The expectations underpinning their use and the reasons for their use. Complementary and alternative medicine use is common within the community. Understanding their use within the context of the family is an important part of clinical care. The Evidence We found no studies addressing complementary and alternative medicine therapies in children or adolescents with diabetes. • A systematic review of all published prevalence studies (n=10) reporting the use of complementary and alternative medicine in the paediatric population found that the reported prevalence varied from 9% to 70%.6(IV) Additional Consensus Statements used to formulate the recommendations and principles of clinical practice are listed in Evidence Table 22.1. Recommendations and Principles • Complementary and alternative medicine may include medicinal (herbal remedies, dietary supplements, vitamins and minerals, naturopathic and homeopathic remedies), or nonmedicinal remedies (such as chiropractic, osteopathy and naturopathy).1(C) 1;6 • Complementary and alternative medicine use is common within the community. (IV) • In order to improve clinical care health care professionals should aim to understand the use of complementary and alternative medicine within the family context.10;13(C) • Families should be advised that no complementary and alternative medicine therapies have been shown to cure diabetes or improve control.10(C) • Ketoacidosis and death have been described when insulin has been omitted as part of an alternative treatment.7 Parents should be warned that insulin should never be significantly reduced or omitted as part of an alternative treatment.(IV) • Families should be advised that complementary and alternative medicine therapies have the potential for adverse effects and for interactions with conventional treatments or other complementary and alternative medicine therapies.10(C) • Health care professionals are able to determine the constituents of any complementary or alternative medicine by enquiries to poisons centres and quoting the medicine’s AUST L or Chapter 22: Complementary and Alternative Medicine Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 213 AUST R numbers.14 Drugs without an AUST L or AUST R number should not be considered for use in hospital.13(C) IV = Evidence obtained from case series, either post-test or pre-test and post-test. C = Consensus statement endorsed by professional organisations Reference List 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. National Center for Complementary and Alternative Medicine (NCCAM) and NIH. What Is Complementary and Alternative Medicine (CAM)? 2003. http://www.nccam.nih.gov/ Panel on Definition and Description, CAM Research Methodology Conference, April 1995.: Defining and describing complementary and alternative medicine. Alternative Therapies in Health & Medicine 3:49-57, 1997 Drew AK, Myers SP: Safety issues in herbal medicine: implications for the health professions. Medical Journal of Australia 166:538-541, 1997 Cranswick N, Lim A: Complementary and Alternative Medicine: Endocrine consequences. (Abstract). Australian Paediatric Endocrine Group, Annual Scientific Meeting, Darwin 2002 Ernst E.: Complementary medicine: its hidden risks. Diabetes Care 24:1486-1488, 2001 Ernst E.: Prevalence of complementary/alternative medicine for children: A systematic review. European Journal of Pediatrics 158:7-11, 1999 Gill GV, Redmond S, Garratt F, Paisey R: Diabetes and alternative medicine: Cause for concern. Diabetic Medicine 11:210-213, 1994 Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, Kessler RC: Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. Journal of the American Medical Association 280:1569-1575, 1998 Spigelblatt L, Laine-Ammara G, Pless IB, Guyver A: The use of alternative medicine by children. Pediatrics 94:811-814, 1994 American Diabetes Association: Unproven Therapies. Diabetes Care 26:142S, 2003 Sandler AD, Brazdziunas D, Cooley WC, Gonzalez de Pijem L, Hirsch D, Kastner TA, Kummer ME, Quint RD, Ruppert ES: Counseling families who choose complementary and alternative medicine for their child with chronic illness or disability. Pediatrics 107:598-601, 2001 Schmidt K, Ernst E: Complementary/alternative medicine for diabetes. How good is advice offered on websites? Diabetic Medicine 20:248-249, 2003 Department of General Medicine, Royal Children's Hospital, and Melbourne. Use of Complementary and Alternative Medicines for Inpatients. 2003. http://www.rch.org.au/genmed/CAMguidelines.htm. Therapeutic Goods Administration. Buying medicines? What's on the Label for me? 2003. http://www.health.gov.au/tga/docs/html/buymed.htm Chapter 22: Complementary and Alternative Medicine Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 214 Resources The full version of these guidelines are available in pdf format on the NHMRC and Australasian Paediatric Endocrine Group websites (http://www.racp.edu.au/apeg/). Diabetes Australia (DA) Diabetes Australia provides a wide variety of booklets/fact sheets on food and general issues pertaining to management of type 1 diabetes. The range of services available in each State or Territory can be obtained by contacting local DA offices. Internet access to the various Diabetes Australia State and Territory Offices is available through links at www.diabetesaustralia.com.au Contact Details for Diabetes Australia States & Territories DA-NSW (02) 9552 9912 DA-Victoria (03) 9667 1777 DA- Queensland (07) 3846 4600 DA- Northern Territory (08) 8927 8488 DA – Tasmania (03) 6234 5223 DA- South Australia (08) 8234 1977 DA – Western Australia (08) 9325 7699 DA – ACT (02) 6288 9830 Juvenile Diabetes Research Foundation (JDRF) JDRF provides a variety of brochures on the management of type 1 diabetes in children and adolescents. Details may be obtained from the JDRF office (1300 363 126), or from the JDRF website [email protected] Health Care Card The Health Care Card is a benefit provided by the Commonwealth Government. It is not means tested on assets or income criteria. To qualify for the Health Care Card ‘the child, because of their disability, requires substantially more care and attention than another child of the same age, without the disability’. The Health Care Card assists families with the cost of prescriptions under the Pharmaceutical Benefits Scheme (PBS) and National Diabetes Services Scheme (NDSS) and with some other concessions. With the Health Care Card the holder can purchase medications on the prescribed list at a reduced cost. Applications for the Health Care Card are made through Centrelink. Eligibility for the Health Care Card is determined on criteria based on the Treating Doctor’s Report (TDR). Resources Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 215 Details regarding the Health Care Card may be obtained from any Centrelink office. Carer Allowance (CA) The Carer Allowance is an additional benefit to the HCC provided by the Commonwealth Government. A submission may be made to obtain the Carer Allowance from Centrelink. It is not means tested on income or assets criteria. Applications for the Carer Allowance are made through Centrelink. Eligibility for the CA is determined on criteria based on the Treating Doctor’s Report (TDR). International Diabetes Federation (IDF) School Information Pack The IDF School Information Pack provides guidance for teachers and other school staff on type 1 diabetes in children and adolescents. The pack consists of: • Medical alert information card. • Diabetes information for schools. • Diabetes Information about schools for parents. • Management of hypoglycaemia poster. • An information flipchart. • Emergency card. • Management plan. The IDF School Information Pack can be obtained from diabetes centres and Diabetes Australia. It can also be downloaded form the Diabetes NSW website http://www.diabetesnsw.com.au/childteens/default.asp?Refid=80 Other Resources A wide variety of educational resources for health professionals and consumers is available through large tertiary paediatric diabetes services. Resources Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 216 Appendix 1: Guidelines Writing Committee Members and Contributors Writing committee members Professor Martin Silink AM (Chair) Paediatric Endocrinologist Institute of Endocrinology and Diabetes The Children’s Hospital at Westmead Westmead NSW 2145 Dr Ann Maguire APEG Fellow (2003) Institute of Endocrinology and Diabetes The Children’s Hospital at Westmead Westmead NSW 2145 Associate Professor Caroline Clarke Paediatric Endocrinologist Monash Medical Centre Clayton VIC 3168 Ms Angela Middlehurst Diabetes Educator Diabetes Australia - NSW Glebe NSW 2037 Associate Professor Jennifer Couper Paediatric Endocrinologist Dept of Endocrinology and Diabetes Women’s And Children’s Hospital North Adelaide SA 5006 Ms Emma Rooney Assistant Director (Diabetes) Cancer Control and Diabetes Section Health Industry and Investment Division Commonwealth Dept of Health and Ageing Canberra ACT 2601 Dr Maria Craig Paediatric Endocrinologist Institute of Endocrinology and Diabetes The Children’s Hospital at Westmead Westmead NSW 2145 Associate Professor Patricia Crock President APEG (Sep 2003-) Paediatric Endocrinologist Dept of Paediatric Endocrinology John Hunter Children’s Hospital Newcastle NSW 2310 Ms Rebecca Davies Director, Juvenile Diabetes Research Foundation St Leonards NSW 2065 Dr Kim Donaghue President APEG (Sep 2001- Sep 2003) Paediatric Endocrinologist Institute of Endocrinology and Diabetes The Children’s Hospital at Westmead Westmead NSW 2145 Dr Lillian Jackson Manager, Diabetes Education Services Diabetes Australia - NSW Glebe NSW 2037 Dr Karen Luxford Program Director National Breast Cancer Centre Camperdown NSW 1450 Appendix 1: Guidelines Writing Committee Members and Contributors Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 217 Contributors Dr Jeremy Allgrove Paediatric Endocrinologist Department of Pediatrics Newham General Hospital United Kingdom Dr Jan Fairchild Paediatric Endocrinologist Dept of Endocrinology and Diabetes Women’s And Children’s Hospital North Adelaide SA 5006 Dr Geoffrey Ambler Paediatric Endocrinologist Institute of Endocrinology and Diabetes The Children’s Hospital at Westmead Westmead NSW 2145 Dr Heather Gilbertson Dietitian Royal Children’s Hospital Parkville VIC 3052 Dr Fergus Cameron Paediatric Endocrinologist Royal Children’s Hospital Parkville VIC 3053 Ms Samantha Clarke Dietitian Institute of Endocrinology and Diabetes The Children’s Hospital at Westmead Westmead NSW 2145 Dr Andrew Cotterill Paediatric Endocrinologist Dept of Endocrinology and Diabetes Matre Children’s Hospital South Brisbane QLD 4101 Associate Professor Noel Cranswick Director, Clinical Pharmacology Royal Children’s Hospital Parkville VIC 3052 Associate Professor Chris Daly Head, Periodontics Faculty of Dentistry University of Sydney NSW 2006 Dr Elizabeth Davis Paediatric Endocrinologist Department of Endocrinology Princess Margaret Hospital Perth WA 6001 Ms Gabrielle Donlevy Dietitian Northern Paediatric and Adolescent Diabetes Service (NeePADS) St Leonards NSW 2065 Dr Anthony Duffin Podiatrist, Institute of Endocrinology and Diabetes The Children’s Hospital at Westmead Westmead NSW 2145 Ms Christie Graham Dietitian Royal Children’s Hospital Parkville VIC 3052 Ms Rachel Hayes Senior Diabetes Dietitian Institute of Endocrinology & Diabetes The Children’s Hospital at Westmead Westmead NSW 2145 Associate Professor Tim Jones Paediatric Endocrinologist Department of Endocrinology Princess Margaret Hospital Perth WA 6001 Dr Bruce King Paediatric Endocrinologist Dept of Paediatric Endocrinology John Hunter Children’s Hospital Newcastle NSW 2310 Dr Anthony Lafferty Paediatric Endocrinologist Department of Endocrinology Princess Margaret Hospital Perth WA 6001 Dr Alissa Lim Clinical Pharmacology Fellow Royal Children’s Hospital Parkville VIC 3052 Ms Melinda Morrison Diabetes Dietitian Diabetes Australia-NSW Glebe NSW 2037 Dr Elizabeth Northam Co-ordinator, Academic and Research Program, Department of Psychology Royal Children’s Hospital Parkville VIC 3052 Appendix 1: Guidelines Writing Committee Members and Contributors Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 218 Ms Carmel Smart Paediatric Diabetes Dietitian John Hunter Children’s Hospital Newcastle NSW 2310 Dr Peter Swift Paediatric Endocrinologist Secretary-General International Society for Pediatric and Adolescent Diabetes Children's Hospital, The Leicester Royal Infirmary United Kingdom Dr Michael Thomsett Paediatric Endocrinologist 131 Wickham Terrace Brisbane QLD 4000 Ms Sheri Todd Research Assistant Murdoch Children’s Research Institute Royal Children’s Hospital Parkville VIC 3052 Ms Joanne Turner Exercise Physiologist/Dietitian Diabetes Australia - NSW Glebe NSW 2037 Dr Charles Verge Paediatric Endocrinologist The Sydney Children’s Hospital Randwick NSW 2031 Professor George Werther Paediatric Endocrinologist Royal Children’s Hospital Parkville VIC 3052 Ms Emma White Diabetes Educator Diabetes Centre Monash Medical Centre Clayton VIC 3168 Associate Professor Richard Widmer Dept of Dentistry The Children’s Hospital at Westmead Westmead NSW 2145 Appendix 1: Guidelines Writing Committee Members and Contributors Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 6 8 16 Karvonen 2000 Craig 2000 Verge 1994 Children aged 0-14 years in New South Wales, Australia (1990-1991) Children aged 0-14 years resident in New South Wales, Australia over the period 1992-1996 WHO DiaMond Project (Multinational Project for Childhood Diabetes). Incidence of T1D from 1990 to 1994 determined in children 14 yrs old from 100 centers in 50 countries Population Children aged 0-14 yrs with T1D N/A Outcome Patients newly diagnosed with T1D by physicians and diabetes educators. T1D incidence T1D incidence N/A N/A T1D incidence Intervention N/A Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 5 Prevalence/incidence of type 1 diabetes in children in Australia/worldwide. Study Internation al Diabetes Federation (IDF) Atlas 1. 1 Chapter 1: Definition, Epidemiology and Classification Appendix 2: Evidence Tables Age-standardized incidence rate of T1D was 14.5 per 100,000 person-yrs Peak incidence at age 11 (girls), and 13 (boys) Seasonal variation (more cases occur in late autumn/winter) Results Australia incidence rate 17.8 per 100,000. New Zealand incidence rate 15.2 per 100,000. Fiji incidence rate 0.1 per 100,000. Finland incidence rate 37.4 per 100,000. T1D incidence varied from 0.1/100,000 per year in China and Venezuela to 36.8/100,000 per year in Sardinia and 36.5/100,000 per year in Finland. In most populations, the incidence increased with age and was the highest among children 10-14 years of age Incidence of T1D from 1990-1996 was 17.8 per 100,000. There was a statistically significant rise in incidence of T1D over this period (p=0.0003) Primary ascertainment using a prospective incidence register established in 1990. Secondary source of ascertainment from National Diabetes Supply Scheme (government subsidised scheme for diabetic supplies) Capture-recapture method, ascertainment estimated to be 99% complete Australian NSW data Prospective register, with two independent sources of case ascertainment. The primary source was reporting of newly diagnosed patients by physicians and diabetes educators. The secondary source was National Diabetes Supply Scheme Australian NSW data Well-defined population based registry; Capture-recapture method used Comments Medline and Pubmed were searched from 1980 -2003 IV IV Well designed representative cohort study Well designed representative cohort study IV Level IV Well designed representative cohort study Design Systematic review of all relevant population based studies 219 children Multicentre international study Adults and included Of 372 with 5 year risk of >50% of developing T1D, 339 were randomised. (169 to the intervention and 170 to the observation arm) 84,228 screened Population Relative of patients with T1D Intervention close observation or low dose s.c. ultralente insulin twice daily (0.25 u/kg/day), plus annual 4 day IV insulin infusion treatment. Outcome Development of diabetes. Median follow up 3.7 years Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 4 Intervention trials to delay or prevent the onset of type 1 diabetes. Study DPT (Diabetes Prevention Trial) 2002 2.1 In people at high risk for diabetes, insulin in the dose described here does not prevent or delay T1D. The annualised rate of progression to diabetes was 15.1% in the intervention group and 14.6% in the observation group (relative risk 0.96, 95% CI 0.69-1.34, p=0.80). Results Diabetes diagnosed in 69 in the intervention group and 70 in the observation group. The majority were asymptomatic (102/139, 73.4%). Data analysed according to intention-to-treat principle, and C o m p l i a n c e : Annual noncompliance rate in intervention group was 5.5%, and 1% in control group Losses to follow-up: annual rate of loss to follow-up was 1.3% Blinding: No blinding of participants and investigators; control group did not receive placebo because intervention involved injections or infusions and some participants were children Comments Randomisation: Participants allocated to intervention or control groups by a centralised computer system, and were stratified by baseline glucose tolerance ands clinical centre RCT Design Level II Technical Reports/Consensus Statements World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Report of a WHO Consultation. Part 1:Diagnosis and Classification. WHO/NCD/NCS/99.2. 1999. Geneva, World Health Organization. Ref Type: Report American Diabetes Association: Type 2 Diabetes in Children and Adolescents. Pediatrics 105:671-680, 2000 American Diabetes Association: Screening for Type 2 Diabetes. Diabetes Care 26:21-24, 2003 World Health Organization. Screening for Type 2 Diabetes. Report of a World Health Organization and International Diabetes Federation meeting. WHO/NMH/MNC/03.1. 2003. Geneva, World Health Organization. Ref Type: Report International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice. Chapter 2: Phases of Diabetes 57 28 31 32 Ref No 1 1. 2 Capture-recapture method, ascertainment was estimated to be 99.4% complete 220 Multicentre international study in Europe and America Adults and children included (3 to 40 years) 552 fulfilled criteria of having confirmed islet cell antibody levels >20 JDFU >30,000 first degree relatives of T1D patients screened 552 randomised to receive either nicotinamide (1.2gm/m2) or placebo. Development of T1D Concluded that nicotinamide (in the dose described) does not delay or prevent the onset of diabetes in high risk individuals. No sig. diff. between nicotinamide and placebo in development of T1D. Of 159 participants who developed diabetes within 5 years, 82 (30%) were on nicotinamide and 77 (28%) were on placebo Study abandoned at interim analysis after 5 years. Analysis by intention-to-treat Losses to follow-up: 1 from each group withdrew consent after randomisation 549/552 participants began their trial medication; Primary variable (diabetes status) obtained for 447/549 (87%) of patients; Placebo group: 48 discontinued treatment, 35 lost to follow-up Treatment group: 47 discontinued treatment, 38 lost to follow-up Blinding: All study personnel blinded to participants’ treatment allocation; emergency unblinding done for 4 participants Technical Reports/Consensus Statements Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice. 8 Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 2.2 ENDIT 2004 Study abandoned by NIH at interim analysis. Pseudorandomisation: (computer generated codes allocated sequentially by national coordinator) monitored by an independent data and safety monitoring board, with predefined stopping rules Quasi-RCT III-1 221 6 Srinivasan 2004 Introduction of new day care programme (DDCP) for newly diagnosed T1D. Number of participants ranged from 20 to 223 with a total of 237 participants in the outpatient/home care group. The mean age of most groups was between 10-13 years. 4 studies were carried out in USA and Canada, 1 in Finland, 1 in Israel Population Children with newly diagnosed type 1 diabetes The pre-DDCP cohort comprised all children newly diagnosed with type 1 diabetes from March 2000 to November 2000 (n = 49). The post-DDCP cohort were those diagnosed from November 2000 to August 2001 (n = 61). Intervention 6 comparative studies of initial hospitalisation compared with home based or outpatient mx. (Siminerio 99 Dougherty 98 Simell 95 Chase 92 Galatzer 82 Spaulding 76) No sig. diff. No sig. diff Decreased from 5.14 days to 1.70 days (range, 0-10) No sig. diff. between the two cohorts in insulin requirement at 12 months (pre-DDCP: 0.9 U/kg [95% CI, 0.8-1.0]; post-DDCP: 0.8 U/kg [95% CI, 0.7-0.9]; P = 0.22), No sig. diff. in HbA(1c) level at 12 months (preDDCP: 8.4% [95% CI, 8.0%-8.9%]; post-DDCP: 8.2% [95% CI, 7.9%8.5%]; P = 0.37) No sig. diff. in adverse events over the first year after diagnosis. Both Others: no. of hosp. contacts, psychosocial effect on child and parents, other adverse events, cost Hospital stay Insulin requirement HbA(1c) Adverse events No sig. diff. Admissions to hospital in first 2 years Acute complications Results No sig. diff. Outcome Metabolic control Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 5 Benefits of ambulatory care versus hospital in-patient care of patient with newly diagnosed type 1 diabetes Study Clar 2003 (Cochrane Systematic Review) 3.1 Australian (Sydney) study relevant to Australian healthcare system Overall there was insufficient high quality data. Outcomes suggest that outpatient management does not lead to any advantage in terms of metabolic control, acute complications, hospitalisations, psychosocial, behavioural or costs Ambulatory stabilisation of children with type 1 diabetes provides similar metabolic outcomes for the child, and comparable levels of diabetes knowledge and similar psychosocial outcomes for the family, to inpatient stabilisation programs. 5 out of 6 were regarded as low quality studies. 2 studies were RCT’s, 3 were retrospective cohort studies and 1 was a prospective cohort study. Comments Rigorous search strategy with appropriate inclusion criteria Comparative study with historical controls Design Systematic Review (Cochrane) III-3 Level I American Diabetes Association: Prevention of Type 1 Diabetes Mellitus. Diabetes Care 26:140, 2003 International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Report of a WHO Consultation. Part 1:Diagnosis and Classification. WHO/NCD/NCS/99.2. 1999. Geneva, World Health Organization. Ref Type: Report Chapter 3: Medical Management 24 7 23 222 8 9 Kirk 2003 Lee 1992 New diagnosis T1D <18 yrs, presenting to Texas children’s hospital, approximately 30-50 cases per year 36 newly diagnosed children with type 1 diabetes Ages 0-19 1994-April 2002 UK An increased risk for poor glycemic control was recorded in children living in one-parent families (p = 0.03) or in families where the father had a low level of education (p = 0.04). Younger age (p = 0.05), a single-parent family (p = 0.05) and poor glycemic control (p = 0.02) were associated with more days of rehospitalization. 36 newly diagnosed children with type 1 diabetes Ages 3-15 April 1986 – January 1989 Sweden Early discharge to hospital family apartment (n = 19) vs. Conventional hospital care n = 19) The control group was treated initially in a hospital ward, while the study group received problem-based learning and familytherapeutic and social support in an out-hospital training apartment. Retrospective Survey of initial management over 8 years following specialist nurse appointment in 1994 Pre 1988 group were all hospitalized at diagnosis. Post 1988 an outpatient focused approach used when possible. Fewer admissions at diagnosis and fewer episodes of readmission in outpatient treated group post 1988 Admission rate Cost From April 1995 onwards mean of 2.0 days, change from 1994 when average of 6.3 days Mean number of days newly diagnosed patients were admitted This institution reported $100,000 saving per year 36 patients were readmitted for diabetes related problems. All of these patients were treated as inpatients at diagnosis. 5/36 (14%) Hospital readmission days: Study group median 1.0 days; control group 2.0 (p=0.83); no significant difference Number able to be fully home managed from diagnosis Glycaemic control HbA1c Hospital readmission Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 7 Forsander 2000 groups reported similar scores for the parental questionnaires Glycaemic control: At 2 years after diagnosis, study group mean HbA1c 6.2 [0.9] versus 6.0 [0.9] in control group (p=0.46); no significant difference At 5 years, study group mean 7.3 [1.3] versus 7.1 [1.3] in control group (p=0.58); no significant difference American healthcare system therefore cost data may not be relevant to Australian health care system. A very small study in City Hospital Birmingham UK. Authors make comment that their figures are not as good as those from the Birmingham Children’s Hospital and relate this to social disadvantage (60% of Asian descent). Unknown number of days each group spent in hospital. Losses to follow-up: 2 children lost to follow-up because they moved to another region Randomisation: Method of randomisation not reported. Retrospective case series notes review Non comparative cohort study RCT III-3 IV II 223 1979 - 1988 UK New T1D (age 11months – 16 years) managed as outpatients between 1974 and 182. N=52 49 were managed as outpatients and 3 admitted for 18-40 hours due to diabetic ketoacidosis 236 newly diagnosed children with type 1 diabetes Ages 10-14 Home base care vs. hospital based care No parents indicated that they would have preferred admission 138/236 received supervised home management Duration of admission in 1979 –1980 was 7 days and in 1987 –1988, 3 days. 22% of home management patients vs. 41% of inpatient managed patients p=0.004 Glycated Hb was 10.2% in home treated group and 10.0% in the hospitalised group. No significant difference (p=0.37) Parental satisfaction as judged by informal feed-back Proportion of children managed without hospital admission Mean duration of hospital stay Comparison of readmission rates Concentration of glycated Haemoglobin Adverse events Clinical audit and not a controlled study. Possible bias as children admitted at diagnosis is likely to been different from those not admitted. American study. 32 Cameron 2002 Case attainment based on Diabetes Register was 67% of children in NSW and ACT. 47 children with T1D <18 years of age from three regional Victorian communities (Horsham, Warrnambool, Sale) were Population Audit of 1,190 children with T1D aged <15years. Compared urban with rural children. Intervention Compared urban with rural children. HbA1c HbA1c Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 31 Study Handelsman 2001 Outcome Median yearly HbA1C for patients were not obviously different between the regional and Results Median HbA1c was 8.2% (interquartile range 7.6-9.1%) Median HbA1c was 8.2% in both urban and rural group. Comments Confirmed homogeneity of metabolic control in NSW and ACT regardless of location, socioeconomic status or system of care. Social disadvantage was assessed using a graded post code-based social disadvantage risk score. Australian study. Homogeneity of metabolic control in Victoria, Australia Historical comparison Retrospective case series Comparative Design Multicentre, population-based, cross-sectional study Differences in glycaemic control between urban and rural children and adolescents with type 1 diabetes in the Australian health care system 12 Swift 1993 3.2 10 Schneider 1983 with outpatient approach (now including savings due to decreased readmission rate) None reported IV Level IV III-3 IV 224 urban centres (HbA1c 8.1% at urban centre, 8.9%, 8.4% and 8.6% at the 3 rural centres). Numbers too small for statistical analysis Literature reviewed until June 1999 Compared behavioural intervention (education or skills training) with control group. Emotional/psychological interventions (18%) Dietary interventions (19%) Skills training (39% studies) Age range 9-21 years. Most studies from USA (67.7%) Intervention Question asked “Do educational and psychosocial interventions for adolescents with type 1 diabetes have beneficial effects on biological and psychosocial outcomes?” Population Systematic review of 62 studies from Health Technology Assessment Program UK. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 28 Metabolic measures Psychosocial Self or parent reports of changes in psychological or interpersonal constructs (e.g. self-efficacy; diabetes-specific stress) Outcome These studies demonstrate the variety of intervention and outcomes that have been studied. All the pre-, post design studies reported some benefit - however because of the low level of study design and small numbers these benefits should be treated as provisional until more rigorous results are available Mean of 12 pooled effect sizes was 0.33 (95% CI 0.04 – 0.70) for glycated haemoglobin with outliers; significant heterogeneity (0.08 without 2 outliers) Mean of 12 pooled effect sizes for psychosocial outcomes was 0.37 (95% CI 0.19-0.55 Results Small to medium effect on HbA1c and psychosocial outcome of educational and psychosocial intervention. Identifies need for future intervention trials The meta-analysis of the RCT’S should be treated with caution due to the variation in studies and intervention 62 studies in total. 25 RCTs reviewed (16 with sufficient detail to enable effect sizes to be calculated). 37 other study designs eg non RCT’s without control groups, pre and post intervention studies Comments Rigorous search strategy with appropriate inclusion criteria. The effect of educational interventions on metabolic and psychological outcomes in children and adolescents with type 1 diabetes. Study Hampson 2001 3.3 compared with 120 age-, sexand duration of diabetesmatched children attending the Royal Children's Hospital (RCH) diabetes clinic in Melbourne Design Systematic review Level I 225 Intervention Animal insulin versus human insulin. No studies assessed these Others: Complications Adverse events Mortality QOL Compliance Cost Socio-economic effects Study Ref No Population Intervention Results No sig diff. Hypoglycaemia Outcome Results Parallel designed studies reported that human insulin was associated with a nonsignificant mean (pooled weighted mean difference) lowering of HbA1c Outcome Glycaemic Control: HbA1c Fasting BGL Insulin dose Treatment of children with type 1 diabetes with insulin glargine Total patient number 2156. 45 RCT’s (24 parallel and 21 crossover) of which 4 studies included children. Population Patients with diabetes mellitus all age groups Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 4.2 Ref No 7 Benefits of animal insulin over human insulin use in children and adolescents with type 1 diabetes Study Richter 2002 (Cochrane systematic review) 4.1 Comments Qualitative assessments not reported Quality of life, mortality and long-term complications not assessed systematically in the RCT’s. Comments Rigorous search strategy. Inclusion criteria included diabetic patients of all ages. Data collection and analysis performed by 2 independent reviewers. Significant heterogeneity detected. Despite heterogeneous study designs participants and locations neither parallel or crossover trials suggested an important difference between insulin species as measured by glycated haemoglobin, fasting plasma glucose and insulin dose. No significant difference in metabolic control or hypoglycaemic episodes was found. Design Design Systematic Review (Cochrane) Level Level I Technical Reports/Consensus Statements International Diabetes Federation Consultative Section on Diabetes Education. International Curriculum for Diabetes Health Professional Education. 2002. Brussels, International Diabetes Federation. Ref Type:Report International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 American Diabetes Association: Standards of Medical Care for Patients With Diabetes Mellitus. Diabetes Care 26:33S, 2003 NSW Health Department: Principles of Care and Consensus Guidelines for the Management of Diabetes Mellitus in Children and Adolescents. 1998 Australian Diabetes Educators Association. National Standards for the Development and Quality Assessment of Services Initiating Insulin in the Ambulatory Setting. 2004. Ref Type: Report National Health and Medical Research Council: The Australian Immunisation Handbook. 8th Edition. 2003 Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice. Chapter 4: Insulin Preparations and Storage 2 14 17 18 19 29 Ref No 1 3.4 226 16 4 fully published open label randomised control trials in patients with type 1 diabetes. Seven published abstracts and One unpublished abstract made available by manufacture, three observational studies 4 published RCT’s in type 1 diabetes (and 2 in type 2 diabetes) Once daily insulin glargine compared with once or twice daily NPH Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents NICE Health Technology Appraisal No 53 2002 One study found less nocturnal. hypo in glargine c/w once daily NPH. But similar when glargine c/w twice daily NPH. Nocturnal hypoglycaemia Severe hypoglycaemia 3 out of 4 studies found no difference in HbA1c. One study found stat. sig. improvement in HbA1c with glargine (trial duration over only 4 weeks therefore cannot be attributed to only glargine) HbA1c 3 studies reported severe hypo. One reported sig less with glargine. 2 studies no sig Fourth study did not distinguish between nocturnal and other hypos. One study showed no diff. One study showed fewer nocturnal hypoglycaemia in glargine group versus NPH group (36% vs 56%, p<0.05). Significantly decreased FPG in 3 out of 4 studies. Fourth study showed no difference FPG Guidance : Recommend that insulin glargine should be considered as a treatment option in people with type 1 diabetes Systematic Review I 227 27 Sarnblad 2003 18 females, eight males 30 adolescents with T1D (16 in metformin group and 14 in placebo group) Inclusion criteria set to minimise risk of recruiting type 2 diabetes subjects 14 in metformin group, 13 in placebo group 27 adolescents with insulin requirement >1unit/kg/day and HbA1c >8% Population Type 1 diabetics oral metformin or placebo for 3 months Intervention Metformin versus placebo for 3 months; 2 month run in period to screen for complications and update diabetes knowledge. The metformin (or placebo) commenced at 500mg per day and gradually increased to max. dose of 1000mg (wt<50kg) 1500mg(wt<7 5kg) or 2000mg (wt>75kg) Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 26 HbA1c Severe hypoglycaemic episode in 2 metformin subjects due to missing meal. Overall mild hypoglycaemia was increased in metformin group (p=0.03) Mean value decreased significantly in the group treated with metformin, from 9.6 Non sig. trend to lower BMI in metformin group (p=0.35) BMI Hypoglycaemia Metformin group mena change -0.14 [0.1] versus placebo +0.02 [0.2] (p=0.01); significant decrease Insulin dose (units/kg/day) Results Mean change in metformin group -0.3% [0.7]; +0.3 [0.7] in placebo group (p=0.03); significant decrease Metformin group had mean reduction -0.9 [3.8] versus placebo -0.5 [3.2] (p=0.03); significant decrease Outcome Fasting BGL (mmol/l) HbA1c Significance of final HbA1c levels not stated, but a recalculation shows the mean difference to be statistically nonsignficant (mean difference 0.50, 95% CI -1.50 to 0.50) Compliance: 11 (79%) in metformin group complied with tablets; 8 (62%) in control group Compliance was defined as acceptable if <25% prescribed pills were retunred to investigators at each visit Losses to follow-up: 3/30 – 1 unwilling to take a second fasting test; 1 due to gastrointestinal discomfort (metformin group); 1 due to acute hepatitis Blinding: Investigators were blinded to group allocation Comments Randomisation: computer generated; method of allocation not reported Metformin as an adjunct therapy to insulin in the treatment of children and adolescents with type 1 diabetes Study Hamilton 2003 4.3 difference RCT Design RCT II Level II 228 Adolescents/young adults(19.3+/3.4yrs) n=10 Type 1 diabetics. Metformin 250mg BD (dose increased to max of 2500mg/day depending on side effects reported.) Insulin dose reduced if required. 2/10 patients had one severe hypoglycaemic episode Severe hypoglycaemic episodes HbA1c at baseline 3months 6months Peripheral glucose uptake divided by mean plasma insulin concentration was increased in metformin (p<0.05) but not in placebo group. Initial insulin sensitivity was inversely correlated to changes in HbA(1c) (r=-0.62; p<0.05) and positively correlated to changes in insulin sensitivity (r=0.77; p<0.01) HbA1c decreased in 7/10 patients (not statistically significant). Peripheral insulin sensitivity (euglycaemic hyperinsulinaemic clamp) at baseline and at end of study [1.0] to 8.7 [1.5] % (P<0.05), but was unchanged in the placebo group (9.5 [1.2] vs 9.2 [1.3]%) No comparative pre-treatment hypo information given (although authors say this translates to approx 40 per 100 patient years) Very small sample size. Not randomised, no controls (results compared to own pre-treatment HbA1c) Side effects: 1 patient in metformin group had nausea and mild abdominal pain during study, 1 had mild abdominal discomfort at final examination; 5 in placebo group had gastrointestinal symptoms near start of study, 1 had stomach pain throughout study In 1 patient (metformin group), sensitivity not measured due to technical problems Losses to follow-up: 4/30 – 2 patients excluded at randomisation due to low HbA1c; 1 patient excluded due to low motivation (many missed doses); 1 patient left study due to nausea Blinding: All patients and investigators were blinded Randomisation: Method not stated Case series (pre -test and post-test) IV Technical Reports/Consensus Statements World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Report of a WHO Consultation. Part 1:Diagnosis and Classification. WHO/NCD/NCS/99.2. 1999. Geneva, World Health Organization. Ref Type: Report American Diabetes Association: Insulin Administration. Diabetes Care 26:121S, 2003 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 National Institute for Clinical Excellence. Type 1 Diabetes (Childhood): Diagnosis and Management of Type 1 Diabetes in Children and Young People (DRAFT). 2004. International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice. 28 Initial metformin dose 500mg daily for 1 week, followed by 500mg twice daily for 3 weeks, then 1000mg twice daily for rest of study period Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 13 29 30 31 Ref No 1 4.4 Gomez 2002 daily insulin dosage 1.2 [0.3] U/kg mean glycated haemoglobin (HbA(1c)) 9.3 [1.2] % mean age =17.0 [1.6] years 229 2 3 Craig 2002 Mortensen 1997 Blood samples and information were collected from March through August 1995 on 2,873 children who were born in 1977 or later and seen in the outpatient clinics. 22 paediatric departments from 18 countries in Europe, Japan, and North America. 1190 children and adolescents aged 1.215.8 years with type 1 diabetes, identified from three hospital-based paediatric diabetes units, four private citybased paediatric practices and 18 regional outreach clinics in NSW and the ACT from 1 September to 31 December, 1999 Population HbA1c levels were determined once and analysed centrally (normal range, 4.4-6.3%; mean, 5.4%). Survey Year of birth, sex, duration of diabetes, height, body weight, insulin regimen, and number of episodes of severe hypoglycaemia during the past 3 months were recorded. HbA(1c) level and incidence of severe hypoglycaemia Outcome Cross sectional audit Intervention Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No Relationship of number of daily insulin injections with glycaemic control. Study 5.1 Chapter 5: Insulin Regimens and delivery Girls on four or more injections had significantly (P < 0.01) higher BMI than girls Adolescents on four or more injections received significantly (P < 0.001) more insulin. No difference in glycaemic control was found among adolescents treated with two, three, and four or more daily injections. HbA1c increased during maturation for both sexes. Sixty percent of the children (n = 1,707) had two injections daily, while 37% (n = 1,071) were on three or more. The incidence of hypo, based on the 3-month period, was 22 per 100 patient-years. Hypoglycaemia (unconsciousness and/or seizures) was related to younger age (0-8 years) and lower HbA1c level. Significant predictors of hypoglycaemia in a Poisson regression model were younger age (P = 0.03), male sex (P = 0.04), longer diabetes duration (P = 0.02), and > 3 daily insulin injections (P = 0.02), but not HbA(1c) level. Average HbA1c was 8.6 +/- 1.7%, but varied significantly (P < 0.0001) between centres. At least one episode of severe hypoglycaemia in the previous three months was reported in 6.7%, and the rate of severe hypoglycaemia was 36/100 patient-years. Significant predictors of HbA1c level in multiple regression model were: duration and insulin dose/kg Results In multiple regression model number of injection per day was not a predictor of HbA1c, but multiple injections (>3 per day) was a predictor of hypoglycaemia. Australian data.. Comments crosssectional clinic data and therefore nonpopulationbased survey Multicentre, populationbased, crosssectional study Design IV Lev el IV 230 17 1441 patients with T1D aged 13-39 years. 726 with no retinopathy at baseline (primary intervention group) and 715 with mild retinopathy (secondary intervention group) Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring (n=704; 352 primary and 352 secondary prevention) OR Intensive insulin therapy (by multiple daily injections or insulin pump) with frequent BG monitoring (n=704; 348 primary and 366 secondary prevention) Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents DCCT 1993 Development of diabetes complications Adverse events: Incidence of hypoglycaemia increase 2-3 fold on intensive therapy (19 versus 62 hypoglycaemic episodes per 100 patient years, p<0.001). Nephropathy: Intensive therapy reduced risk of microalbuminuria by 39% (95% CI 21-52) and albuminaria by 54% (95% CI 19-74); Intensive therapy reduced the mean adjusted risk of microalbuminuria by 34% (p=0.04) in in patients with no retinopathy at baseline and by 43% in those with mild retinopathy at baseline (p=0.001) Neuropathy: At 5 years, intensive therapy reduced incidence of clinical neuropathy by 69% ; 95% CI 24-87 (3% in intensively treated group vs 10% in conventionally treated group) p=0.006 in patients with no retinopathy at baseline; and by 57% (95% CI 29-73); p0.002 in those with mild retinopathy at baseline; combined 60% (95% CI 38-74), p0.002 on twice-daily insulin. Retinopathy: intensive therapy reduced the risk of retinopathy by 76% (95% CI 62-85) in patients with no retinopathy at baseline (p0.002), and by 54% (95% CI 39-66) in those with mild retinopathy at baseline (p<0.001); combined 63% (95% CI 52-71), p0.002. Losses to follow-up: 99% of patients completed study; >95% of all scheduled examinations completed; 11 patients died; 32 patients assigned to inactive status for some time during trial due to unavailability or investigator’s decision that continuation of treatment would be Research group blinded to effects of the two treatment regimens Blinding: Standard therapy group blinded to HbA1c results; intensive therapy group could not be blinded to Hba1c because they were using it as a management tool Landmark study. Rigorous multicentre study supervised by NIH, USA See other DCCT references Follow up period of 6.5 years (trial terminated by independent monitoring committee) RCT II 231 20 Bougneres 1993 186 patients aged 10-18 yr with IDDM, who were previously treated with two daily insulin injections, were included without any selection into a randomized trial (1 year). Of 195 adolescents in the DCCT adolescent cohort, 175 (91%) participated in EDIC (Epidemiology of Diabetes Interventions and Complications) HbA1c They were either switched to three injections (regular prebreakfast, regular prelunch, and [regular+ultralente] predinner) (n=91) remained on two injections ([regular+intermediary] prebreakfast and predinner) subcutaneous OR Diabetes complications Observational four year follow up from close of DCCT (DCCT = Intensive insulin therapy and multiple daily injections with frequent BG monitoring OR Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring) Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 18 White 2001 (EDIC follow up of DCCT adolescent cohort) Retinopathy The prevalence of worsening retinopathy and of progression to proliferative or severe nonproliferative retinopathy were reduced by 74% (p <.001) and 78% (p <.007), respectively, in the former intensive therapy group compared with the former conventional group. GHb, decreased from 9.8 +/- 0.1 to 9.3 +/0.2% (P < 0.05) in the three-injection group, whereas it increased from 9.5 +/- 0.3 to 9.8 +/0.3% (P < 0.05) in the two-injection group, resulting in a modest (0.75%) but significant difference (P < 0.05) between GHb change in the two groups. The difference reached 1.4% (P < 0.0002) in patients with GHb > 11.2% at entry. Concluded that even though the diff. between HbA1c lessened during EDIC, the benefit of intensive therapy still persisted. The subsequent first 4 years of EDIC mean HbA1c was similar for former intensive and former conventional groups (8.38% vs 8.45%). HbA1c During 7.4 years of DCCT mean HbA1c was lower with intensive therapy than conventional therapy (8.06% vs 9.76%; p <.0001) Losses to follow-up: 19 primary refusals Randomisation: table of random numbers Multicentre INSERM study centres in France. Blinding: Retinopathy assessors were blinded to the DCCT assignment of participants Compliance: Average time spent receiving assigned treatment = 97%, including 95 women assigned to conventional therapy who received intensive therapy during pregnancy or while planning a pregnancy Rigorous study. Supervised by NIH (see other entries for DCCT). hazardous RCT RCT II II 232 Frequency of severe hypoglycaemia and DKA BMI between 3rd & 60th percentiles for age and sex. Population 50 type 1 diabetic children (3-18 yrs) Mean age 11.5 [3.5] 2nd group of 25 children (randomised then crossed over to opposite) C: 12.7 mm in arm D: 8 mm in arm 1st group of 25 children (randomised then crossed over to opposite) A: 12.7 mm in thigh B: 8 mm in thigh Intervention 2 injections performed on each child on 2 groups of children. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 30 Outcome Frequency of intramuscular injections by ultrasonography Conclusion: 8mm needles significantly reduce risk of IM injections in slim or normal weight diabetic children and Significant reduction with 8mm needle p < 0.01 arm p< 0.001 thigh 38% of injections with 8mm needle were in muscle (48% in the arm and 28% in the thigh region). Results With 12.7 mm needles 86% of injections were intramuscular (88% in arm, 84% in thigh) Compliance: Dietary compliance assessed by dietician or physician who was minimally involved in direct patient management – this was assessed by dietary recall after randomisation (not included in analysis); 14 secondary refusals during trial, where patients asked to be switched to the other regimen (this part analysed by intention-to-treat) All measurements (using ultrasound) were performed by the same operator 25 children received injection in the thigh, 25 in the arm; method of selecting injection site not stated Order of injections with different needle lengths was randomised Comments Open label crossover study There were 205 enrolled, 19 primary refusals following randomisation and these patients were excluded from the analysis .Of the remaining 186 patients there were no differences in baseline characteristics. The frequency of hypoglycaemia and DKA was similar in the two groups. The length of needle for the injection for insulin therapy in the treatment of children with type 1 diabetes Study Tubiana-Rufi 1999 5.2 injections (n=95). Design RCT Level II 233 44 49 WeissbergBenchell 2003 NHS NICE 2003 Population Standardised mean difference was 0.58 (95% CI 0.34-0.83) lower in pump patients. This represented reduced total daily insulin dose by 14% in pump patients 0.95% HbA1c improvement on CSII (CI 0.8 – 1.1) Total daily insulin dose Insufficient data to be included in meta analysis, but descriptive trend towards less hypoglycaemia, and risk of DKA was inconclusive Side effects: DKA Hypoglycaemia Paediatric and adult studies analysed together Publication bias assessed by comparing results from unpublished data from abstracts presented at major meetings. All parallel studies pooled without taking account of individual study design No distinction made between studies of different designs and quality. No published RCTs in the paediatric Not sufficient data to include in meta analysis, but descriptive trend to decreased total dose on CSII. Insulin requirement Appropriate inclusion criteria used however details of how inclusion criteria were applied are not stated. Articles obtained by searching Medline PubMed and reference lists of review and other articles. English studies only. Side effects not reported Data examined by 2 reviewers. Provided an effect size corrected for possible publication bias Some statistical heterogeneity between studies was evident Appropriate inclusion criteria for selected articles. Comments Search strategy included Medline, Embase and Cochrane database. Other data from manufacturer’s and patient support groups. included paediatric section Improvement in mean BGL on CSII of 17.31 mg% (approx 1mmol/l) with CI of 13.45-21.16. Mean blood glucose HbA1c Standardised mean difference was 0.44 (95% CI 0.2-0.63) lower in pump patients Results Standardised mean difference in BGL was 0.56 (95% CI 0.35 -0.77) lower in pump patients HbA1c Outcome Mean BGL Appropriate search strategy and inclusion criteria used. Optimised s.c. insulin injections Or Continuous s.c. insulin infusion CSII Optimised s.c. insulin injections Or Intervention Continuous s.c. insulin infusion Systematic review of all insulin pump studies Age range 2.3-49.8 years, mean 26+/- 10.8years 1547 patients total 52 studies (12 studies paediatric, 33 adult, 7 mixed adult/paediatric) Timeframe 2.5 to 24 months. Overall 301 patients received insulin pump, 299 received insulin injections. 12 RCTs Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 43 Children and adolescents with type 1 diabetes and management with insulin pump therapy Study Pickup 2002 5.3 adolescents. Systematic Review/ Technology Appraisal Systematic review of 52 studies (mixed study designs including RCTs) Design Systematic review of RCTs T I Level I 234 599 patients with T1D attending diabetes clinics at Guy’s and St Thomas Hospitals UK. Population Health technology Assessment., UK. Intervention allocation to either near patient testing (NPT) n=302 (ie HbA1c results available at the time of consultation) or not n=297 Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 40 Benefits of near patient testing of HbA1c at outpatient visits. Outcome Number of management changes made during consultation NPT leads to more management changes in this with poor glycaemic control In those with good control: no diff Results In those with poor control: more likely to have management changes made if NPT used; odds ratio 1.75 (95% CI 1.12-2.72) Blinding: Administrativc staff who handed out tickets to allocate patients to groups were unaware of Comments Randomisation: Assignment of patients to groups according to whether number of ticket given on arrival was odd or even. Design Quasi-RCT Technical Reports/Consensus Statements Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Study Grieve 1999 6.1 No other significant adverse events recorded in either study. No increase in serious hypoglycaemia; Number of events too small for statistical analysis (1 in each group). Technical reports and Consensus Statements used to formulate the recommendations and principles of clinical practice. Chapter 6: Glycaemic Control Ref No 1 61 5.4 One study found no difference in glycated Hbat 6 months follow-up there was no significant difference between CSII and MDI (8.5 vs 8.7%, p=NS). A second study found clear benefit on glycated haemoglobin.after 4 months follow-up GHb was significantly lower in CSII than MDI (8.8 vs 9.6%, p<0.05). Only 2 RCTs in adolescents. Glycated Haemoglobin (GHb) included adolescent section which included 2 RCT’s CSII compared with MDI population. All paediatric studies identified were case series. which identified 8 paediatric studies (case series) Level III-1 235 Population 1441 patients with T1D aged 13-39 years. 726 with no retinopathy at baseline (primary intervention group) and 715 with mild retinopathy (secondary intervention group) Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring (n=704; 352 primary and 352 secondary prevention) OR Intervention Intensive insulin therapy (by multiple daily injections or insulin pump) with frequent BG monitoring (n=704; 348 primary and 366 secondary prevention) Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 1 Outcome Development of diabetes complications Nephropathy: Intensive therapy reduced risk of microalbuminuria by 39% (95% CI 21-52) and albuminaria by 54% (95% CI 19-74); Intensive therapy reduced the mean adjusted risk of microalbuminuria by 34% (p=0.04) in in patients with no retinopathy at baseline and by 43% in those with mild Neuropathy: At 5 years, intensive therapy reduced incidence of clinical neuropathy by 69% ; 95% CI 24-87 (3% in intensively treated group vs 10% in conventionally treated group) p=0.006 in patients with no retinopathy at baseline; and by 57% (95% CI 29-73); p0.002 in those with mild retinopathy at baseline; combined 60% (95% CI 38-74), p0.002 Results Retinopathy: intensive therapy reduced the risk of retinopathy by 76% (95% CI 6285) in patients with no retinopathy at baseline (p0.002), and by 54% (95% CI 39-66) in those with mild retinopathy at baseline (p<0.001); combined 63% (95% CI 52-71), p0.002. Benefits of improved glycaemic control on development of microvascular and macrovascular complications. Study DCCT 1993 6.2 Research group Blinding: Standard therapy group blinded to HbA1c results; intensive therapy group could not be blinded to Hba1c because they were using it as a management tool Comments Landmark study. Rigorous multicentre study supervised by NIH, USA See other DCCT references Follow up period of 6.5 years (trial terminated by independent monitoring committee) Equipment failure: NPT – 1 test not processed Conventional testing – 5 tests not processed which group was NPT or not Doctors and patients were not aware iof group allocation until the time of intervention, by which it was impossible to reverse the allocation Design RCT Level II 236 2 Mean follow up OR 125 adolescents with no retinopathy and 70 with mild retinopathy Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring (n=114) Intensive insulin therapy (n=95) (by multiple daily injections or insulin pump) with frequent BG monitoring Adolescent subgroup of DCCT trial. Age 13-17 years Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents DCCT 1994 Development of diabetes complications Nephropathy: Intensive therapy group had 10% reduction in microalbuminaria (95% CI –70% to 52%; p=0.745 in those with no retinopathy; and by 55% (95% CI 3% to Retinopathy: Intensive therapy decreased the risk of retinopathy by 53% (CI 1-78%, p=0.048) (in those with no retinopathy) and 70% (CI 25-88%, p=0.010) (in those with mild retinopathy) Adverse events: Incidence of hypoglycaemia increase 2-3 fold on intensive therapy (19 versus 62 hypoglycaemic episodes per 100 patient years, p<0.001). retinopathy at baseline (p=0.001) Blinding: Standard therapy group blinded to HbA1c results; intensive therapy group could nto be blinded to HbA1c as they were using it as Compliance: Average time spent receiving assigned treatment = 97%, including 95 women assigned to conventional therapy who received intensive therapy during pregnancy or while planning a pregnancy Landmark study. See other DCCT references Losses to follow-up: 99% of patients completed study; >95% of all scheduled examinations completed; 11 patients died; 32 patients assigned to inactive status for some time during trial due to unavailability or investigator’s decision that continuation of treatment would be hazardous blinded to effects of the two treatment regimens RCT II 237 3 1441 patients with T1D 726 with no retinopathy at Intensive insulin therapy (by multiple daily injections or insulin pump) with frequent BG monitoring Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents DCCT 1995 7.4 years (for adolescents) Development and progression of retinopathy Mean HbA1c during DCCT was dominant predictor of retinopathy progression, and the risk gradients were similar in the two groups; a 10% lower HbA1c (e.g., 8 vs. 9%); p=0.042 in those with mild retinopathy Independent data monitoring committee determined that study results warranted terminating trial after mean follo-up of 6.5 years (overall) Landmark study. See other DCCT references Losses to follow-up: No patients voluntarily withdrew; 2 patients died; 2 patients assigned to inactive status for some time >95% of scheduled examinations were completed; overall time spent in assigned treatment was 95%; a management tool; Research group blnded to the effects of the two treatment regimens; Investigators and patients unaware of outcome data unless predetermined ‘alert’ criteria (e.g. development of retinopathy) were reached; Retinopathy assessed by operators who were unaware of treatment group assignment RCT II 238 5 Nathan 2003 Of 1441 patients who participated in the DCCT, 1229 patients participated in EDIC (Epidemiology of Diabetes 1441 patients with T1D 726 with no retinopathy at baseline and 715 with mild retinopathy Four year follow up from close of DCCT (DCCT = Intensive insulin therapy with frequent BG monitoring OR Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring) Primary prevention cohort (intensive insulin treatment n=348 vs conventional standard treatment n=352) Secondary intervention cohort (intensive insulin treatment n=366 versus standard conventional treatment n=352) Convention therapy with 1 or 2 insulin injections daily and once daily monitoring. OR Primary prevention cohort (intensive insulin treatment n=348 vs conventional standard treatment n=352) Secondary intervention cohort (intensive insulin treatment n=366 versus standard conventional treatment n=352) Intensive insulin therapy (by multiple daily injections or insulin pump) with frequent BG monitoring Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring. OR Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 4 DCCT 1996 Follow up period of 6.5 years. Patients with HbA1c levels <6.5% exclcued from study baseline and 715 with mild retinopathy B-mode ultrasound of the internal and common carotid arteries to measure intimal thickness (in 1994-1996 and 1998-2000) Development of diabetes complications In DCCT, as HbA1c was reduced below 8% there were continuing relative reductions in the risk of complications, whereas there was a slower rate of increase in the risk of hypoglycaemia. Therefore, the DCCT continues to recommend implementation of intensive therapy with the goal of achieving normal glycaemia as early as possible in as many IDDM patients as is safely possible Mean progression of the intima-media thickness sig. less in group that received intensive therapy during DCCT than in group that received conventional therapy (progression of the intima-media thickness of the common carotid artery, 0.032 vs. 0.046 mm; P=0.01; and progression of the combined intima-media thickness of the Although the magnitude of the absolute risk reduction declines with continuing proportional reductions in HbA1c, there are still meaningful further reductions in risk as the HbA1c is reduced toward the normal range. Proportional reductions in HbA1c are accompanied by proportional reductions in the risk of complications. Hazard rates of retinopathy progression microalb. and neuropathy are continuous but nonlinear over the entire range of HbA1c values in all groups. Recommend: intensive therapy with the goal of achieving near-normal glycaemia should be implemented as early as possible Total glycaemic exposure was dominant factor assoc. with risk of retinopathy progression 7.2%) is assoc. with a 43% lower risk in intensive gp and a 45% lower risk in conventional gp. Blinding: Assessment of intima-media thickness carried out by a single operator who was blinded to As for DCCT Retinopathy graded at a central facility Blinding: Standard therapy group blinded to HbA1c results; intensive therapy could not be blinded to HbA1c because they were using it as a management tool; Research group blinded to the effects of the two treatment regimens Blinding: Participants and clinics blinded to HbA1c values unless they reached a predefined level of 13%, where unmaksing occurred to enable treatment of patient; Research group blinded to the effects of the two treatment regimens See other DCCT references RCT RCT II II 239 9 Craig 2002 1190 children and adolescents aged 1.2-15.8 years with type 1 diabetes, identified from three hospitalbased paediatric diabetes units, four private citybased paediatric practices and 18 regional outreach clinics in NSW and the ACT from 1 September to 31 December, 1999 Diabetes complications HbA(1c) level and incidence of severe hypoglycaemia Observational four year follow up from close of DCCT (DCCT = Intensive insulin therapy and multiple daily injections with frequent BG monitoring OR Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring) Cross sectional audit Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 6 White 2001 (EDIC follow up of DCCT adolescent cohort) Interventions and Complications) N = 611 conventional and n = 618 intensive therapy. Of 195 adolescents in the DCCT adolescent cohort, 175 (91%) participated in EDIC (Epidemiology of Diabetes Interventions and Complications) Median HbA1c 8.2% (IQ range 7.6-9.1%) in both urban and rural group. Significant predictors of hypoglycaemia in a Poisson regression model were younger age (P = 0.03), male sex (P = 0.04), longer diabetes duration (P = 0.02), and > 3 daily insulin injections (P = 0.02), but not HbA(1c) level. At least one episode of severe hypoglycaemia in the previous three months was reported in 6.7%, and the rate of severe hypoglycaemia was 36/100 patient-years. Retinopathy The prevalence of worsening retinopathy and of progression to proliferative or severe nonproliferative retinopathy were reduced by 74% (p <.001) and 78% (p <.007), respectively, in the former intensive therapy group compared with the former conventional group. Significant predictors of HbA1c level in multiple regression model were: duration and insulin dose/kg Concluded that even though the diff. between HbA1c lessened during EDIC, the benefit of intensive therapy still persisted. The subsequent first 4 years of EDIC mean HbA1c was similar for former intensive and former conventional groups (8.38% vs 8.45%). HbA1c During 7.4 years of DCCT mean HbA1c was lower with intensive therapy than conventional therapy (8.06% vs 9.76%; p <.0001) common and internal carotid arteries, 0.155 vs. 0.007; P=0.02) Fewer than 25% achieve the recommended HbA1c <7.5% In multiple regression model number of injection per day was not a predictor of HbA1c, but multiple injections (>3 per day) was a predictor of hypoglycaemia. Blinding: Retinopathy assessors were blinded to the DCCT assignment of participants . Rigorous study. Supervised by NIH (see other entries for DCCT). patientt’s treatment assignments Multicentre, populationbased, crosssectional study RCT IV II 240 Case attainment based on Diabetes Register was 67% of children in NSW and ACT. Audit of 1,190 children with T1D. HbA1c Median HbA1c 8.2% (IQ range 7.6-9.1%) in both urban and rural group. Fewer than 25% achieve the recommended HbA1c <7.5% Confirmed homogeneity of metabolic control in NSW and ACT regardless of location, socioeconomic status or system of care. Multicentre, populationbased, crosssectional study IV 112 families eligible, 8 declined to participate Population Children and adolescents ages 8-13 yrs with T1D (N=104) Intervention low GI diet (GI 77) versus high GI diet (GI 79) HbA1c Hypoglycaemia Hyperglycaemia Weight, height, dietary intake, quality of life. Outcome At 3, 6, 12 months Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 6, 16 Mean GI of diets was not different in the 2 groups despite differences in Results No difference in HbA1c at 3 and 6 months. After 12mths flexible low GI diet pts had significantly better HbA1c (8.05 vs 8.62, p=0.05). This difference between groups was significant, even after adjusting for baseline values (P=0.05). There were fewer episodes of excessive hyperglycaemia defined as >15 /month (35 vs 66%, P=0.006) and better QOL for children and parents in flexible-low GI diet. There were no differences in number of hypoglycaemic episodes. Losses to follow-up: 15 participants dropped out (14%), 11 from measured CHO diet and 4 from flexible-low GI diet. Of the 89 Blinding: Assessor of dietary adherence not blinded to participant’s diet allocation, but all other data nalysis performed by another researcher blinded to diet allocation Comments Randomisation: Computer-generated random numbers, method of allocation concealment not stated Design RCT Level II Technical Reports/Consensus Statements National Institute for Clinical Excellence. Type 1 Diabetes (Childhood): Diagnosis and Management of Type 1 Diabetes in Children and Young People (DRAFT). 2004. American Diabetes Association: Tests of glycemia in diabetes. Diabetes Care 26:S106-S108, 2003 American Diabetes Association: ADA position statement. Urine glucose and ketone determination. Clinical practice recommendations 1995. Diabetes Care 18(suppl):20, 1995 Coster S, Gulliford MC, Seed PT, Powrie JK, Swaminathan R: Monitoring blood glucose control in diabetes mellitus: a systematic review. Health Technology Assessment 4:1-93, 2000 International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Low glycaemic index diets in the management of type 1 diabetes in children and adolescents Study Gilbertson 2001 & Gilbertson 2003 7.1 Compared urban with rural children. Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice. 10 Chapter 7: Nutrition 43 Ref No 11 12 13 15 39 6.3 Handelsman 2001 241 17 14 studies, 356 subjects (203 with type 1 diabetes, 153 with type 2 diabetes) Meta-analysis of RCT’s to determine whether low-GI diets, compared with conventional or high-GI diets, improved overall glycaemic control in individuals with diabetes, as assessed by reduced HbA(1c) or fructosamine levels low-GI diets, compared with conventional or high-GI diets diets (average GI difference 22 (range 2-37)) Glycaemic control (HbA1c and fructosamine level) Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Brand Miller 2003 macronutrient intake and food choice with the use of 3-d food diaries In the 8 studies in which HbA1c was determined the low GI diet has a small but clinically useful effect on medium-term glycaemic control in patients with diabetes. (decrease of HbA1c of 0.43%, CI 0.72-0.13)). If final HbA1c values were adjusted for baseline values the mean difference was reduced to -0.34 units (CI -0.64 to -0.05 assuming independence. Children with diabetes who receive low-GI dietary advice do not report more limited food choices or a diet with worse macronutrient composition than do children who consume a traditional carbohydrate-exchange diet After 12 mo, intakes of dietary fat , carbohydrate, protein, total sugars, and fibre did not differ significantly between the CHOx and Low GI groups, respectively no differences in reported macronutrient intakes during any of the recording periods. dietary instruction (GI 77 vs 79). The differences therefore could not be explained on GI of the 2 dietary approaches. Findings suggest dietary instruction based on flexible low GI has benefits over weighed CHO exchange dietary advice. Many studies involved less than 25 Studies not specific for children or T1D. Only 2 included children with T1D One study included 104 children with type 1 diabetes. Conclusion was low-GI foods in place of conventional or high-GI foods has a small but clinically useful effect on medium-term glycaemic control. Only 1 study gave SD’s for individual low-GI or high-GI differences and these data were assumed for the statistical analysis of remaining studies. Inclusion criteria included: English studies, 1981-2001, properly randomised, cross-over or parallel, type 1 or 2 DM, identified in Medline using “glycemic index” in title. Intent-to-treat analysis performed on assumption subjects adhered to dietary advice provided at entry to study. completing the study, 4 did not complete a food diary at 6 months and 6 dod not complete one at 12 months Meta-analysis of RCT’s I 242 18 7 children with type 1 diabetes; 6 males, 1 female Average age 12 ± 2 years Low GI versus high GI diet (over 6 weeks for each, separated by a week interval) Cholesterol Glycaemic index Reduced after low GI diet but not after high GI diet (final figures and statistical sig-nificance not given for the comparison of high and low GI diets) Mean GI for low GI diet 68.7 [sem 2.5] versus 81.5 [sem 1.1] for high GI diet, p< 0.005 Participants received dietary advice on an individual basis to maximise adherence Adherence: None reported Losses to follow-up: Blinding: Not feasible for participants Randomisation: Crossover – order of diets randomised; Method of randomisation not stated subjects and were of short duration Ref No 4 Of 711 intensively treated subjects in the DCCT, 687 subjects enrolled Population DCCT population – adults and adolescents Self reported retrospective dietary behaviour Intervention 84 item questionnaire to determine whether specific diet-related behaviours practised by T1D patients in intensive treatment group of the DCCT were associated with lower HbA1c values. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Study Delahanty 1993 HbA1c Outcome Over-treating hypoglycaemia and consuming extra snacks Those who adhered to prescribed meal plan >90% of time had average HbA1c 0.9% lower than subjects adhering Results Adherence to prescribed meal plan and adjusting food and/or insulin in response to hyperglycaemia were associated with lower HbA1c levels. Survey instrument pretested with 101 intensively treated participants in the feasibility stage Comments 623 of 687 (90%) potential participants completed the questionnaire 7.2 Adjusting insulin dose for carbohydrate quantity in the management of type 1 diabetes in children and adolescents Collier 1988 All were randomised crossover or parallel experimental design of 12 days to 12 months duration (mean 10 weeks) with modification of at least 2 meals per day. Design RCT RCT (Crossover) Level IV (for this outcom e) II 243 7 6 month and 1 year follow up Mean age 40 (SD9) Mean diabetes duration 16.6 yr (SD9.6) 169 adults with T1D in secondary care clinics in 3 English health districts. Subjects had moderately to poor diabetes control (HbA1c 7.5-12%) and duration of diabetes > 2 years. DAFNE is adult education in flexible, intensive insulin management. Randomised to receive training immediately (n=69) or later (in 6 months (n=72) Training in (DAFNE) dose adjustment for carbohydrate intake. Unchanged – severe hypoglycaemia in 12/67 vs 11/72 (p=0.68) ADDQoL significantly improved in immediate trained subjects after 1 year (t=2.9, P<0.01) Impact of diabetes on quality of life (ADDQoL) Impact of diabetes on dietary freedom improved in immediate trained group (t=5.4, P<0.0001) Severe hypos HbA1c Population 10 patients with insulin dependent diabetes Age 7-12 USA Trial length: 2 days Intervention Sucrose-free diet (2% calories from sucrose) vs. Sucrose-containing isocaloric diet (10% calories from sucrose) Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 21 Results No significant differences: Area under the glucose response curve -3672 +/- 240 mg/dl per hr (Sucrose-free) vs. 3575 +/- 285 mg/dl per hr (Sucrose-containing) p=0.74 No difference in urinary glucose 35.6 +/- 7.5 (Sucrosefree) vs. 34.5 +/- 7.5 gm/day (Sucrose containing) p=0.84 Urinary glucose Blinding: Not stated Randomisation: Method not stated Comments Crossover design: participants received both diets, each for 2 days consecutively, in random order Losses to follow-up: 1016 letters sent, 423 replied, 299 expressed interest in study, 169 randomised, 27 did not participate after randomisation so intention to treat analysis was not possible. Possible bias in that groups consisted of volunteers. Relevance to children is debatable. Randomisation: computer generated random number list. Allocation by use of sealed opaque envelopes in consecutive order Outcome Change in blood glucose (18 measurements per day) The effect of moderate use of sugars on glycaemic control in children and adolescents with type 1 diabetes Study Loghmani 1991 7.3 DAFNE study group 2002 Adjusting insulin dose for meal size and content and consistent consumption of an evening snack were assoc. with lower HbA1c (p<0.03 for differences between responding <50%, =50% or >50% of the time) Sig. better in immediately trained DAFNE patients than those trained after 6 months (mean HbA1c 8.4% vs 9.4%, (t=6.1, P<0.0001). beyond the meal plan were associated with higher HbA1c levels. Design RCT RCT Level II II 244 23 Schwingshan dl 1994 (28 patients initially gave consent) 24 type 1 diabetes patients Age 8-26 Austria 9 patients with type 1 diabetes Age 11-16 USA All subjects rendered euglycaemic with insulin clamp overnight prior to study, then placed on 0.35 mU/kg/min insulin infusion during 4 hour intense study period to see effect of sucrose in diet. Sucrose free diet (n=11) vs. Sucrose (5%) containing diet (n=13) Trial length: a mean period of observation of 83 days (range 42-127 days) Trial length: 2 days Sucrose (2% ) free diet vs. Sucrose (17%) containing diet Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 22 Rickard 1998 HbA1c glucose response No significant difference: 9.0% (sucrose diet) vs. 9.1% (sucrose free diet) Higher glycaemic response to low sucrose diet attributed to increased starch content. Peak glucose response was approx 1 hour earlier (p<0.01) and was lower (p<0.01) with sugar-containing diet than with sugar-free diet Significant difference: Area under the glucose response curve 37 +/- 3.5 (SEM) mmol/L (sucrose-free) vs.42 +/4.7 mmol/L (sucrose containing) P=0.01. Losses to followup: Data from 4 children excluded from analysis (3 Blinding: Not stated Blinding: Not stated Randomisation: Pseudorandomised – patients allocated to treatment gropups based on their ability to attend hospital on one of two days for dietary assessment Randomisation: Method not stated Results should be regarded as preliminary due to small study size, short duration and limited power to detect differences Crossover design: participants received both diets, each for 2 days consecutively, in random order All mealtimes monitored by one of the researchers to verify that the correct food was served and eaten QuasiRCT RCT III-1 II 245 Sucrose (7%) added to snacks (n=8) vs. Sucrose free (1%) (n=8) Trial length: 5 days Oatmeal alone (OM) vs. Oatmeal + sucrose (OMS) vs. Oatmeal + protein (OMP) vs. Oatmeal + protein + sucrose (OMPS) Trial length: 4 successive Saturdays Mean blood glucose Change in blood glucose No significant difference: 8.8 nM (sucrose group) vs. 7.4 nM (sucrosefree) on day 5 Study suggests a small amount (up to 14%) of simple sugar replacinfg a portion of complex carbohydrate may not cause an exaggerated glycaemic response Combined peak times of breakfasts without added protein and fat (mean 37.5 [SEM8] min (SEM) vs 54.4 [8] min, p<0.05 for breakfasts with added protein and fat. No significant differences in peak glucose values, change of rise, glucose area under the curve (p>0.05). Blinding: Membership of each group unknown to patients, dieticians and physicians Blinding: Not reported Randomisation: Method not stated, hiowever snacks were colour-coded by a third party Randomisation: Latin square, where patiets were randomised to four different breakfasts on four different days RCT RCT II II Technical Reports/Consensus Statements American Diabetes Association: Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 26 Suppl 1:S51-S61, 2003 NHMRC. Dietary Guidelines for Children and Adolescents in Australia incorporating the Infant Feeding Guidelines for Health Workers. 2003. Ref Type: Report Franz MJ, Bantle JP, Beebe CA, Brunzell JD, Chiasson JL, Garg A, Holzmeister LA, Hoogwerf B, Mayer-Davis E, Mooradian AD, Purnell JQ, Wheeler M: Evidence-Based Nutrition Principles and Recommendations for the Treatment and Prevention of Diabetes and Related Complications. Diabetes Care 25:148, 2002 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 37 Ref No 1 2 3 16 type 1 diabetes patients Age 16-39 USA 8 IDD patients Age 7-16 USA Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice. 25 Wise 1989 7.4 24 Wang 1991 Patients in both groups receievd dietary education from the sdame dietician First 8 volunteers selected. because food records unusable, 1 because blood sampling was not possible) 246 7 Mosher 1998 Population Adolescents withT1D were assigned to groups with either lower or higher than 9% glycosylated haemoglobin (HbA1c), and submitted to 12 weeks of supervised training followed by 12 weeks of unsupervised training (n = 12 per group) (age 14.0+/-1.2 years) Duration of diabetes 5.0+/-3.1 years. 10 male adolescents with T1D (aged 17.2+/1.2 years) and 10 adolescent nondiabetic (ND) subjects (19.4+/1.3years). Mixed endurance and calisthenic/strength activities performed at a rapid pace three times weekly for 12 weeks Intervention 12 weeks of supervised training followed by 12 weeks of unsupervised training (n = 12 per group). Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 6 No selection protocol indicated. Data analysed using a 2x2 analysis of variance (ANOVA) for repeated measures. Did not follow up after study period to see if benefit was maintained Only one subject with IDDM experienced hypoglycaemia after a single exercise session. Both subject groups improved their cardiorespiratory endurance (p < .05). Lean body mass of T1D subjects increased by 3.5% (p < .05). Subjects with and without T1D lowered their percent body fat (p < .05 and .001, respectively). Strength improvement of IDDM subjects ranged from 13.7% (p < .001) to 44.4% (p < .01), depending upon the manoeuvre. Fasting blood plasma glucose for all subjects was unchanged by training, but glycosylated haemoglobin A1c of T1D subjects was reduced by 0.96 percentage point (p < .05). Reductions of HbA1c benefited subjects with poor preconditioning glycaemic control. Hypoglycaemia Cardiorespiratory endurance Lean body mass Strength Fasting blood plasma glucose and HbA1c Comments Patients were selected from clinic patients. Short term training programme (12 weeks) only The average levels of HbA1c in poorly and well controlled diabetic patients were not affected by training (p<0.05) , a finding indicating that irrespective of the quality of glycemia prior to exercise training, glycaemic control in adolescents with T1D does not improve in response to exercise training alone Aerobic capacity in untrained group remained stable for the duration of the study (p<0.05) Results Supervised training caused a 17% rise in the patients' aerobic capacity which during the ensuing period of unsupervised training decreased to pre-training levels (p<0.05), thus suggesting a poor compliance with unsupervised training. HbA1c Outcome Aerobic capacity was estimated by Aerobic Power Index submaximal test using an ergomedic 818 exercise bike. Long-term effects of physical activity in children and adolescents with type 1 diabetes Study Roberts 2002 8.1 Chapter 8: Physical Activity Pretest, posttest interventi on trial with control group Design Pre test and post test IV Level IV 247 Peak aerobic capacity HbA1 and FBG The experimental group significantly (P less than 0.05) increased their peak aerobic capacity when compared with baseline values (47.14 +/- 1.94 versus 50.69 +/- 1.30). Did not follow up after study period to see if benefit was maintained Losses to follow-up: Not stated, but patients were required to attend at least 75% of exercise classes to be be included in the final analyses Blinding: Not stated Randomisation: Method of randomisation not stated Population 745 Finnish children at diagnosis of T1DM Intervention Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 2 Outcome Frequency of DKA Results Higher rate of DKA in those aged < 2 years or > 10 years (< 2 years: 53.3%; 2-10 years: 16.9%; > 10 years: 33.3%). Children from families with poor parental educational level had DKA more often than those from families with high parental education (24.4% v 16.9%, p<0.05). DKA less common in those with residual insulin secretion (serum C peptide > 0.10 nmol/L), p<0.05 Aetiology, epidemiology, risk factors, cerebral oedema and management of diabetic ketoacidosis Study Komulainen 1996 9.1 Chapter 9: Diabetic Ketoacidosis Comments RCT Design Cross sectional Technical Reports/Consensus Statements National Institute for Clinical Excellence. Type 1 Diabetes (Childhood): Diagnosis and Management of Type 1 Diabetes in Children and Young People (DRAFT). 2004. Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Experimental group of children (N = 9) took part in a 30-min vigorous exercise program three times a week for 12 wk; the control group (N = 10) did not Ref No 2 4 9 Children aged 511 yr with T1D Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice. 8 Low-density lipoprotein cholesterol was decreased in subjects with IDDM (p < .05), but not total cholesterol or triglycerides. The experimental group significantly (P less than 0.05) decreased their HbA1 and FBG while the control group showed no change. 8.2 Campaigne 1984 Lipids Level IV II 248 4 5 6 7 8 11 Yki-Jarvinen 1984 Christensen 1974 Barnes 1978 Bolli 1979 MacGillivray 1982 Pinkey 1994 13 T1DM patients with DKA (Group A - severe ketoacidosis, n = 5, Group B (moderate ketoacidosis, n = 8), 38 healthy T1DM patients, 25 patients with acute ketoacidosis, 20 non diabetic controls. Population-based 5 pituitary-ablated T1DM patients and 5 T1DM patients with normal pituitary function 14 newly diagnosed T1DM patients after disappearance of ketosis and after 3 months of insulin therapy; 14 non diabetic controls 14 patients with diabetes (10 with DKA); 23 nondiabetic controls 15 diabetic subjects with DKA; 6 non diabetic controls Withdrawal of insulin for 12hours in both groups; cortisol replacement in pituitary-ablated patients IV "low-dose" insulin (6-10 U/hour) Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 3 Barrett 1982 Frequency of DKA Measurement of diurnal concentrations of glucose, regulatory hormones, and electrolytes were measured serially over 25 hours Measurement of plasma and urinary catecholamines, before and during treatment Measurement of glucose, ketone bodies, growth hormone, cortisol at baseline and 12 hours Plasma norephinephrine and ephinephrine levels Insulin sensitivity (IS) and hepatic glucose production measured using euglycaemic insulin clamp Insulin resistance (Glucose clearance rate) Severe DKA (pH < 7.1 and/or Patients with DKA had elevated adrenaline and cortisol levels, 50% had elevated glucagon and growth hormone levels Mean glucose clearance during insulin treatment in those with DKA was significantly slower than in the controls (half time of fall in plasma glucose 6.1 + 0.6 vs 0.31 + 0.03 hours,.P < 0.001) IS, as measured by rate of glucose metabolism, was 35% lower in newly diagnosed T1DM patients compared with controls (P < 0.005); after 3 months of insulin therapy in subjects with diabetes, IS was comparable in both groups. Plasma norephinephrine levels were elevated in all DKA patients and correlatd with degree of metabolic decompensation (as measured by plasma carbon dioxide, P<0.02). compared with controls; ephinephrine was elevated in half of those with DKA Delayed onset of hyperglycaemia and ketogenesis in pituitary-ablated diabetics compared with controls (p<0.05); cortisol replacement partially increased glucose and ketone concentrations In group A plasma catecholamines were significantly higher than in group B, both before and in the course of therapy (p<0.05). Study demonstrated a causal associaton between elevated counter-regulatory hormones and ketoacidosis Study demonstrated a causal associaton between sympathetic activity and degree of ketoacidosis Small number of cases but groups comparable in age, weight and diabetes duration. Insulin requirement significantly lower in pituitary ablated subjects (p<0.05) Non-diabetic control group used for comparison Not randomised; non-diabetic control group used for comparison Population Case-control Cohort study Case-control Case-control Case-control Case-control III-3 III-2 III-2 III-2 III-2 III-2 III-2 249 13 15 17 18 19 20 Mallare 2003 Kent 1994 PinhasHamiel 1997 Scott 1997 Flood 2001 Morris 1997 DARTS/ 26 young females with T1DM with a history of recurrent DKA and poorly controlled diabetes; matched control group of patients with stable diabetes Adolescents with T2M diagnosed 1982 -1995. USA Adolescents with T2M (n=50) compared with matched group with T1DM 247 admissions with DKA, age < 21 years Children aged <16 years of age at diagnosis of type 1 diabetes from Oulu (Finland, n = 43) and Toronto (n = 87) during 1984-5 139 new onset type 1 diabetes patients; age 0.5 to 18 years; from 1995 to 1998 The prescribed insulin dose and Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 12 Daneman 1990 cohort of 230 patients with T1DM aged < 21 years Associations between Presumed viral infection present in 17.8% of cases of DKA, bacterial infection in 12.9% (these were more common in children aged < 3 years, p=0.03) 25 (28%) of the 89 patients DKA was present in >25% of patients with T2DM Clinical features at presentation Rate and predictors of DKA 7/ 28 (25%) African-American adolescents with T2DM presented with DKA 38% presented in DKA. Associations: no private health insurance (odds ratio 3.17 (95% CI 1.2-8.3) p=0.03); missed diagnosis (68% in DKA vs 32% where diagnosis not missed, odds ratio 4.6 (95% CI 1.9-11.7), p=0.001), 5/26 (19%) died during a mean follow up period of 10.5 years. Causes of death not certain, but DKA “probably” caused death in 2 cases; rates of DKA fell during follow up into adulthood Clinical features at presentation Mortality, cause of death Prevalence of DKA, risk factors for DKA Frequency of DKA, risk factors for DKA bicarbonate < 10) in 16%, mild DKA (pH 7.10-7.35 or bicarbonate 10-21 mmol/L) in 10%. One death. Severe DKA was associated with age < 5 years (p<0.05). Amongst the Finnish group, those from multiplex families had a higher C-peptide concentration and lower frequency of ketoacidosis than those from simplex families (p < 0.05) Direct evidence of poor Only 42/60 had ICA performed; cases of T1DM may have been misclassified as T2DM Small series, but study suggests that mortality rate is high for (female) patients with recurrent DKA and poorly controlled diabetes Case series Retrospective cohort study Case control study IV IV III-2 IV III-3 Case control study / interrupted time series Retrospective Case Series IV III-3 Retrospective Cohort study (Case series) Comparative Cohort study based prospective cohort study 250 22 23 Musey 1995 Cohn 1997 Admissions to African American patients with newly diagnosed or established diabetes: 56 adults, age 37.4 + 1.7 years, 56 episodes of DKA over 3 months Urban hospital in USA Medical, educational, and psychosocial interventions volume of insulin prescriptions supplied were used to calculate days of maximum possible insulin coverage per annum, expressed as the adherence index. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 21 Golden 1985 89 patients, who attended a teaching hospital paediatric or young-adult diabetes clinic in 1993 and 1994. (mean age 16 (SD 7) years, diabetes duration 8 (4) years, and glycosylated haemoglobin (HbA1c) 8.4 (1.9)%) 44 children with a history of recurrent DKA MEMO Collaboration. (Diabetes Audit and Research in Tayside Scotland. Medicines Monitoring Unit) Prevalence of DKA, Aetiology of DKA Incidence of recurrent DKA glycaemic control (HbA1c), episodes of diabetic ketoacidosis, and all hospital admissions for acute complications and the adherence index were modelled. The rate of recurrent DKA decreased from a pre-referral mean of 25.2 episodes to a post-referral mean of 2.6 per 100 patient-months (P <0.0001). Metabolic control improved: HbA1c decreased from 14.1% to 10.7% (P < 0.0001). DKA decreased whether or not psychotherapy was used. Of those with known diabetes, (75% of DKA episodes), 67% were due to cessation of insulin. 50% stopped insulin due to lack of money to buy insulin or transportation to the hospital; 21% stopped insulin due to lack of appetite; 14% stopped insulin because of behavioural or psychological reasons; 14% because they did not know how to manage diabetes on sick days More females than males were Adherence index was inversely related to hospital admissions for diabetic ketoacidosis (p < 0.001) and all hospital admissions related to acute diabetes complications (p = 0.008). obtained less insulin than their prescribed dose (mean deficit 115 (68; range 9-246] insulin days/annum). There was a significant inverse association between HbA1c and the adherence index (R2 = 0.39; p < 0.001). Gender differences not likely to Patient group > 18 years of age, but sample can be considered representative for aetiology of DKA in adolescents (the group most likely to have recurrent DKA) No control group compliance with insulin therapy in young patients with IDDM Cohort study Cohort study (consecutive series) Time series study IV IV III-3 251 25 26 Rewers 2002 Liss 1998 25 children (aged 9-17 years) with T1DM at least 1 year with DKA and parents; Dallas clinic, USA Controls: children with T1DM (no history of DKA hospitalization) and parents n=25 Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 24 al Adsani 2000 hospital with principal diagnosis of T1DM (n = 2,270) children, aged 018 years, during 1991 59 patients with T1DM (30 males, 29 females), aged 18 to 30 years, 3 year study period, Kuwait 1243 children with T1DM aged < 19 years from Denver, Colorado were followed from Jan 1, 1996 to Dec 31, 2000 35/88 admissions to hospital were for DKA; 23 females vs 12 males ,NS: p > 0.05). Insulin omission was the most common cause of DKA (11/35); infection in 2/35 Incidence of DKA was 8/100 person-years and increased with age in girls (P<.001 for trend). In multivariate analyses, stratified by age (<13 vs > or =13 years), the risk of DKA in younger children increased with higher HbA1c (RR, 1.68 per 1% increase; 95% CI 1.451.94) and higher insulin dose (RR, 1.40 per 0.2 U/kg per day; 95% CI, 1.20-1.64). In older children, the risk of DKA increased with higher HbA1c (RR, 1.43; 95% CI, 1.30-1.58), higher insulin dose (RR, 1.13; 95% CI, 1.02-1.25), underinsurance (RR, 2.18; 95% CI, 1.65-2.95), and presence of psychiatric disorders (for boys, RR, 1.59; 95% CI, 0.96-2.65; for girls, RR, 3.22; 95% CI, 2.25-4.61). More diagnoses reported by DKA children than controls (mean 1.9, SD 1.9 v 0.2, SD 0.4; p0.001) Majority cases: anxiety, affective and disruptive behaviour disorders 88% of cases met criteria for at least 1 psych disorder v 28% controls(p0.001) Self-esteem & social competence lower among cases Prevalence and aetiology of DKA Psychiatric disorders (DISC) Child behaviour checklist Family Assessment Measure Brief symptom Inventory (parents) Incidence and aetiology of DKA admitted with DKA (n=578 vs n=444) and recurrent DKA (23.5% vs 14.2%, p<0.0001); the largest gender difference was for adolescents gender differences Cases and controls matched on age, sex, ethnicity DKA subjects were in poor control at study entry and diagnosis as reported by mean number of hospitalisations and A&E visits compared with controls (both p0.001) be due to differences in incidence of T1DM (females = males) Case-control Prospective Cohort study Retrospective Cohort (case series) IV IV IV 252 28 29 30 31 32 Mecklenburg 1986 The Diabetes Control and Complication s Trial Research Group 1995 Bode BW 1996 Boland 1999 Levy-Marchal 2001 1,260 children aged < 15 years at the time of diagnosis of T1DM from 24 centres in Europe 217 patients on CSII followed for one year 1441 patients, aged 13 to 39, with T1DM for 115 years. Average length of follow-up 6.5 years (range 3-9) 26 centres in the US, 3 in Canada 225 patients using CSII; compared with use of multiple daily injections in same patients 75 adolescents aged 12-20 years 1995 – 1998, USA Frederiksborg County, Denmark. 1960-1979 compared with 1943-1963; adolescents and young adults Treatment with CSII (n=25) vs multiple daily injections (n=50) Conventional vs intensive diabetes treatment Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 27 Ellemann 1984 Incidence and predictors of DKA Incidence of DKA and hypoglycaemia, psychosocial outcomes Incidence of DKA and severe hypoglycaemia Frequencies of infusion system failure and DKA rate Adverse events: mortality, morbidity, DKA, hypoglycaemia Incidence of DKA, risk factors for DKA No statistically difference in rate of DKA between two groups (1/100 patient years in CSII and 2/100 patient years in MDI group, NS) Odds ratio for DKA in the under 5 age-group was 1.02 (95%-CI:0.69-1.49) relative to the older children; DKA recorded in 11 centres: significant variation between centres in the frequency of DKA (range 26 to 67%) An inverse correlation between the frequency of DKA and the background incidence of T1DM was found in these centres No difference in rate of DKA between two groups Amongst intensively treated patients, the DKA rate was higher in those treated with CSII than with multiple daily injections (3.09/100 patient years vs 1.39 per 100 patient years, P=0.003) No difference in rate of DKA between two groups (pns) Families of cases scored lower on problem-solving and diabetes-specific ‘warmthcaring’ Incidence of DKA at the county hospital increased from 60 per 100,000 (1943-1963) to 120 per 100,000 (1960-1979). Mortality decreased in second time period. Recurrent DKA was associated with lower socioeconomic status. 7 episodes of DKA Not randomised (patients selected CSII or MDI) Highly selected, healthy T1DM patients who received attentive clinical management and frequent health education; so rates of AE may be different in children May not be representative today due to improved pump technology and education See other DCCT references Stastistical significance not reported Cohort study Cohort study Cohort study (interrupted time series) RCT Prospective Cohort study Cohort study IV III-2 III-2 II IV IV 253 34 35 36 Laing 1999 Edge 2001 Glaser 2001 Cases of CE in the UK, reported through the British Paediatric Surveillance Unit between October 1995 and September 1998. Episodes of DKA reported by 225 paediatricians identified as caring for children with diabetes, between March 1996 and February 1998. 61 children with DKA and CE, compared to children with DKA and no CE, 181 randomly selected and 174 children matched to the CE children Children with newly diagnosed T1DM (n=35) from 1990-98, mean age 9.2+/4.1 years, United Arab Emirates 23 752 patients with T1DM aged < 30 years, diagnosed from 1972-93 and followed to 1997, UK Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 33 Punnose 2002 Logistic analysis for the factors associated with CE. Mortality from DKA and CE Occurrence of CE 61/6977 (0.9%) hospitalisation for DKA CE significantly associated with (compared to randomly selected group): Lower initial partial pressure of arterial carbon dioxide: RR for each decrease of 7.8 mmHg, 3.4 (95%CI 1.9-6.3) (p < 0.001) Higher initial serum nitrogen concentration: RR for each increase of 9 mg per decilitre 1.7 (95%CI 12-2.5, p = 0.003) (these were also both Mortality rate from acute complications of diabetes were higher than any other causespecific rates in those aged < 20 years (SMR 273, 95% CI 196 – 381 in males; SMR 281 95% CI 201 – 303 in females); overall 54% of male and 76% of female deaths were certified to DKA The risk of developing CE was 6.8 per 1000 episodes of DKA in all patients with diabetes (34 cases of CE and 2940 cases of DKA) The risk was higher in newly diagnosed patients (11.9 per 1000 episodes) as opposed to patients with established diabetes (3.8 per 1000), p = 0.039. Out of the 34 cases of CE 8 resulted in death (24%) Mortality Cases of CE and DKA 28/35 (80%) patients presented with DKA and 28% developed recurrent DKA in follow up Incidence of DKA Large study using BPSU (British Paediatric Surveillance System); number of cases may be under-reported Age-specific mortality rates not reported for DKA Comparative study with historical controls Cross sectional (audit) Population based cohort study Cohort Study/ interrupted time series IV IV III-3 III-3 254 38 39 40 Edge 1999 Bello 1990 Duck 1988 32 cases of DKA and brain The group included 11 cases of cerebral oedema. Retrospective case note review of 1006 episodes of DKA. Deaths caused by diabetes in patients under the age of 20 between 1990 and 1996 in the UK from Office of National Statistics (England and Wales 69 cases of DKA and CE Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 37 Rosenbloom 1990 Predictors of brain herniation Data for the 11 cases of cerebral oedema were compared with 20 randomly chosen cases of DKA without cerebral oedema Death Risk factors for CE CE associated with: Younger age (8.6years vs 13.8years, p<0.05) Longer duration of symptoms (49 hours vs 16 hours, p<0.001) New T1D(8 patients vs 1 patient, p<0.01) Overall rate of fluid administration was inversely Incidence in new onset T1D was 3.3%, compared with known diabetics (0.23%, p<0.05). 116 deaths notified and 83 were caused by diabetes. The standardised mortality ratio was 2.3 (95%CI 1.9 to 2.9), highest for the age group 1 -4 at 9.2 (95%CI 5.4 to 14.7) DKA or hyperglycaemia was implicated in 83% (69/83) deaths in patients under the age of 20 between 1990 and 1996 in the UK. CE causes 69% (25/36) of deaths in children with diabetes under the age of 12. Overall frequency of cerebral oedema was 0.7% of all DKA cases. significant when compared to the control group who were matched to the CE patients) Treatment with bicarbonate was associated with CE: RR 4.2 (95%CI 1.5-12.1) (p = 0.008) Initial serum glucose and bicarbonate concentration not associated with CE CE appeared to be associated with younger age and new onset T1DM Historical controls used for comparised Statistical significance not reported for most comparisons Case series Case series Retrospective review of cases, including published and unpublished reports Cross sectional III-3 IV IV IV 255 42 43 44 Hale 1997 Durr 1992 Bureau 1980 8 dogs with 7 patients with uncontrolled T1DM Group 1: 119 patients aged 13 months to 30 years, 219 episodes of DKA (retrospective review) Group 2: 40 patients aged 1.5 to 20 years studied prospectively USA 4 children with T1DM aged < 5 years with DKA leading to CE compared to 10 aged matched controls with DKS but no CE USA Bicarbonate infusion Group 2: 48-hour treatment plan to provide the volume of sodium deficit evenly, with half the deficit given in the first 42 hours Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 41 Harris 1990 herniation Delivery of oxygen to Correlates of CE (glucose, sodium, bicarbonate, vasopressin, haematocrit) Children with CE vs. children with no CE: Weight, serum glucose, minimum serum sodium, minimum serum osmolarity, age, body surface area, initial serum sodium, initial serum bicarbonate Complication rate, change in serum sodium as serum glucose declined Weight: 13.0 ± 3.7 vs. 9.1 ± 2.2kg (p<0.05) Serum glucose: 26.3 ± 3.3 vs. 43.1 ±19.7 mmol/l (p<0.05) Minimum serum sodium: 128.8 ± 4.4 vs.142.2 ± 8.9 (p < 0.02) Minimum serum osmolarity: 265.5 ± 10vs. 296.7 ± 15.3 (p < 0.01) No difference in initial age, body surface area, serum sodium, serum bicarbonate values 6/7 had evidence of CE on brain CT scan. Initial CE correlated with BGL and inversely with bicarbonate, but not with other variables The change in calculated effective plasma osmolality predicted the progression of CE during therapy (using regression analysis) Bicarbonate therapy in DKA correlated with the time of onset of herniation (r = -0.32, p = 0.04). 4/40 cases occurred at fluid intakes < 4L/m2/day. During treatment, "calculated" serum sodium concentrations fell significantly (p<0.05) and were less than 130 mEq/L in 33% of cases at the time of herniation Group 1: complications were more likely to occur among patients with a failure of the concentration of sodium to rise as glucose declined (P<0.01) Group 2: Serum sodium concentration = rose in 55/58 (95%) of episodes as glucose declined. No patient had a major complication Not a human study;however .Small number of cases Small number of cases Case control Case series Case control Cohort study III-2 IV IV III-3 256 46 47 48 Mel 1995 Monroe 1997 Bonadio 1988 Children with DKA and CE, age range 1 to 15 years, 1972 to 1992 Victoria, Australia Children admitted with DKA during an 18-month period (n = 79) USA 63 paediatric emergency department visits for DKA USA 153 children admitted for one or more episodes of DKA over 12 years Age < 19 years USA Rapid correction of dehydration (over 6 hours) with fluid isotonic for sodium vs. dehydration over 24h using half normal saline. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 45 Mahoney 1999 experimental DKA Pediatric risk of mortality (PRISM) scores were significantly correlated with length of stay 27 patients had serum pH < 7.20 or bicarbonate < 10 mmol/L at admission, 25 (92%) had persistence of metabolic acidosis after three hours of outpatient therapy and were hospitalized. 36 patients had serum pH > 7.20 or bicarbonate concentration > 10 mmol/L (at admission, 34 (94%) had Predictors of need for admission for management of DKA (compared with outpatient management) decreased cerebral O2 availability (p<0.05); cerebral hypoxia contributed to the brain dysfunction 9 cases of brain herniation; Severity of acidosis, hypercapnoea and rate of initial fluid administration were risk factors. None of the children with pH > 7.1 and PCO2 > 20 mm Hg had brain herniation. In 119 patients with pH < 7.1 or < 20 mm Hg, 0/32 receiving less than 25 mL/kg, 1/ 42 receiving 25-50 mL/kg, and 8/40 receiving more than 50 mL/kg of IV fluid during the first 4 hours of therapy sustained brain herniation (p<0.001 for < 50mL/kg vs > 50mL/kg). Decline in serum glucose concentration between admission and onset of brain herniation was not a significant predictor of CE (NS) CE incidence: 0.19% (6/3134) vs. 0.18% (6/3373) Hospital and ICU length of stay, need for ICU admission CE Frequency and predictors of brain herniation cerebral tissue included as such a study could not be performed in humans but demonstrates potential harm of bicarbonate therapy Case series Retrospective case series Retrospective case series Cohort study IV IV IV IV 257 53 54 55 56 57 Adrogue 1982 Winter 1979 Zipf 1979 Gibby 1978 Wilson 1982 44 patients with DKA (39/44 IDDM, five patients are newly diagnosed) Mean age 26.8 ± 11.6 years (range 21 adults with DKA 9 children aged 917 Case report 9 year old boy Adults with DKA without extreme volume deficit 102 children with acute gastroenteritis Red-cell 2,3diphosphoglycerate (DPG) concentration; tissue oxygenation Length of time in DKA Total insulin dose required to treat DKA DKA was considered corrected when the pH was > 7.3, bicarbonate > 15mEq/L and serum A: No phosphate replacement B: 1 dose of 15 mmol phosphate replacement therapy (given as the sodium salt) at 4 hours C: 3 doses of 15 mmol phosphate replacement therapy Adverse events Plasma bicarbonate increment at 2, 4, 8, 16, and 24 hours after admission Accuracy of clinical assessment of dehydration, as judged by subsequent weight recovery in hospital 11 treated with IV phosphate in doses (mean 118 mmol; range 83-320 mmol) to maintain normal plasma phosphate; 10 untreated controls Potassium phosphate infusion (20-40 meq per litre of fluid) Group 1: (n=12) normal saline infused at ~14 mL/kg per hour in the initial 4 hours ~7 mL/kg per hour) during subsequent 4 hours. Group 2 (n=11), normal saline was infused at half the rates of Group 1 Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 49 Mackenzie 1989 resolution of metabolic acidosis within three hours of initiating outpatient therapy and were discharged home. The relapse rate in each group was similar. Degree of dehydration was overestimated by a mean of 3.2%; leading to unnecessary hospital admissions and overtreatment with intravenous fluid. Statistically significantly greater increment in bicarbonate level from admission at 4 hours in Group 1 vs Group 2 (3.7 vs 0.7 mmol/L) and at 24 hours Group 1 vs Group 2 (13.2 vs 8.4 mmol/L). Results suggest that slower fluid deficit correction with an isotonic solution results in earlier reversal of acidosis Potassium replacement during treatment of DKA using potassium phosphate salt. Despite resolution of DKA he developed hypocalcaemia, hypomagnesaemia and hyperphosphataemia Transient hypocalcemia (n=6), transient hypomagnesemia (n=5), carpopedal spasms (n=1) Significantly lower red-cell 2,3-DPG concentrations were found between 2 and 6 days after admission in controls vs treated patients; no difference in tissue oxygenation was found between groups No significant difference seen between groups of admission biochemical data. Serum phosphate is slightly different at outset in the patients treated with sodium phosphate compared to Blinding: Not stated Randomisation: No description of how randomisation took place. The phosphate load in potassium phosphate may cause low calcium and magnesium III-3 II RCT IV III-2 III-3 Cohort study Case series Case report Controlled trial Interrupted time series 258 58 35 patients with DKA IV potassium replacement as phosphate (4.7 to 28.5 mg/kg, N = 13) or chloride (N = 13), or no potassium replacement other than normal diet (N = 9) (given as the sodium salt) at 2, 6, and 10 hours Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Becker 1983 14–58) USA Diagnosis of DKA: blood pH < 7.25, plasma glucose > 250 mg/dL, bicarbonate level < 14 mEq/L, serum ketones positive at a dilution > 1:2 Serum calcium and phosphate; Phosphate excretion ketones were negative. untreated controls, but this difference is not significant. At 4 hours there was no significant difference in the serum phosphate between the intervention groups. At 8 hours the serum phosphate level was significantly higher in group B treated with 1 dose of 15 mmol phosphate replacement therapy at 4 hours, compared to no phosphate treatment. The serum phosphate level remained raised in the group but raise was not significantly for 16 and 24 hours. At 8, 16 and 24 hours serum phosphate level was significantly higher in group C, treated with 3 dose of 15 mmol phosphate replacement therapy at 2, 6 and 10 hours, compared to no phosphate treatment. Time course to development of DKA did not correlate with any admission biochemical data. The rate of correction of arterial blood pH and the mean duration of time required to correct the DKA was no different in any of the three groups. No difference among the three groups in the total amount of insulin necessary to correct the DKA. No clinical benefit of phosphate therapy found. Significantly lower serum phosphorus concentrations at 24 and 36 hours occurred in patients treated with phosphate, significantly more phosphorus was and excreted during the first 12 hours of the study than either of the other two groups of patients. The use of phosphorus Losses to follow-up: Not stated Cohort study III-2 259 60 61 Hale 1984 Morris 1986 21 adults with severe DKA (pH 6.9–7.14) Mean age; Bicarbonate: 34 ± 5 years, Controls; 28 ± 4. USA Inclusion criteria: Plasma glucose level 250 mg/dL, Serum testing acetone + ve at > 1:2 dilution, Serum bicarbonate level 15 mEq/L Arterial pH 6.9–7.14, Age 15 years. 32 patients with DKA, age range 15 to 80 years, all treated with normal saline and IM insulin 25 patients, age range 13 to 84 years, severe DKA (pH < 7.2, bicarbonate < 10meq/L) Hypokalaemia and hyperkalaemia diagnosis; potassium requirements during first 24 hours of treatment for DKA Rate of fall of BGL; change in biochemical parameters Primary outcome: overall rate of recovery of DKA Secondary outcome: number of concomitant complications during treatment All patients treated with saline (8 saline alone; 11 also received bicarbonate (up to 250 meq), 7 received bicarbonate (> 250 meq) 16 treated with 150 mmol bicarbonate; 16 treated with normal saline alone Intravenous bicarbonate infused over 30 min: 133.8 mEq for arterial pH of 6.9–6.99, or 89.2 mEq for arterial pH 7.1–7.14), Repeated every 2 hours until pH was 7.15 or more Comparison: no bicarbonate therapy Treatment regimen for all patients to treat DKA (irrespective of adjunct bicarbonate therapy): Insulin: 0.30 U/Kg body weight; _ IV bolus, 1.2 IM injection; then hourly injections of 7 U IM) Intravenous fluid as 0.9% saline or 0.45% saline at 250 to 1000 mL/h depending on patients’ state of hydration. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 59 Soler 1972 supplements did not cause abnormalities in calcium metabolism but did not prevent late hypophosphatemia 3/25 patients had hypokalaemia (<3.5meq/L) and 5/25 hyperkalaemia (>5.5 meq/L) at diagnosis Potassium requirement was significantly greater in those receiving higher dose of bicarbonate No difference in rate of fall of BGL; significantly slower fall in blood lactate, lactate: pyruvate ratio, and total ketones in patients treated with bicarbonate compared with saline group Comparison of patients before and after bicarbonate therapy: At randomisation there was no difference in the biochemical profile between the two groups. No significant differences were - seen in the rate of change of pH, ketone bodies, bicarbonate levels, and plasma lactate levels. No significant differences were noted in the recovery time in the two groups in terms of the number of hours required for glucose levels to reach 250 mg/dL (4.9 ± 1.3 h vs. 4.2 ± 1.0 h in the bicarbonate vs. control group respectively) and for bicarbonate to reach 15 mEq/L (21 ± 4.3 vs. 21 ± 4.0 h, respectively) No statistically significant differences in CSF glucose, bicarbonate, pH, lactate and ketones at three time points (0, 6–8, 10–12 h). There was no effect of mental status. Initially there appeared to be a greater decline in BGLs No description of selection of patients (adults). Randomisation: No description of method of randomisation Blinding: Not stated Losses to follow-up: 2/34 Ramdomisation: No description of how randomisation took place. Blinding: Not stated Losses to follow-up: Not stated RCT RCT Case series II II IV 260 64 65 Edwards 1977 Drop 1977 14 children with DKA, aged 5 to 17 years, with 18 episodes of DKA 22 children with DKA, aged 21 months to 16 years USA 48 patients with DKA Rates of hypoglycaemia and hypokalaemia Rate of correction of ketoacidosis and change in biochemical parameters Rate of clearance of ketones and fall in BGL Treatment with low-dose IM insulin vs high dose SC or IV insulin Treatment with insulin: lowdose IV insulin infusion (0.1 U/kg/hr, n=11) or high-dose intermittent subcutaneous injections (1 to 2.2 U/kg/hr, n=11) Treatment with 0.1 U/kg/hr IV insulin infusion vs SC insulin Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 63 Kitabchi 1976 in the control group compared to the bicarbonate group, although this was not statistically significant. Frequency of hypokalaemia (potassium <3.3 mEq/L): Measured by decline in serum potassium over time showed no significant difference with or without bicarbonate Episodes of hypoglycaemia: (0 vs. 1 episode respectively) and total insulin delivery administered for complete control (124±22 vs. 92±11 units respectively) did not significantly differ between the two groups. IV fluid therapy over 8 hours did not significantly differ in the amount of sodium (33 ± 31 vs. 451 ± 74 mEq), chloride (333 ± 31 vs. 451 ± 74 mEq), potassium (67 ± 21 vs. 70 ± 17 mEq), or dextrose (36 ± 11 vs. 40 ± 8 g) administered in the bicarbonate or treatment groups, respectively. Lower incidence of hypokalaemia in low dose group; higher rate of hypoglycaemia in high dose group; no difference in rate of drop of BGL or change in other biochemical parameters (NS) There were no statistically significant differences in rate of correction of ketoacidosis, rate of reduction of plasma glucose, or decline in plasma osmolality. The incidence and severity of hypokalemia were higher in patients receiving SC insulin. Serum ketones persisted longer in the IV group; “both regimens of insulin administration are equally effective” Randomisation: Random number table Blinding: Not feasible Losses to follow-up: Statistical significance not reported for comparison of hypokalaemia between groups Randomisation: Method of randomisation not described Randomisation: Method of randomisation not described RCT RCT RCT II III-2 II 261 67 68 69 70 71 73 Burghen 1980 Umpierrez 2003 Soler 1975 Franklin 1982 Curtis 2001 Linares 1996 Children admitted with DKA over a 4 year period: 132 patient visits in 45 patients (newly diagnosed caese excluded) Mild DKA (pH > 7.20, bicarbonate Single case of CE and DKA Single case of CE and DKA 51 patients in severe DKA 45 adults with DKA 17 children (mean age 7.4 years) with newly diagnosed T1DM and DKA; 3 children with established T1DM and DKA 32 children with DKA (range 6.2 to 15.8 years) Adolescent female with lifethreatening DKA-related CE who responded to combination of mannitol and hypertonic saline. Mannitol Time to correction of acidosis; prediction of patients suitable for outpatient management Time to correction of hyperglycaemia and acidosis Time to correction of hyperglycaemia/resolution of DKA, safety, cost Hourly SC aspart (n=15) vs 2nd hourly SC aspart (n=15) vs IV regular insulin (n=15) IM insulin (n=18); IV infusion (n=18); IV bolus insulin (n=25) Time to correction of hyperglycaemia, ketosis Low-dose (0.1 U/kg/h) vs highdose (1.0 U/kg/h) insulin Treatment with “low-dose” IM insulin (mean dose 0.29 U/kg) Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 66 Baum 1975 Acidosis was corrected within 6 hours in 33/72 (46%) of mild DKA episodes vs 3/60 (5%) of moderate-severe DKA (P < 0.0001) Acidosis was corrected within 6 hours in 69% of mild and 11% of moderate-severe DKA (P < 0.0001) Resolution of CE and ophthalmoplegia after mannitol therapy IM insulin resulted in gradual fall in blood glucose; 2-hour plasma insulin values were “within the range which in adults has been associated with a maximum fall in blood glucose concentration”. No adverse effects Reduction in glucose was slower in low-dose group (P < 0.01) Reduction in ketones, bicarbonate, cortisol, and glucagon was similar in both groups (NS) Hypokalemia (K < 3.4 meq/L) occurred in 3/16 low-dose and 10/16 high-dose patients No difference between 3 groups in time to correction of hyperglycaemia, resolution of DKA, incidence of hypoglycaemia or length of hospital stay (NS) SC insulin was associated with a significantly lower hospitalisation cost (p<0.05) Slower fall in blood glucose with IM regimen Authors concluded that initial laboratory values can help predict patients who may be considered for outpatient management (mild DKA), but the study decesign cannot address this adequately because of retrospective design This is the first report of the use of hypertonic saline in the treatment of cerebral oedema due to DKA Not randomised Abstract only – insufficient details for critical appraisal Losses to follow-up: None reported Blinding: Not feasible Randomisation: Method of randomisation not stated None reported No control group Case series Single case Single case Prospective cohort study IV III-2 II II RCT RCT III-3 Cohort study (two single arms) 262 Management of surgery and fasting in children and adolescents with diabetes Ref No 3 Population 19 peri operative children and adolescents with type I diabetes mellitus Intervention Intravenous insulin infusion (n=9, gp 1) versus subcutaneous insulin (n=10, gp 2) Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Study Kaufman 1996 Outcome Blood glucose levels Results The mean bedside BGL were higher 1 h prior to surgery and during the intraoperative period (p < 0.05) in those receiving sc insulin. In the postoperative period, BGL were higher at multiple times for up to 3 days in those treated with sc compared to IV. To achieve glycaemic control, insulin dosage needs to be increased on the day of surgery and for approximately 2 postoperative days Infusion give better BGL control than sc. Comments On the day of surgery and during postoperative days 1 and 2, patients in group 1 received a greater insulin dosage than group 2 subjects (p < 0.025). In group 1, insulin dosage was increased 23% and 15% over baseline for postoperative days 1 and 2, respectively, then, by day 3, was decreased back toward the baseline. As only one study was found the majority of the suggested protocol in the Surgery and Fasting chapter is based on consensus. 10.1 Design Retrospective case series Level III-3 Technical Reports/Consensus Statements Dunger DB, Sperling MA, Acerini CL, Bohn DJ, Daneman D, Danne TPA, Glaser NS, Hanas R, Hintz RL, Levitsky LL, Savage MO, Tasker RC, Wolfsdorf JI: ESPE / LWPES consensus statement on diabetic ketoacidosis in children and adolescents. Archives of Disease in Childhood 89:188-194, 2003 American Diabetes Association., Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI, Wall BM: Hyperglycemic crises in patients with diabetes mellitus. Diabetes Care 26 Suppl 1:S109-S117, 2003 International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice. Chapter 10: Surgery and Fasting 72 10 Ref No 1 9.2 >10 mmol/L, n=60) Moderate-severe DKA (pH < 7.20, bicarbonate < 10 mmol/L, n=72) USA 263 Technical Reports/Consensus Statements Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Consensus Statements used to formulate the recommendations and principles of clinical practice 11 Collier 1987 52 adult insulintreated patients attending an emergency department with severe hypoglycaemia Population 29 adult patients attending an accident and emergency department in hypoglycaemic coma Outcome Recovery after hypoglycaemia Recovery after hypoglycaemia Intervention Randomized to treatment with either intravenous dextrose (25g); n=14 or intramuscular glucagon (1mg); n=15, administered into the right thigh Intravenous glucagon (1 mg); n=25 was compared with intravenous dextrose (25 g); n=24 Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 10 Consciousness assessed throughout the study by the same observer Losses to follow-up: 1 patient with coexisting Addison’s disease excluded from analysis (received both glucagon and dextrose but onoy regained normal consciousness after receiving hydrocortisone) Intravenous glucagon and dextrose were effective in the treatment of hypoglycaemic coma. There was a difference in the glycaemic profile after intravenous glucagon compared with intravenous dextrose Recovery of a normal level of consciousness after glucagon was slower than after dextrose (6.5 (range 2-16) vs. 4.0 min (range 1-15), respectively; P <0..001). Although IV glucagon is an option, IM glucose is faster Should be balanced against the advantages of ease of administration and a lower incidence of serious adverse effects Two patients in the glucagontreated group, who failed to show satisfactory recovery after 15 min, required additional treatment with intravenous dextrose. Randomisation: Method not stated Small numbers and results and analysis poorly reported Adult study IM glucagon is valuable in severe hypoglycaemia outside hospital. The slightly slower and less predictable recovery may make it a less attractive option than IV dextrose in the emergency department,. Comments Randomisation: Method of randomisation not stated Results Normal conscious level slower after glucagon than dextrose (9.0 (range 5-30) vs 3.0 (range 215) min, p <0.01) Management of severe hypoglycaemia: to treat with intravenous glucose or intramuscular/intravenous glucagon Study Patrick 1990 11.1 RCT Design RCT II Level II No studies were identified. One review article was found, others included advice, personal practice. Therefore the regimen suggested in the Sick Day Management chapter is based on current consensus guidelines. Insulin adjustment during “sick days”/intercurrent illnesses in children and adolescents with Type 1 diabetes Chapter 11: Sick Day Management Ref No 7 8 10.2 264 33 episodes of impending or mild hypoglycaemia in 28 children (ages 6.6 ± 0.7 years) with T1D Blood glucose was 3.44 ± 0.15 mmol/l before and 8.11 ± 0.72 mmol/l 30 min after glucagon. In 14 children, relative hypoglycaemia recurred, requiring retreatment (3.48 ± 0.18 to 6.94 ± 0.72 mmol/l). In four children, a third dose was required. The glucagon was well tolerated. In 28 of the 33 episodes of impending hypoglycaemia, the children remained at home and fully recovered. Five children were taken to their local hospital because of concerns of dehydration or fever, but none for hypoglycaemia. BGL Recurrence of hypoglycaemia Side effects of glucagon Need for admission Only reported study of its kind and needs to be repeated in other centres. Case series Ref No 23 Population Adolescent subgroup of Intervention Intensive insulin therapy (n=95) (by multiple daily Outcome Development of diabetes complications Effects of intensive diabetes management on the incidence of hypoglycaemia. Results Retinopathy: Intensive therapy decreased the Comments Landmark study. See other DCCT references Design RCT Technical Reports/Consensus Statements Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Study DCCT 1994 12.1 If the blood glucose did not increase within 30 min, the initial dosage was doubled and given at that time. The patients’ selfglucose monitoring devices, aqueous glucagon, standard insulin syringes, and frequent phone contact with a physician and/or a diabetes nurse educator were used in this study. Using a standard U100 insulin syringe, children ages 2 years received two "units" (20 g) of glucagon subcutaneously and those ages >2 years received one unit/year of age up to 15 units (150 g). Consensus Statements used to formulate the recommendations and principles of clinical practice. 13 Chapter 12: Hypoglycaemia Ref No 7 16 17 11.2 Haymond 2001 1 patient had already receieved subcutaneous glucagon administered at home by a relative before arriving at the emergency dept. Mini-dose glucagon rescue, using subcutaneous injections, is effective in managing children with type 1 diabetes during episodes of impending hypoglycaemia due to gastroenteritis or poor oral intake of carbohydrate. Level II IV 265 25 1190 children and adolescents aged 1.2-15.8 years with type 1 diabetes, identified from three hospitalbased paediatric diabetes units, four private citybased paediatric practices and 18 regional outreach Cross sectional audit Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Craig 2002 Mean follow up 7.4 years (for adolescents) OR 125 adolescents with no retinopathy and 70 with mild retinopathy Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring (n=114) injections or insulin pump) with frequent BG monitoring DCCT trial. Age 13-17 years HbA(1c) level HbA1c Episodes of hypoglycaemia At least one episode of severe hypoglycaemia in the previous three months was reported in 6.7%, and the rate of severe hypoglycaemia was 36/100 patient-years. Significant predictors of HbA1c level in multiple regression model were: duration (b = 0.05; 95% CI, 0.02-0.07) and insulin dose/kg (b = 0.46; 95% CI, 0.27-0.66). HbA1c (%+/-SE): 8.06+/-0.13 vs 9.76+/-0.12 (reduction of 1.7% +/-SE 0.18) Severe hypoglycaemia: RR 2.96 (95% CI 1.90-4.62) Hypoglycaemia resulting in coma or seizure: RR 2.93 (95%CI 1.75-4.90) Overweight: RR 2.11 95% CI 1.31-3.40) Diabetic ketoacidosis: RR 0.2 (95% CI 0..32-1.23) Nephropathy: Intensive therapy group had 10% reduction in microalbuminaria (95% CI –70% to 52%; p=0.745 in those with no retinopathy; and by 55% (95% CI 3% to 9%); p=0.042 in those with mild retinopathy risk of retinopathy by 53% (CI 1-78%, p=0.048) (in those with no retinopathy) and 70% (CI 25-88%, p=0.010) (in those with mild retinopathy) Fewer than 25% achieve the recommended HbA1c <7.5% Independent data monitoring committee determined that study results warranted terminating trial after mean follo-up of 6.5 years (overall) In multiple regression model number of injection per day was not a predictor of HbA1c, but multiple injections (>3 per day) was a predictor of hypoglycaemia. Losses to follow-up: No patients voluntarily withdrew; 2 patients died; 2 patients assigned to inactive status for some time >95% of scheduled examinations were completed; overall time spent in assigned treatment was 95%; Blinding: Standard therapy group blinded to HbA1c results; intensive therapy group could nto be blinded to HbA1c as they were using it as a management tool; Research group blnded to the effects of the two treatment regimens; Investigators and patients unaware of outcome data unless predetermined ‘alert’ criteria (e.g. development of retinopathy) were reached; Retinopathy assessed by operators who were unaware of treatment group assignment Multicentre, populationbased, crosssectional study IV 266 27 29 Davis 1998 DCCT 709 patients were studied yielding 2027 patient years of data (mean (SD) age: 12.3 (4.4); range 0-18 years, duration IDDM: 4.9 (3.8) years). 1441 patients with Rates of severe (coma, convulsion) and moderate (requiring assistance for treatment) hypoglycaemia were studied prospectively over a four year period Case attainment based on Diabetes Register was 67% of children in NSW and ACT. A large population based sample of T1D children and adolescents. Audit of 1,190 children with T1D. Intensive insulin therapy (by Compared urban with rural children. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 26 Handelsma n 2001 clinics in NSW and the ACT from 1 September to 31 December, 1999 Development of diabetes Severe hypoglycaemia Details of hypoglycaemia were recorded at clinic visits every three months when glycated haemoglobin (HbA1c) was also measured. HbA1c Severe hypoglycaemia Retinopathy: intensive therapy This increase was particularly marked in younger children (< 6 years) in whom severe hypoglycaemia increased from 14.9 to 42.1 episodes/100 patient years in 1995. In parallel with this there was an increase in the rate of hypoglycaemia, especially in the fourth year of the study, when severe hypoglycaemia increased from 4.8 to 15.6 episodes/100 patient years. Over the four years mean (SD) clinic HbA1c steadily fell from 10.2 (1.6)% in 1992 to 8.8 (1.5)% in 1995(p<0.01). the prevalence of severe hypoglycaemia (coma or convulsion) was 36 episodes per 100 patient years Incidence of severe hypoglycaemia was 7.8 and moderate was 15.4 episodes/100 patient years. Median HbA1c 8.2% (IQ range 7.6-9.1%) in both urban and rural group. Median HbA1c 8.2% (IQ range 7.6-9.1%) in both urban and rural group. Significant predictors of hypoglycaemia in a Poisson regression model were younger age (P = 0.03), male sex (P = 0.04), longer diabetes duration (P = 0.02), and > 3 daily insulin injections (P = 0.02), but not HbA(1c) level. Landmark study. Australian study (Perth) Attempts to achieve improved metabolic control must be accompanied by efforts to minimise the effects of significant hypoglycaemia, particularly in the younger age group. Fewer than 25% achieve the recommended HbA1c <7.5% Confirmed homogeneity of metabolic control in NSW and ACT regardless of location, socioeconomic status or system of care. RCT All diabetic children attending the Princess Margaret Hospital over 4 years were included. Case ascertainment for Western Australia >99%. Thus this is a population based prospective observational study Multicentre, populationbased, crosssectional study II IV IV 267 T1D aged 13-39 years. 726 with no retinopathy at baseline (primary intervention group) and 715 with mild retinopathy (secondary intervention group) Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring (n=704; 352 primary and 352 secondary prevention) OR multiple daily injections or insulin pump) with frequent BG monitoring (n=704; 348 primary and 366 secondary prevention) Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 1993 complications Adverse events: Incidence of hypoglycaemia increase 2-3 fold on intensive therapy (19 versus 62 hypoglycaemic episodes per 100 patient years, p<0.001). Nephropathy: Intensive therapy reduced risk of microalbuminuria by 39% (95% CI 21-52) and albuminaria by 54% (95% CI 19-74); Intensive therapy reduced the mean adjusted risk of microalbuminuria by 34% (p=0.04) in in patients with no retinopathy at baseline and by 43% in those with mild retinopathy at baseline (p=0.001) Neuropathy: At 5 years, intensive therapy reduced incidence of clinical neuropathy by 69% ; 95% CI 24-87 (3% in intensively treated group vs 10% in conventionally treated group) p=0.006 in patients with no retinopathy at baseline; and by 57% (95% CI 29-73); p0.002 in those with mild retinopathy at baseline; combined 60% (95% CI 38-74), p0.002 reduced the risk of retinopathy by 76% (95% CI 62-85) in patients with no retinopathy at baseline (p0.002), and by 54% (95% CI 39-66) in those with mild retinopathy at baseline (p<0.001); combined 63% (95% CI 52-71), p0.002. Compliance: Average time spent receiving assigned treatment = 97%, including 95 women assigned to conventional therapy who received intensive therapy during pregnancy or while planning a pregnancy Losses to follow-up: 99% of patients completed study; >95% of all scheduled examinations completed; 11 patients died; 32 patients assigned to inactive status for some time during trial due to unavailability or investigator’s decision that continuation of treatment would be hazardous Research group blinded to effects of the two treatment regimens Blinding: Standard therapy group blinded to HbA1c results; intensive therapy group could not be blinded to Hba1c because they were using it as a management tool Rigorous multicentre study supervised by NIH, USA See other DCCT references Follow up period of 6.5 years (trial terminated by independent monitoring committee) 268 52 adult insulintreated patients attending an emergency department with severe hypoglycaemia Population 29 adult patients attending an accident and emergency department in hypoglycaemic coma Outcome Recovery after hypoglycaemia Recovery after hypoglycaemia Intervention Randomized to treatment with either intravenous dextrose (25g); n=14 or intramuscular glucagon (1mg); n=15, administered into the right thigh Intravenous glucagon (1 mg); n=25 was compared with intravenous dextrose (25 g); n=24 Although IV glucagon is an option, IM glucose is faster Recovery of a normal level of consciousness after glucagon was slower than after dextrose (6.5 (range 2-16) vs. 4.0 min (range 1-15), respectively; P <0..001). There was a difference in the glycaemic profile after intravenous glucagon compared with intravenous dextrose Should be balanced against the advantages of ease of administration and a lower incidence of serious adverse effects Intravenous glucagon and dextrose were effective in the treatment of hypoglycaemic coma. The slightly slower and less predictable recovery may make it a less attractive option than IV dextrose in the emergency department,. IM glucagon is valuable in severe hypoglycaemia outside hospital. Results Normal conscious level slower after glucagon than dextrose (9.0 (range 5-30) vs 3.0 (range 2-15) min, p <0.01) Ref No 6 Population Follow up study from Northam 98 None Intervention Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Study Northam 2001 Outcome WISC-III and subtests of WISC-III used for IQ, Results Six years after onset of diabetes, children with T1D Effects of hypoglycaemia on cognitive function in children and adolescents with type 1 diabetes 50 Collier 1987 12.3 Ref No 49 Comments Subjects enrolled from Royal Children’s Hospital, Losses to follow-up: 1 patient with coexisting Addison’s disease excluded from analysis (received both glucagon and dextrose but onoy regained normal consciousness after receiving hydrocortisone) 1 patient had already receieved subcutaneous glucagon administered at home by a relative before arriving at the emergency dept. Consciousness assessed throughout the study by the same observer Randomisation: Method not stated Two patients in the glucagontreated group, who failed to show satisfactory recovery after 15 min, required additional treatment with intravenous dextrose. Small numbers and results and analysis poorly reported Adult study Comments Randomisation: Method of randomisation not stated Management of severe hypoglycaemia: to treat with intravenous glucose or intramuscular/intravenous glucagon? Study Patrick 1990 12.2 Design Comparative cohort study RCT Design RCT Level III-2 II Level II 269 8 Rovet 1997 100 controls (50 boys, 50 girls) mean age 13.1 +/2.5 years. 103 T1D (50 boys, 53 girls) Mean age 13.5 yrs +/-2.3 years) 21 children with T1D (age 5.511.8yrs) and 10 healthy controls N/A Normal controls WISC-R and WAIS-R IQ Attentional functioning NEPSY (dev. Neuropsych assessment) T1D and one episode of severe hypo (n=11) T1D with no hypo (n=10). WISC-R attention, processing speed. Memeory tested with RAVLT, Executive functions with COWAT Divided into 3 groups Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 7 Hannonen 2003 study 90 patients (aged 6-17 years, mean 12.1 +/- 2.9) who had been previously assessed soon after Dx and 2 years later were re-evaluated 6 years after onset of diabetes. 84 controls (12.1+/-2.8 years, p=NS). Those with seizure history had lower verbal IQ than controls and greater difficulty with IQ poorer performance in early onset (p=0.01) Memory – Digit span both T1D with & without hypoglycaemia scored lower compared with controls (p<0.01) T1D attention scores lower in several but not all aspects of attention Phonological processes in T1D with hypos scored lower than controls (p<0.05) Severe hypo assoc. with lower verbal and full-scale intelligence quotient scores. Children with history of severe hypoglycaemia had more neuropsychological impairments (7 of 11) than without hypoglycaemia (3 of 10). Attention – T1D without hypos had test scores significantly lower than controls (p<0.05) Attention, processing speed, & executive skills were esp. affected when onset was before 4 yrs old. performed more poorly than controls on verbal IQ (F=8.07, p<0.01), ful scale IQ (F=5.33.P<0.05) attention (F=2.63, P<0.05), processing speed (F=4.81, P<0.01), longterm memory (F=3.58,P<0.01), and executive skills (F=4.57, P<0.05). Patients and controls recruited from Hosp for Sick Children, Toronto, Canada. Comparison between controls and diabetes subjects were by t tests and ANOVA’s. Finnish Study. Clinic patients with diabetes-otherwise well. No special selection criteria. Retrospective history of hypoglycaemia Melbourne. Analysis of variance was used to examine group differences, effects of age of onset. Comparative cohort study Comparative cohort study III-2 III-2 270 10 39 40 Hershey 1999 Holmes 1985 Sansbury 1997 28 T1D children 41 children with T1D 16 Children With Type 1 Diabetes Mean Age 12.1 +/-2.6 Years (Range 9.4-17.7 Years) Mean age at diagnosis was 4.5 years+/-3.0years. mean HbA1c 8.4% (range 7.59.4) Nondiabetic children (n = 16) and 25 children with type 1 diabetes HbA1c Duration Age at onset Divided in 4 groups depending upon age of onset and length of duration Randomised at diagnosis to either intensive (IT) (n = 13) or conventional (CT) (n = 12) diabetes therapy Follow up at 1, 3, 7 years 9 had hypoglycaemic seizure Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 9 Rovet 1999 Behaviour checklist Matching figures Verbal subtests WISC-R WISC-R Episodes of severe hypoglycaemia were prospectively ascertained. All children were tested on memory tasks that have been closely linked to medial temporal functioning and on reaction time measures Perceptual, fine motor, visuomotor, visual memory and attention Verbal IQ Poor metabolic control assoc with lower vocab subtest scores. Inc duration assoc with lower matching figures score. Reading and memory impairment in early onset groups Increased age assoc with decreased IQ score Larger studies needed, but extreme caution in imposing overly strict standards for glucose control in young patients with type 1 diabetes would be indicated because of the increased risk of hypoglycaemia associated with IT regimens. IQ scores lower in early onset and longer duration There were no effects on fullscale IQ, performance IQ, supplementary spatial or achievement tests. IT had a threefold higher rate of severe hypoglycaemia than the CT group; and performed less accurately on a spatial memory task, performed more slowly (p=0.01), but not less accurately, on a pattern recognition task than did the CT group or control subjects. Hypo seizure patients scored lower (p<0.01) some aspects of attention. At 7 years those with hypo seizures more likely to have verbal IQ decline (67% vs 14%, p<0.05) Comparison with nondiabetic participants was not randomised Randomisation: Method of randomisation not stated The study’s strengths were its extended time frame and detailed testing 7 years after diagnosis. Limiting factors include small sample size, lack of longitudinally assessed controls, and possible bias within groups and recall inaccuracies of diabetes data management. Cohort study Cohort study RCT Prospective and retrospective data collection IV IV II (for compariso n of IT and CT); III-3 for compa rison of IT or CT with nondia betic contro ls IV 271 27 Tubiana- 165 French Population 88 youths, 8 to 13 years old at onset of IDDM 83 were white (94%), 5 were black (6%) Intervention None A standardized scale (FACES III) was Psychiatric diagnoses were derived independently of HbA1 values Levels of HbA1 were also assessed repeatedly. Outcome Evaluated repeatedly during a 9-year follow-up period, on average, using a standardized psychiatric protocol. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 16 and 41 During observation period 44 patients (50%) had one or more episode of psychiatric disorder and 35 (40%) received the diagnosis of non-compliance with medical treatment. More diabetic families than comparison families fell into According to the final multivariate model of repeatedly assessed HbA1, non-compliance with medical treatment (irrespective of duration) and the interaction between nondepressive psychiatric disorder and IDDM duration contributed to worse metabolic control. Interaction terms between IDDM duration (or age) and psychiatric variables were significantly related to metabolic control. In univariate longitudinal analyses, the psychiatric diagnosis of non-compliance with medical treatment was significantly related to HbA1 level. There was a trend of an association between any major psychiatric disorder, as well as non-depressive disorder, and HbA1. Social competence, self-esteem, and aspects of family functioning at IDDM onset and initial psychiatric status did not predict non-compliance. However, noncompliance was associated with having major psychiatric disorder later in the course of IDDM Non-compliance tended to emerge in middle adolescence and was found to be protracted. Results The cumulative risk for non adherence over the 9 years was 0.4 Comments Sample derived from patients sequentially admitted to Pittsburgh 1978-1985. Approx 75% of suitable families were recruited. Those who declined did not differ significantly. The incidence and risk factors for non-adherence with treatment regimens in children and adolescents with type 1 diabetes. Study Kovacs 1992 and 1996 13.1 Cross-sectional Design Longitudinal Observational study. IV Level IV Technical Reports/Consensus Statements International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Consensus Statements used to formulate the recommendations and principles of clinical practice. Chapter 13: Psychosocial Aspects 56 57 Ref No 37 12.4 272 41 children with T1D from paediatric diabetes clinic. 28 30 31 32 33 34 Frank 1996 Ott 2000 Hentinen 1992 Burroughs 1993 Kyngas 2000 Littlefield Diet and monitoring are problem areas Diet Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Participants completed the Rosenberg Adherence was lowest for diet and home blood glucose monitoring. Adolescents reporting lower adherence tended to report mean age 15yrs 193 Compliance with insulin treatment 81%. Compliance Only 19% reported complete compliance with all aspects of diabetes management. Dietary compliance is best predictor of metabolic control Co-operation Predictors of compliance Monitoring Showed best adherence Self efficacy was the mediating variable for mastery experiency Family adaptation significantly and positively correlated to parent’s education level. Compliant patients more likely to have tertiary education, fewer hospitalisations the categories of disengaged with low levels of cohesion, and rigid with low levels of adaptability. Scores of cohesion and adaptability were significantly and positively correlated with both children's and parents' adherence scores, but not with HbA1c levels. Children from rigidly disengaged families had a more hypoglycaemias and 6 times more ketoacidosis than the other diabetic children. Parental responsibility Insulin treatment Personal responsibility Adherence Self-efficacy Compared compliant with non compliant patients used to determine if family cohesion and adaptability (i) differed in diabetic children's families, as compared to other families; (ii) were related to an adherence measure; or (iii) were related to metabolic control. 21 adolescents aged 13-18 yrs 289 adolescents with T1D. age 13-17 yrs 47 children, Finland Mean age 21.7 +/-0.55 143 adolescents with T1D Canada diabetic children aged 7-13 y and their parents.. Rufi 1998 Treatment Names selected from Finnish Insurance Register IV IV Cross sectional Questionnaire IV IV IV IV Questionnaire Cross sectional survey Questionnaire Retrospective medical record audit plus telephone interview multicentre study 273 37 and 38 39 Johnston 1992 and 1990 Morris 1997 89 patients, who attended a teaching Mean age 11.9yrs DARTS/ MEMO Collaboration . (Diabetes Audit and Research in Tayside Scotland. Medicines Monitoring Unit) Mean age 12.8 yrs 140 children with T1D and their mothers. Mean duration of T1D = 5.5 years. Joslin Clinic, Boston consecutive patients (aged 13-18 yr) with insulindependent diabetes mellitus recruited during their regular quarterly visit to a diabetes clinic in a large urban hospital. 57 children The prescribed insulin dose and volume of insulin prescriptions supplied were used to calculate days of maximum possible insulin coverage per annum, expressed as the adherence index. Interviews 3 times over 2 week period Associations between glycaemic control (HbA1c), episodes of diabetic ketoacidosis, and all hospital admissions for acute complications and the adherence index were modelled. Effects of age and duration on metabolic control and adherence. Psychological predictors of compliance Self-Esteem Scale, the Children's Depression Inventory, an assessment of the frequency of binging in the past 3 mo, and parallel forms of an adherence scale and a self-efficacy scale that were developed for use in this study. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 36 Jacobson 1987 1992 Direct evidence of poor compliance with insulin therapy in young patients with IDDM There was a significant inverse association between HbA1c and the adherence index (R2 = 0.39; p < 0.001). Study demonstrated direct evidence of poor compliance Adherence index was inversely related to hospital admissions for diabetic ketoacidosis (p < 0.001) and all hospital admissions related to acute diabetes complications (p = 0.008). All patients <30years attending clinic were studied. Assesses at baseline and 1.6 years later 18 month follow up adherence in adolescents with insulindependent diabetes mellitus is associated with behavioural and psychological variables Insulin was prescribed at 48IU/day and mean insulin collected from pharmacies was 58IU/day. However, 25 (28%) of the 89 patients obtained less insulin than their prescribed dose (mean deficit 115 (68; range 9-246] insulin days/annum) Older patients were less adherent and had worse HbA1c Patients with higher self reported self esteem, and parent reported confidence, adjustment and social functioning were more adherent Adolescents (13-15yrs) less compliant than children (912yrs). There was no sex difference in reported binging, but, as expected, adolescent females reported less adherence overall (F[7,184] = 2.5, P = 0.018). Together, the psychological variables accounted for 50% of the variance in adherence. lower self-esteem (r = 0.45, P less than 0.001) and selfefficacy (r = 0.57, P less than 0.001), more depressive symptoms (r = -0.50, P less than 0.001), more binging (r = -0.36, P less than 0.001), and had higher HbA1c (r = 0.24, P less than 0.001) than those with higher adherence scores. Comparative study Longitudinal Longitudinal III-3 IV IV 274 45 Goldston 1997 91 adolescents attending diabetes outpatient clinic appointments IDDM self-care autonomy was assessed using two wellvalidated measures. Three measures of psychological maturity (cognitive function, socialcognitive development, and academic achievement) were also collected for each child. Semistructured and structured interview instruments and self-report questionnaires were used to determine history of suicidal thoughts and behaviour, serious noncompliance with the Between-group differences in treatment adherence, diabetes knowledge, glycaemic control, and hospitalization rates were explored. Based on these scores, participants were categorized as exhibiting constrained, appropriate , or excessive self-care autonomy. Composite indexes of self-care autonomy / psychological maturity were formed, and the ratio of the selfcare autonomy index to the psychological maturity index quantified each child's deviation from developmentally appropriate IDDM self-care autonomy. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 43 Wysocki 1996 hospital paediatric or young-adult diabetes clinic in 1993 and 1994. (mean age 16 (SD 7) years, diabetes duration 8 (4) years, and glycosylated haemoglobin (HbA1c) 8.4 (1.9)%) 100 T1D youths Diagnosable psychiatric disorder and not living in a twoparent home were related to non-compliance with medical treatment. Duration of IDDM and psychiatric diagnosis were related to both suicidal ideation within the previous year and lifetime suicidal ideation. The rate of suicidal ideation among the diabetic adolescents was higher than expected, but the rate of suicide attempts was comparable with that reported for the general population. Suicidal thoughts were strongly associated with serious non-compliance with the medical regimen. Excessive self-care autonomy increased with age and was less common among intact two-parent families but was unrelated to other demographic factors. Controlling for age revealed that the excessive self-care autonomy group demonstrated less favourable treatment adherence, diabetes knowledge, hospitalization rates, and, marginally, glycaemic control. with insulin therapy. Diagnosable psychiatric disorder and not living in a two-parent home were related to noncompliance with medical treatment. Scottish study Semistructured and structured interview instruments and self-report questionnaires cross-sectional study IV IV 275 47 48 Peveler 1992 Rydall 1997 mean age 15+/-2 years 91 young women with IDDM Studied at base line and 5 yrs later Prevalence and persistence of disordered eating behaviour (on the basis of self-reported eating and weight-loss practices, including the intentional omission or underdosing of insulin to control weight) and the Of the 65 women with normal eating behaviour at base Eating disorder features and insulin misuse for shape and weight control were not found in IDDM or non-diabetic boys, and these two groups did not differ in their body weight. At base line, 26 of 91 young women (29 percent) had highly or moderately disordered eating behaviour, which persisted in 16 (18 percent) and improved in 10 (11 percent). Fifteen percent had omitted or reduced their dose of insulin to influence their shape and weight. Nine percent of the IDDM girls met diagnostic criteria for an operational version of 'Eating disorder not otherwise specified.' However, clinical eating disorders were no more common among adolescent girls with IDDM than among nondiabetic control subjects. Mean HbA1c in eating disorder group was significantly higher than those without eating disorders (10% compared with 8.9%, p<0.02)) Adolescent girls with IDDM were heavier than nondiabetic female control subjects and were dieting more intensively to control their shape and weight. Mean duration of T1D 6.4years A crosssectional survey of eating habits and attitudes conducted in 76 adolescents with IDDM, and age- and sex-matched non-diabetic control subjects Assessed by standardized research interview adapted for use with patients with diabetes (EDE). Glycaemic control was assessed by GHb assay Those with eating disorders were less likely to follow food plan or perform blood glucose monitoring. Mean age 15.1 years Incidence of bulimia nervosa 12% Incidence of anorexia nervosa 1% 12% reported intentional insulin under treatment as a method of weight control Mean age of eating disorder patients 16.2 years. Questionnaire HbA1c level Clinical information from hospital notes Toronto, Canada 103 Female T1D patients attending diabetes clinic. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 46 Rodin 1991 medical regimen, current psychiatric disorder, hopelessness, and selfefficacy expectations. N/A High incidence of intentional insulin omission to control High incidence of insulin omission in girls. Case series cross-sectional survey Survey questionnaire and medical note review IV IV IV 276 association of such eating disorders with metabolic control, diabetic retinopathy, and urinary albumin excretion. Disordered eating at base line was associated with retinopathy four years later (P=0.004), when 86 percent of the young women with highly disordered eating behaviour, 43 percent of those with moderately disordered eating behaviour, and 24 percent of those with nondisordered eating behaviour had retinopathy. At base line, the mean (+/-SD) haemoglobin A(1c) value was higher in the group with highly disordered eating behaviour (11.1+/-1.2 percent) than in the groups whose eating behaviour was moderately disordered (8.9+/-1.7 percent) or nondisordered (8.7+/-1.6 percent, P<0.001). Omission or underdosing of insulin lose weight was reported by 12 of 88 young women (14 percent) at base line and 30 (34 percent) at follow-up (P=0.003). line (71 percent), 14 (15 percent) had disordered eating at follow-up. weight Literature reviewed until June 1999 Compared behavioural intervention (education or skills training) with control group. Emotional/psychological interventions (18%) Dietary interventions (19%) Metabolic measures Skills training (39% studies) Age range 9-21 years. Most studies from USA (67.7%) Outcome Psychosocial Self or parent reports of changes in psychological or interpersonal constructs (e.g. self-efficacy; diabetes-specific stress) Intervention Question asked “Do educational and psychosocial interventions for adolescents with type 1 diabetes have beneficial effects on biological and psychosocial outcomes?” Population Systematic review of 62 studies from Health Technology Assessment Program UK. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 52 These studies demonstrate the variety of intervention and outcomes that have been studied. All the pre-, post Mean of 12 pooled effect sizes was 0.33 (95% CI 0.04 – 0.70) for glycated haemoglobin with outliers; significant heterogeneity (0.08 without 2 outliers) Mean of 12 pooled effect sizes for psychosocial outcomes was 0.37 (95% CI 0.19-0.55 Results Small to medium effect on HbA1c and psychosocial outcome of educational and psychosocial intervention. Identifies need for future intervention trials The meta-analysis of the RCT’S should be treated with caution due to the variation in studies and intervention 62 studies in total. 25 RCTs reviewed (16 with sufficient detail to enable effect sizes to be calculated). 37 other study designs eg non RCT’s without control groups, pre and post intervention studies Comments Rigorous search strategy with appropriate inclusion criteria. The effect of psychosocial interventions on metabolic and psychological outcomes in children and adolescents with type 1 diabetes. Study Hampson 2001 13.2 and the duration of diabetes was 7+/-4 years. Design Systematic review Level I 277 55 Laffel 2003 Haemoglobin A1c was measured at each visit. Patients in both study groups were seen at 3- to 4-month intervals and were followed prospectively for 1 year. Of 128 eligible families attending Joslin clinic (USA) 105 agreed to participate. Patients of families not particiapating were slightly older but otherwise not Both groups had similar frequencies of blood glucose monitoring (BGM) and insulin dosing. Measures of family involvement in diabetes tasks, DFC, and quality of life were performed at baseline and after 1 year. Family relationships, psychological adjustment to diabetes, treatment adherence and diabetic control were assessed at baseline, after 6 and 12 months treatment Randomised to a familyfocused teamwork (TW) intervention or to standard multidisciplinary diabetes care (SC). Interested families who met the inclusion criteria (n=178) completed two screening questionnaires; of 132 families exceeding the cutoff score, 119 (90%) enrolled in the study Families paid $100 to promote adherence and for completing questionnaire. Randomized 119 families of adolescents with diabetes to 3 months' treatment with either BFST, an education and support Group (ES), or current therapy (CT). 105 children and adolescents, 8 to 17 years of age, with T1DM for < or =6 years. Aged 14.3 +/-1.3 yrs, diabetes duration 5.2 +/-3.7 years. 51 males, 68 females. RCT Of Behavioural Family Systems Therapy (BFST) For Families Of Adolescents With Diabetes Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 53 Wysocki 2001 In multivariate analysis, TW intervention and the daily frequency of BGM significantly predicted HbA1c (R (2) = 0.17, P =.05). Families exposed to the TW intervention maintained or increased family involvement significantly more than families exposed to SC (P =.05). BFST yielded some improvement in parentadolescent relationship. Factors mediating the effectiveness of BFST need to be clarified. After 1 year, A1c was 8.2% +/1.1% in TW compared with 8.7% +/- 1.5% in SC (P <.05). There were no effects on treatment adherence. No significant differences on HbA1c between groups were noted. Compared with CT and ES, BFST yielded lasting improvement in parentadolescent relations and reduced diabetes-specific conflict (p<0.05). At 12 months BFST effects on psychological adjustment to diabetes differed from CT group (p,<0.05) but not from the ES group. Other studies published after the Hampson 2001 Health Technology Appraisal Systematic Review design studies reported some benefit - however because of the low level of study design and small numbers these benefits should be treated as provisional until more rigorous results are available After enrolment, two further patients were excluded (I because of severe eating disorder; 1 because of Losses to follow-up: Three families (2.8%) discontinued study participation because of insurance-related transfer of care; these were excluded from analyses All scheduled intervention sessions were completed by 87% of BFST families and 91% of ES families Randomisation: Method of randomisation not stated Losses to follow-up/response rates: Post-treatment evaluations were completed by 87% of BFST families and 12-month follow-up by 108 families (91%) Randomisation: Method of randomisation not stated. Despite careful randomisation, the three groups differed at baseline along many meaningful dimensions. The BFST group included significantly fewer intact families and more single-parent families. RCT RCT II II 278 105 patients who met selection criteria attending Yale Diabetes clinic were invited to participate and 77 agreed. Those who refused were not significantly different in age, gender, ethnicity. Seventy-seven patients (43 females, 95% white) 12 to 20 years (mean = 14.2 +/- 1.9; duration, 8.7 +/3.9) 77 patients electing to initiate intensive diabetes management (IDM) were randomly assigned to one of two groups: with or without coping skills training (CST), which consists of 6 small group sessions and monthly follow-up to help youth cope with their lives in the context of diabetes management; skills included social problem solving, cognitive behaviour modification, and conflict resolution. Clinical data (glycosylated haemoglobin level, height, weight, adverse effects) were collected monthly. Data were collected before the intervention and at 3, 6, and 12 months after the intervention by using the Self-Efficacy for Diabetes Scale, Children's Depression Inventory, Issues in Coping with IDDM, and the Diabetes Quality of Life: Youth scales. Losses to follow-up/attendance: Attendance at sessions was 98% All CST groups were audiotaped and reviewed to ensure coping skills were taught consistently across the groups Conclusion: The addition of behavioural intervention to IDM in adolescence results in improved metabolic control and quality of life over 1 year Technical Reports/Consensus Statements Blinding: Diabetes care providers and research assistants collecting data were blinded to study group of participants The CST and IDM groups were comparable at baseline. Randomisation: Method of randomisation not stated Final sample incuded 100 famiies (50 in each group) diagnosis of a learning disorder) In males, CST did not affect adverse outcomes of IDM hypoglycaemia, diabetic ketoacidosis, and weight gain, but CST decreased the incidence of weight gain (P =.05) and hypoglycaemia in females (P =.03). Successful family involvement may assist in the preservation of health and the prevention of long-term diabetes complications for youth with diabetes. CST subjects had lower glycosylated haemoglobin (P =.001) and better diabetes (P =.002) and medical (P =. 04) self-efficacy, and less impact of diabetes on their quality of life (P =.005) than youth receiving IDM alone after 1 year. Ambulatory TW intervention prevented the expected deterioration in glycaemic control seen with SC in youths with T1DM of < or =6 years' duration. Despite increased family involvement, the TW group reported no increase in Diabetes Related Family Conflict or decrease in quality of life. Consensus Statements used to formulate the recommendations and principles of clinical practice. 59 Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 13.3 Grey 2000 At entry, HbA1c was 8.4% +/1.3% in TW and 8.3% +/- 1.0% in SC. Patients (n = 100) completed followup, (50 in TW and 50 in SC). significantly different. RCT II 279 Mean follow up 7.4 years (for adolescents) OR 125 adolescents with no retinopathy and 70 with mild retinopathy Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring (n=114) Intervention Intensive insulin therapy (n=95) (by multiple daily injections or insulin pump) with frequent BG monitoring Population Adolescent subgroup of DCCT trial. Age 13-17 years Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 2 Outcome Development of diabetes complications Nephropathy: Intensive therapy group had 10% reduction in microalbuminaria (95% CI –70% to 52%; p=0.745 in those with no retinopathy; and by 55% (95% CI 3% to 9%); p=0.042 in those with mild retinopathy Results Retinopathy: Intensive therapy decreased the risk of retinopathy by 53% (CI 1-78%, p=0.048) (in those with no retinopathy) and 70% (CI 25-88%, p=0.010) (in those with mild retinopathy) Effect of intensive diabetes management on microvascular and macrovascular complications in adolescents. Study DCCT 1994 14.1 Independent data monitoring committee determined that study results warranted terminating trial after mean Losses to follow-up: No patients voluntarily withdrew; 2 patients died; 2 patients assigned to inactive status for some time >95% of scheduled examinations were completed; overall time spent in assigned treatment was 95%; Blinding: Standard therapy group blinded to HbA1c results; intensive therapy group could nto be blinded to HbA1c as they were using it as a management tool; Research group blnded to the effects of the two treatment regimens; Investigators and patients unaware of outcome data unless predetermined ‘alert’ criteria (e.g. development of retinopathy) were reached; Retinopathy assessed by operators who were unaware of treatment group assignment Comments Landmark study. See other DCCT references Design RCT International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 National Institute for Clinical Excellence. Type 1 Diabetes (Childhood): Diagnosis and Management of Type 1 Diabetes in Children and Young People (DRAFT). 2004. Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Chapter 14: Diabetes Complications 35 60 61 1 Level II 280 63 DCCT 1993 1441 patients with T1D aged 13-39 years. 726 with no retinopathy at baseline (primary intervention group) and 715 with mild Patients with recognised risk factors (other than diabetes) were excluded from the trial 1441 patients with T1D 726 with no retinopathy at baseline and 715 with mild retinopathy OR Intensive insulin therapy (by multiple daily injections or insulin pump) with frequent BG monitoring (n=704; 348 primary and 366 secondary prevention) Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring OR Intensive insulin therapy (by multiple daily injections or insulin pump) with frequent BG monitoring Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 20 DCCT 1995 Development of diabetes complications Development of diabetes macrovascular complications Retinopathy: intensive therapy reduced the risk of retinopathy by 76% (95% CI 62-85) in patients with no retinopathy at baseline (p0.002), and by 54% (95% CI 39-66) in those with mild retinopathy at baseline (p<0.001); combined 63% (95% CI 52-71), p0.002. The reduction in some, but not all, cardiovascular risk factors suggests a potential beneficial effect of intensive therapy on macrovascular disease in insulin-dependent diabetes mellitus Mean total serum cholesterol, LDL, cholesterol, and triglycerides were significantly reduced in intensive-tx gp (p < or = 0.01), as was the development of LDL cholesterol levels > 160 mg/dl. There were no differences in the cumulative incidence of hypertension. Differences were not statistically sig (p = 0.08). No. of major macrovascular events was twice as high in conventional tx gp (40 events) as in intensive-treatment group (23 events). Adherence: 49 patients deviated from intensive to conventional therapy for some period of the study; 104 deviated form conventional to intensive therapy (95 of these were pregnant women); Overall intensively-treated patients spent >98% of their time on the assigned treatment, and conventionally-treated patients spent 97% of their tiome on that therapy Landmark study. Rigorous multicentre study supervised by NIH, USA See other DCCT references Follow up period of 6.5 years (trial terminated by independent monitoring committee) Losses to follow-up: 11 patients died during the study and 8 dropped out. At the end of the study all 8 were determined to be alive and healthy, with no history of major macrovascular events; >95% of scheduled outcome date were obtained Analysis: All analyses carried out on an intention-to-treat basis Blinding: Morbidity and Mortlaity Committee classified deaths and cardiovascular events without knowledge of treatment assignment, according to preestablished criteria follo-up of 6.5 years (overall) See other DCCT references RCT RCT II II 281 95 Of 1441 patients who participated in the DCCT, 1229 patients participated in EDIC (Epidemiology of Diabetes Interventions and Complications) N = 611 Four year follow up from close of DCCT (DCCT = Intensive insulin therapy with frequent BG monitoring OR Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring) Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring (n=704; 352 primary and 352 secondary prevention) Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Nathan 2003 retinopathy (secondary intervention group) B-mode ultrasound of the internal and common carotid arteries to measure intimal thickness (in 19941996 and 1998-2000) Adverse events: Incidence of hypoglycaemia increase 2-3 fold on intensive therapy (19 versus 62 hypoglycaemic episodes per 100 patient years, p<0.001). Mean progression of the intima-media thickness sig. less in group that received intensive therapy during DCCT than in group that received conventional therapy (progression of the intimamedia thickness of the common carotid artery, 0.032 vs. 0.046 mm; P=0.01; and progression of the combined intima-media Nephropathy: Intensive therapy reduced risk of microalbuminuria by 39% (95% CI 21-52) and albuminaria by 54% (95% CI 19-74); Intensive therapy reduced the mean adjusted risk of microalbuminuria by 34% (p=0.04) in in patients with no retinopathy at baseline and by 43% in those with mild retinopathy at baseline (p=0.001) Neuropathy: At 5 years, intensive therapy reduced incidence of clinical neuropathy by 69% ; 95% CI 24-87 (3% in intensively treated group vs 10% in conventionally treated group) p=0.006 in patients with no retinopathy at baseline; and by 57% (95% CI 29-73); p0.002 in those with mild retinopathy at baseline; combined 60% (95% CI 38-74), p0.002 Blinding: Assessment of intima-media thickness carried out by a single operator who was blinded to patientt’s treatment assignments As for DCCT Compliance: Average time spent receiving assigned treatment = 97%, including 95 women assigned to conventional therapy who received intensive therapy during pregnancy or while planning a pregnancy Losses to follow-up: 99% of patients completed study; >95% of all scheduled examinations completed; 11 patients died; 32 patients assigned to inactive status for some time during trial due to unavailability or investigator’s decision that continuation of treatment would be hazardous Research group blinded to effects of the two treatment regimens Blinding: Standard therapy group blinded to HbA1c results; intensive therapy group could not be blinded to Hba1c because they were using it as a management tool RCT II 282 thickness of the common and internal carotid arteries, -0.155 vs. 0.007; P=0.02) Technical Reports/Consensus Statements International Society for Pediatric and Adolescent Diabetes: Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 National Health and Medical Research Council: Screening for Diabetic Retinopathy. In Clinical Practice Guidelines for the Management of Diabetic Retinopathy. Canberra, Australian Government Publishing Service, 1997, p. 23-33 American Diabetes Association: Standards of Medical Care for Patients With Diabetes Mellitus. Diabetes Care 26:33S, 2003 American Diabetes Association: Management of Dyslipidemia in Children and Adolescents With Diabetes. Diabetes Care 26:2194-2197, 2003 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Consensus Statements used to formulate the recommendations and principles of clinical practice. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Studies were included if they specifically addressed the frequency of screening for coeliac disease in children and adolescents with type 1 diabetes. While many studies described the prevalence of autoantibodies in children and adolescents with type 1 diabetes, we did not find any relevant studies that specifically addressed the frequency of How frequently should children and adolescents with Type 1 diabetes be screened for coeliac disease? Studies were included if they specifically addressed the frequency of screening for thyroid disease in children and adolescents with type 1 diabetes. While many studies described the prevalence of autoantibodies in children and adolescents with type 1 diabetes, we did not find any relevant studies that specifically addressed the frequency of screening. In the absence of other evidence the current consensus guidelines form the basis for the screening recommendations. Articles describing prevalence of thyroid disease in children with type 1 diabetes are mentioned in the text. How frequently should children and adolescents with type 1 diabetes be screened for thyroid disease? Chapter 15: Other Complications and Associated Conditions 110 111 122 Ref No 21 42 14.2 Studies were included if they specifically addressed the frequency of screening for macrovascular disease in children and adolescents with type 1 diabetes. While some studies described the prevalence of macrovascular complications in children and adolescents with type 1 diabetes, we did not find any relevant studies that specifically addressed the frequency of screening. In the absence of other evidence the current consensus guidelines form the basis for the screening recommendations. Articles relating to macrovascular disease in children and adolescents with type 1 diabetes are mentioned in the text. How frequently should children and adolescents with type 1 diabetes be screened for macrovascular complications? Studies were included if they specifically addressed the frequency of screening for microvascular disease in children and adolescents with type 1 diabetes. While some studies described the prevalence of microvascular complications in children and adolescents with type 1 diabetes, we did not find any relevant studies that specifically addressed the frequency of screening. In the absence of other evidence the current consensus guidelines form the basis for the screening recommendations. Articles describing prevalence of microvascular complications in children with type 1 diabetes are mentioned in the text. How frequently should children and adolescents with type 1 diabetes be screened for microvascular (retinopathy, nephropathy, neuropathy) complications? conventional and n = 618 intensive therapy. 283 Effect of a gluten free diet (GFD) in asymptomatic patients with type 1 diabetes found to have coeliac disease on routine screening. 63 Acerini 1998 8 with diagnosed coeliac disease 167 children & adolescents with TID screened with EMA and IgA (+/AGA). Population 18 patients detected out of 776 children with T1D by retrospectively screening stored serum samples. Screened by antireticulin and antigliadin antibodies. Confirmed diagnosis by jejunal biopsy. Children and adolescents (mean age 11.4) with type1 diabetes. Gluten free diet (GFD) Intervention Exclusive GFD Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 57 Study Saukkonen 2002 Antibody status, symptoms, BMI SDS, HbA1c , Repeat small bowel biopsies Weight Height HbA1c Outcome HbA1c reduction with gluten All had normal antibody tests after 3-6 months of GFD Asymptomatic patients reported no change in wellbeing on the GFD, although trend for BMI SDS to increase was not significant (p=0.248) Height did not change before or after dx. Weight for height did not change before diagnosis, but there was a significant increase after dx and intro of GFD (p=0.02) Eleven (6.6%) antibody positive ,9 had biopsies: 8 coeliac (1 'classical'; 1 anaemia; 3 'atypical'; 3 asymptomatic). GFD did not affect glycaemic control HbA1c Only one patient reported symptoms at the time of diagnosis. 2 patients had iron deficiency anaemia. However on retrospective questioning 9 reported GI symptoms (mostly flatulence, which resolved in all but 2 patients. Results Prevalence 2.4% of type 1 diabetics. UK study. Clinic population at john Radcliff Hospital, Oxford. Serological screening is effective, although the therapeutic benefit of dietary therapy in asymptomatic cases remains uncertain One patient died, cause of death not stated. Short follow up period. Details up to one year post diagnosis of coeliac disease only. Comments Nationwide screening programme for Childhood Diabetes in Finland ( DiMe) study. Overt GI symptoms reported in 1 patient before disclosure of diagnosis. Articles chosen if they addressed the question of GFD in truly asymptomatic children and adolescents with type 1 diabetes detected on routine screening. 15.1 Case series longitudinal follow-up Design Retrospective case series IV Level IV screening. In the absence of other evidence the current consensus guidelines form the basis for the screening recommendations. Articles describing the prevalence of coeliac disease in children with type 1 diabetes are mentioned in the text. 284 Technical Reports/Consensus Statements International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 NSW Health Department: Principles of Care and Consensus Guidelines for the Management of Diabetes Mellitus in Children and Adolescents. 1998 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 National Institute for Clinical Excellence. Type 1 Diabetes (Childhood): Diagnosis and Management of Type 1 Diabetes in Children and Young People (DRAFT). 2004. Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Consensus Statements used to formulate the recommendations and principles of clinical practice. Population 67 diabetic children and a comparison group matched for age, sex, and social class. N/A Intervention Outcome Questionnaire, clinical examination, and biomechanical assessment for foot pathology (limited joint mobility, plantar callus, skin conditions) contact with podiatry services and knowledge Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 1 The effect of type 1 diabetes on joint mobility in the feet of young people. Study Barnett 1995 16.1 Among the diabetic group there was ignorance and misconceptions, and previous contact with a podiatrist was minimal. 42 children with diabetes had received foot health education compared with 27 in the comparison group. Increased incidence of abnormal skin conditions (53 children with diabetes, 27 comparison group). Increased biomechanical anomalies (limited joint mobility) (58 children with diabetes, 34 comparison group); Results Increased foot pathology (limited joint mobility, plantar callus) in the children with diabetes (52 children) compared with comparison group (28 children); Comments Design Comparative study Level IV Studies were included if they specifically addressed the frequency of screening for foot complications in children and adolescents with type 1 diabetes. While many studies described the prevalence we did not find any relevant studies that specifically addressed the frequency of screening. In the absence of other evidence the current consensus guidelines form the basis for the screening recommendations. How frequently should children and adolescents with Type 1 diabetes be screened for foot complications? Chapter 16: Foot Care 46 59 60 74 Ref No 45 15.2 free diet was not significant (p=0.697) 285 N/A Limited joint mobility was defined as less than the fifth percent reference for controls Also screened for diabetes complications (retinopathy and nephropathy) Hands, feet and hips were examined. Foot length, arch length, joint mobility, peak pressure and pressure time integrals were evaluated Thickness of the skin on the plantar surface of the foot and plantar aponeurosis were examined using ultrasound. Ref No Population Intervention Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Study 302 diabetic adolescents and 51 non-diabetic controls (aged 11.5-20 years). 216 young people with Type 1 diabetes mellitus and 57 controls Outcome Results Diabetic adolescents showing LJM in any of these areas, except the prayer sign, were more likely to have retinopathy (odds ratio 2.53, CI: 1.534.18). Those with LJM in the foot were more likely to have albumin excretion rates >7.5 microg/min (OR 2.06, CI: 1.16-3.68). Limited active IP joint extension, a positive 'prayer sign', occurred in 35% of diabetic adolescents and 14% of controls. 13% of diabetics had limited passive extension of the interphalangeal (IP) joints of the hands compared to 0% in controls. fifth metacarpophalangeal (MCP) joint in 26% first metatarsophalangeal (MTP) joint in 18% subtalar (ST) joint in 35%, Males were nearly 3 times more likely to have thickened plantar aponeurosis. Reduced motion was found in diabetic adolescents at the: Thickened plantar aponeurosis was associated with foot size, male gender and subtalar joint limited joint mobility (P < 0.01). The plantar aponeurosis was significantly thicker in the diabetic subjects than controls. Skin was not significantly thicker in the diabetic subjects. The management of high plantar pressure and callus in adolescents with type 1 diabetes. 19 Duffin 1999 16.2 14 Duffin 2002 Comments Clinic population. Referred for diabetes complications screening. Any patients with known joint condition or arthritis was excluded Any patients with known joint condition or arthritis was excluded Design Comparative study Level IV IV 286 17 diabetic subjects with high peak plantar pressure and 17 diabetic subjects with plantar callus 211 adolescents with diabetes and 57 non-diabetic controls Treatment with foot orthosis, cushioning or combination of both Peak plantar pressure 12 months after intervention Combination of cushioning and orthosis: significant decrease (p<0.001) Orthosis alone: significant decrease in peak plantar pressure (p=0.05) Cushioning alone: significant decrease in peak plantar pressure (p=0.001) Clinic population. Referred for diabetes complications screening. Any patients with known joint condition or arthritis was excluded Technical Reports/Consensus Statements Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Consensus Statements used to formulate the recommendations and principles of clinical practice. 3 Case series study with interventional phase (pre-test, post test). IV Population 64 children and adolescents (8-15 years of age) with diabetes treated and monitored according to a standard medical protocol and receiving extensive preventive oral health care based on individual needs. N/A Intervention Results Patients with less good metabolic control (>8.0% Hb A(Ic)) had higher glucose levels in resting saliva (p < 0.05) Patients with less good metabolic control (>8.0% Hb A(Ic)) had significantly higher caries incidence (p < 0.05) compared to those with good metabolic control. The most influential determinants for high caries development during the 3year follow-up period were metabolic control (odds ratio, OR = 5.7), poor oral hygiene (OR = 6.5), previous caries Outcome Data on blood glucose and glycosylated haemoglobin (Hb A(Ic)) were collected from the medical records. Whole saliva was collected every 3rd month and secretion rate, buffer capacity, glucose concentration, mutans streptococci and lactobacilli counts were determined. Dental examinations, including radiographs, were carried out once a year. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 4 The effect of type 1 diabetes on dental health in children and adolescents. Study Twetman 2002 17.1 Comments Design Observational case series and retrospective medical note survey Level IV Studies were included if they specifically addressed the frequency of screening for dental complications in children and adolescents with type 1 diabetes. While many studies described the prevalence we did not find any relevant studies that specifically addressed the frequency of screening. In the absence of other evidence the current consensus guidelines form the basis for the screening recommendations. How frequently should children and adolescents with Type 1 diabetes have a dental review? Chapter 17: Dental Health Ref No 20 16.3 Duffin 2003 287 7 8 9 Pinson 1995 Marin 2002 Takahashi 2001 Thirty-nine periodontally Twenty diabetic patients with good metabolic control, twenty diabetic patients with poor metabolic control and forty healthy subjects 117 Japanese T1DM subjects (53 male, 64 female, mean age +/- SD, 16 +/- 6.5 years) 26 type I diabetic patients and 24 control subjects (average age 13.4years) Thirty juvenile diabetics and 30 healthy individuals N/A N/A Glycosylated haemoglobin (GHb) to obtain a measure of diabetic control. N/A Microbiological tests for four periodontal pathogens, Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Prevotella intermedia and Capnocytophaga Clinical examination for signs of periodontitis, gingivitis. Periodontal markers: Plaque, gingival, mobility, probing depth, attachment level, bleeding on probing, and marginal bone loss. Glycosylated haemoglobin Clinical periodontal details: plaque index, gingival fluid flow, gingival index, probing depths, clinical attachment levels, recession, and bleeding on probing Evaluated for dental caries and oral mucosal lesions, with the performance of basal and stimulated sialometry, periodontal variables such as the presence of bacterial plaque, gingival status and attachment losses N/A Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 6 MirallesJorda 2002 In the T1DM subjects, the Periodontitis group had a significantly longer mean duration of diabetes and a higher percentages of subjects harbouring P. gingivalis and P. intermedia than the T1DM subjects : 12 had periodontitis, 32 had gingivitis and 73 were periodontally healthy There was no significant association between the level of control of diabetes (GHb) and clinical variables. However, comparisons based on site-specific measurements showed the gingival index to be somewhat higher among the diabetics (p = 0.0002), and examination of interaction effect plots showed the diabetic group to have higher average gingival index for most teeth and higher or the same plaque index levels on all teeth relative to controls. Poor glycaemic control associated with periodontal disease (p<0.05) The diabetic group had better oral hygiene habits. No statistically significant differences in the overall means for the 2 groups for average attachment loss, probing depths, recession, gingival index, plaque index, gingival fluid flow, or bleeding on probing. No difference between groups for salivary flow, dental caries or mucosal lesions. experience (OR = 5.3) and high levels of salivary lactobacilli (OR = 5.0). Diabetics had significantly more periodontal attachment loss than non diabetics. Observational case series Observational case series Observational case series Observational case series IV IV IV IV 288 Serum IgG antibody levels against P. gingivalis were significantly elevated in the Periodontitis group compared with Gingivitis and Periodontally Healthy groups. Periodontally Healthy group. Mean follow up 7.4 years (for adolescents) OR 125 adolescents with no retinopathy and 70 with mild retinopathy Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring (n=114) Intervention Intensive insulin therapy (n=95) (by multiple daily injections or insulin pump) with frequent BG monitoring Population Adolescent subgroup of DCCT trial. Age 13-17 years Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 2 HbA1c Episodes of hypoglycaemia Outcome Development of diabetes complications Severe hypoglycaemia: RR 2.96 (95% CI 1.90-4.62) Hypoglycaemia resulting in coma or seizure: RR 2.93 (95%CI 1.75-4.90) Overweight: RR 2.11 95% CI Diabetic ketoacidosis: RR 0.2 (95% CI 0..32-1.23) Nephropathy: Intensive therapy group had 10% reduction in microalbuminaria (95% CI –70% to 52%; p=0.745 in those with no retinopathy; and by 55% (95% CI 3% to 9%); p=0.042 in those with mild retinopathy Results Retinopathy: Intensive therapy decreased the risk of retinopathy by 53% (CI 1-78%, p=0.048) (in those with no retinopathy) and 70% (CI 25-88%, p=0.010) (in those with mild retinopathy) Losses to follow-up: No patients voluntarily withdrew; 2 patients died; 2 patients assigned to inactive status for some time Blinding: Standard therapy group blinded to HbA1c results; intensive therapy group could nto be blinded to HbA1c as they were using it as a management tool; Research group blnded to the effects of the two treatment regimens; Investigators and patients unaware of outcome data unless predetermined ‘alert’ criteria (e.g. development of retinopathy) were reached; Retinopathy assessed by operators who were unaware of treatment group assignment Comments Landmark study. See other DCCT references Technical Reports/Consensus Statements Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Difficulties in glycaemic control in adolescents compared with adults. Study DCCT 1994 18.1 ochracea Consensus Statements used to formulate the recommendations and principles of clinical practice. Chapter 18: Adolescent Health Issues Ref No 12 17.2 healthy, agematched nondiabetics controls. Design RCT Level II 289 3 1441 patients with T1D aged 13-39 years. 726 with no retinopathy at baseline (primary intervention group) and 715 with mild retinopathy (secondary intervention group) Conventional therapy with 1 or 2 insulin injections daily and once daily monitoring (n=704; 352 primary and 352 secondary prevention) OR Intensive insulin therapy (by multiple daily injections or insulin pump) with frequent BG monitoring (n=704; 348 primary and 366 secondary prevention) Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents DCCT 1993 Development of diabetes complications Nephropathy: Intensive therapy reduced risk of microalbuminuria by 39% (95% CI 21-52) and albuminaria by 54% (95% CI 19-74); Intensive therapy reduced the mean adjusted risk of microalbuminuria by 34% (p=0.04) in in patients with no retinopathy at baseline and by 43% in those with mild retinopathy at baseline (p=0.001) Neuropathy: At 5 years, intensive therapy reduced incidence of clinical neuropathy by 69% ; 95% CI 24-87 (3% in intensively treated group vs 10% in conventionally treated group) p=0.006 in patients with no retinopathy at baseline; and by 57% (95% CI 29-73); p0.002 in those with mild retinopathy at baseline; combined 60% (95% CI 38-74), p0.002 Retinopathy: intensive therapy reduced the risk of retinopathy by 76% (95% CI 62-85) in patients with no retinopathy at baseline (p0.002), and by 54% (95% CI 39-66) in those with mild retinopathy at baseline (p<0.001); combined 63% (95% CI 52-71), p0.002. HbA1c (%+/-SE): 8.06+/-0.13 vs 9.76+/-0.12 (reduction of 1.7% +/-SE 0.18) 1.31-3.40) Compliance: Average time spent receiving assigned treatment = 97%, including 95 women assigned Losses to follow-up: 99% of patients completed study; >95% of all scheduled examinations completed; 11 patients died; 32 patients assigned to inactive status for some time during trial due to unavailability or investigator’s decision that continuation of treatment would be hazardous Research group blinded to effects of the two treatment regimens Blinding: Standard therapy group blinded to HbA1c results; intensive therapy group could not be blinded to Hba1c because they were using it as a management tool Independent data monitoring committee determined that study results warranted terminating trial after mean follo-up of 6.5 years (overall) Landmark study. Rigorous multicentre study supervised by NIH, USA See other DCCT references Follow up period of 6.5 years (trial terminated by independent monitoring committee) >95% of scheduled examinations were completed; overall time spent in assigned treatment was 95%; RCT II 290 16 17 Eiser 1993 Kipps 2002 229 subjects T1D >18 and < 16 between the years of 1985 and 1995 Oxford, UK UK 69 T1D patients 164 interviewed by a single nurse 222 audit of notes. Patient questionnaire 2 years pre transfer: 98% Rate of clinical attendance (at least 6 monthly) p < 0.0005 2 years pre transfer vs. 2 years post transfer 2 years post transfer: 61%, 2 years post transfer: 81% 1 year pre transfer: 87% rated about 3.4 out of 5 (0=not important, 5=very important) 17.9 years range (13.3 -22.4 years) Importance of visits before transfer Mean age of transfer 27.3% offered reason 44.8% any age up to 25 yrs 15.9 yrs 48.6% between ages of 17 & 20 yrs 5.7% before age of 17 yrs Pt knowledge of transfer reasons Mean age of transfer Best age of transfer 1.9% Don’t care 1.9% Don’t know 14.3% GP only Results 72.3% Public hospital Age (15-18) Outcome Preferred source of further adult care 42.9% Private specialist Intervention Patient questionnaire Australia Population 105 T1D patients Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 15 Current transition processes and outcomes for adolescents with type 1 diabetes moving to the adult care system. Study Court 1993 18.2 Adverse events: Incidence of hypoglycaemia increase 2-3 fold on intensive therapy (19 versus 62 hypoglycaemic episodes per 100 patient years, p<0.001). Comments 105 responses out of 152 questionnaires sent to conventional therapy who received intensive therapy during pregnancy or while planning a pregnancy Survey Survey Design Survey IV IV Level IV 291 18 Canada Two different hospitals. 212 subjects with type 1 diabetes Transfer between Oct 1990 and Oct 1995. Patient Questionnaire 9.9 ± 1.9 vs. 11.4 ± 1.9%, p = 0.0004 57% satisfied 20% not sat. 24% indifferent 10% very important 43% important 46% not important 1% discouraging 18.5 ± 0.1 years 18.8 ± 0.2 years Mean HbA1c at 2 yrs before tx comparing patients at clinic 2 yrs post tx . Satisfaction with transfer Patients perception of importance of meeting adult clinic staff prior to transfer Mean age of transfer (mean ± SEM) Suggested age of transfer (mean ± SEM) Adult care services now used Unrelated to transfer outcome (attendance clinic) Age at transfer 54% endocrinologist 65% felt later transfer would be better. 30% diabetes clinic 39% felt transfer was at correct time. 21% felt should have had transfer earlier 79% Attendance of first appointment in new clinic Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Pacaud 1996 86% p < 0.0005 2 years pre transfer vs. 2 years post transfer 2 years post transfer: 24%, 2 years post transfer: 45% 1 year pre transfer: 54% 2 years pre transfer: 77% Transfer letter identified in clinical record Rate of clinical attendance (3-4 monthly) Survey IV 292 20 Jefferson 2003 302 paediatricians surveyed in UK 42 young people with T1D Attending adolescent or transition clinic questionnaire Patient Questionnaire Definitely; 11/42 (26%) have some idea; 7/42 (17%) don’t know; 24/42 (57%) Definitely; 1/42 (2%) have some idea; 6/42 (14%) don’t know; 35/42 (84%) Definitely; 3/42 (7%) have some idea; 6/42 (14%) don’t know; 33/42 (79%) Definitely; 0/42 (0%) have some idea; 2/42 (5%) don’t know; 40/42 (95%) Yes, more than once; 8/42 (19%) Yes, once; 3/42 (7%) no; 23/42 (55%)not sure 8/42 (19%) Yes, more than once; 4/42 (9.5%) Yes, once; 4/42 (9.5%) no; 23/42 (55%) not sure 11/42 (26%) 14% at 14-16 yrs 31% at 16 years 45% at 16-20 years 53% transfer young people into a young Where will the adult clinic be held? How often will appointments be? Which doctor will you see? Which nurse will you see? Have you met any of the doctors at the adult clinic? Have you met any of the nurses at the adult clinic? Age of transfer Definitely; 6/42 (14%) have some idea; 3/42 (7%) don’t know; 33/42 (79%) When the adult clinic is held? 27.5% (17% delay was more than 1 year) A delay of more than 6 months bxn last visit at paed. clinic and first visit at adult clinic Do you know : Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 19 Datta 2003 32.8% responded yes Problem with transition from paediatric to adult care 13% no regular contact 3% family physician Survey Survey IV IV 293 21 Finland 1980-1983 61 cases of adolescent T1D followed one yr before and 1 yr after transfer HbA1c measured at 3 monthly intervals Diabetes clinics in seven U.S. and four European cities, Population 341 adults with type 1 diabetes, 332 with type 2 diabetes, and 363 non-diabetic spouse control subjects. N/A Intervention Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 22 Outcome Driving mishaps Mean age of transfer Mean HbA1c The effect of type 1 diabetes on driving performance. Study Cox 2003 18.3 Salmi 1986 One-half of the T1D drivers and three-quarters of the T2D drivers had never discussed hypoglycaemia and driving with their physicians. Crashes among T1D drivers were associated with more frequent episodes of hypoglycaemic stupor while driving, less frequent blood glucose monitoring before driving, and the use of insulin injection therapy as compared with pump therapy. T2D drivers had driving mishap rates similar to nondiabetic spouses, and the use of insulin or oral agents for treatment had no effect on the occurrence of driving mishaps. Results T1D drivers reported significantly more crashes, moving violations, episodes of hypoglycaemic stupor, required assistance, and mild hypoglycaemia while driving as compared with T2D drivers or spouse control subjects (P < 0.01-0.001). 17.5 ± 0.5 years (range 16.5-18.8) Comments Type and severity of driving mishaps not described 1 year after transfer: 9.9 ± 1.7 (n = 49) p < 0.001 1st visit at the adult clinic 11.2 ± 2.3 (n = 49) adult diabetes clinic 1 year before transfer: 11.2 ± 2.2 (n = 49) Design Questionnaire Non experimental descriptive case series Level IV IV 294 23 37 adults with type 1 diabetes who drove a simulator during continuous euglycaemia and progressive hypoglycaemia. 16 men, 21 women. Mean age 35.3+/-7.1 years . Mean duration of diabetes 17.5+/10.0 years. Mean HbA1c 8.5+/-1.8% N/A During testing, driving performance, EEG, and corrective behaviours (drinking a soda or discontinuing driving) were continually monitored, and BG, symptom perception, and judgement concerning impairment were assessed every 5 min. Mean +/- SD euglycaemia performance was used to quantify z scores for performance in 3 hypoglycaemic ranges (4.0-3.4, 3.3-2.8, and <2.8 mmol/l). Population Patients with type 1 diabetes and eating disorders Intervention N/A Outcome Data were extracted from the relevant casecontrol and follow-up studies Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 47 Eating disorders in children and adolescents with type 1 diabetes. Study Nielsen 2002 18.4 Cox 2000 Bulimia Nervosa is increased (OR = 2.9) in T1D. Comments Recruited through advertisements. Simulated driving experience, not real life Results Incidence of anorexia nervosa not significantly increased in T1D. High beta and low theta activity and awareness of both hypoglycaemia and the need to treat low BG influenced corrective behaviour. Awareness of impaired driving was associated with neuroglycopaenic symptoms. increased beta-wave activity, and awareness of hypoglycaemia. Driving impairment was related to increased neurogenic symptoms and increased thetawave activity. Corrective actions did not occur until BG was <2.8 mmol/l (P<0.05). Compared with euglycaemia hypoglycaemic subjects engaged in more driving across the midline (P<0.01 for BG<2.8 mmol/l), more speeding (P<0.01 for BG 2.84.0 mmol/l and inappropriate baraking (P<0.01 for BG 2.84.0 mmol/l) During all three hypoglycaemic BG ranges, driving was significantly impaired, and subjects were aware of their impaired driving. Design Meta-analysis of all relevant case-control and follow-up studies Case series Level IV IV 295 49 NeumarkSztainer 2002 Source of data: 1. Diabetes database and 2 previous population based studies 2. Danish nationwide psychiatric admission case register 70 adolescent females and 73 adolescent males with type 1 diabetes. Mean age 15.3+/2.3 years (12-21 years) Patients with type 1 diabetes and eating disorders (age range 0-29 years). N/A N/A Data on BMI and glycosylated haemoglobin (HbA1c) were drawn from medical records. AHEAD (Assessing Health and Eating among Adolescents with Diabetes) survey. Indexes of mortality: crude mortality rate (CMR) (a percentage), SMR, rate ratio (RR) (mortality per 1,000 person-years of observation), risk difference (RD), and survival analysis. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 48 Nielsen 2002 Family cohesion was negatively associated with disordered eating among females (r = -0.52; P < Higher levels of weight dissatisfaction tended to be associated with unhealthy weight control/disordered eating; associations with BMI were inconsistent. Weight control/disordered eating behaviours were not associated with age, parental level of education, family structure, or race/ethnicity. Among the females, 10.3% reported skipping insulin and 7.4% reported taking less insulin to control their weight. Only one male reported doing either of these behaviours. Unhealthy weight control practices: in 37.9% of the females and 15.9% of the males. More females (92.4%) than males (53.6%) reported weight control behavious to lose weight or prevent weight gain (P<0.001). Crude mortality rates were 2.5, 6.5, and 34.8%, respectively. Mortality rate was 2.2 (per 1,000 person-years) for T1D, 7.3 for anorexia cases, and 34.6 for concurrent cases. With 10 years of follow-up, 13 of 510 females with type 1 diabetes, 43 of 658 females with anorexia nervosa, and 8 of 23 concurrent case subjects had died. Insulin misuse (IM) is increased when ED coexists with T1D (OR 12.6) Anorexia nervosa has higher mortality than type 1 diabetes on all indexes of mortality. Co-existing ED in T1D increases the overall common OR for retinopathy to 4.8 ED-NOS and subthreshold ED was increased (OR =2) in females with T1D. 246 adolescents invited to participate. 143 agreed (58%) Questionnaire Population register based follow up study IV IV 296 51 52 Affenito 1997 Rydall 1997 mean age 15+/-2 years and the duration of diabetes was 7+/-4 years. 91 young women with IDDM Sweden 90 with T1D (1846 years of age) Mean age 28.8 years Recruited from diabetes clinics throughout Connecticut and Massachusetts Adolescent males with T1D compared with that of healthy age-matched male controls Studied at base line and 5 yrs later N/A Group differences in the degree of dietary restraint, binge eating, and bulimic behaviours anti weight, shape, and eating concerns were assessed with the Eating Disorder Examination (EDE) and the Bulimia Test Revised (BULITR). Prevalence and persistence of disordered eating behaviour (on the basis of self-reported eating and weight-loss practices, including the intentional omission or underdosing of insulin to control weight) and the association of such eating disorders with metabolic control, diabetic retinopathy, and urinary albumin excretion. Categorized into one of 3 groups according to the Diagnostic Statistical Manual of Mental Disorders (DSM-III-R) criteria for eating disorders: the clinical group (n = 14), the subclinical group (partially fulfilling the diagnostic criteria; n = 13), and the control group (n = 63). Eating Disorder Inventory for Children and an interview. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 50 Svensson 2003 Omission or underdosing of insulin lose weight was reported by 12 of 88 young women (14 percent) at base line and 30 (34 percent) at follow-up (P=0.003). At base line, the mean (+/-SD) haemoglobin A(1c) value was higher in the group with highly disordered eating behaviour (11.1+/-1.2 percent) than in the groups whose eating behaviour was Of the 65 women with normal eating behaviour at base line (71 percent), 14 (15 percent) had disordered eating at follow-up. The severity of bulimic behaviours, weight concerns, reduced BMI, and decreased frequency of blood glucose monitoring were associated with elevated HBA(1c) At base line, 26 of 91 young women (29 percent) had highly or moderately disordered eating behaviour, which persisted in 16 (18 percent) and improved in 10 (11 percent). Women with(p<0.05) subclinical and clinical eating disorders had clinically elevated HbA(1c) results. The Control HbA1c was 8.3+/-1.6. subclinical group HbA1c 10+/-1.5% , clinical group HbA1c 10.4+/-2.6% (p=0.05) and more diabetes-related complications, compared with the control subjects (Control group 0.6, subclinical group 1.23, p=0.03, clinical group 1.23,p=0.03). Male T1D patients had higher Drive for Thinness scores (p=0.002) Correlations between disordered eating and HbA1c levels were significant among females (r = 0.33; P < 0.01) and males (r = 0.26; P < 0.05). Male patients were heavier than controls males (p = 0.004) 0.001) and males (r = -0.41; P < 0.001), but correlations with other measures of family environment (control, independence, and responsibility for diabetes management) were not significant. High incidence of intentional insulin omission to control weight Diabetes complications by self-report or chart review. Case series Cohort study. Questionnaire Questionnaire and interview IV IV IV 297 Mean duration of T1D 6.4years Mean age 15.1 years Toronto, Canada 103 Female T1D patients attending diabetes clinic. A cross-sectional survey of eating habits and attitudes conducted in 76 adolescents with IDDM, and ageand sex-matched non-diabetic control subjects N/A Questionnaire HbA1c level Clinical information from hospital notes Assessed by standardized research interview adapted for use with patients with diabetes (EDE). Glycaemic control was assessed by GHb assay Mean HbA1c in eating disorder group was significantly higher than those without eating disorders (10% compared with 8.9%, p<0.02)) Those with eating disorders were less likely to follow food plan or perform blood glucose monitoring. Mean age of eating disorder patients 16.2 years. Incidence of bulimia nervosa 12% Incidence of anorexia nervosa 1% Eating disorder features and insulin misuse for shape and weight control were not found in IDDM or non-diabetic boys, and these two groups did not differ in their body weight. 12% reported intentional insulin under treatment as a method of weight control Fifteen percent had omitted or reduced their dose of insulin to influence their shape and weight. Nine percent of the IDDM girls met diagnostic criteria for an operational version of 'Eating disorder not otherwise specified.' However, clinical eating disorders were no more common among adolescent girls with IDDM than among non-diabetic control subjects. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Technical Reports and Consensus Statements used to formulate the recommendations and principles of clinical practice. 55 Rodin 1991 18.5 54 Peveler 1992 Disordered eating at base line was associated with retinopathy four years later (P=0.004), when 86 percent of the young women with highly disordered eating behaviour, 43 percent of those with moderately disordered eating behaviour, and 24 percent of those with nondisordered eating behaviour had retinopathy. Adolescent girls with IDDM were heavier than non-diabetic female control subjects and were dieting more intensively to control their shape and weight. moderately disordered (8.9+/-1.7 percent) or nondisordered (8.7+/-1.6 percent, P<0.001). High incidence of insulin omission in girls. Survey questionnaire and medical note review Cross-sectional survey IV IV 298 9 10 Davis 1996 Matyka 1999 29 prepubertal T1D 12 children aged 12.4+/-2.6 years, age (range 11.115.4 years), duration of diabetes 5.9+/- 3 years. Population 24 school aged children with T1D (14 with hypo and 10 controls with no hypo) Controls were children with T1D who did not have mild hypo episode Hyperglycaemia or euglycaemia (Effect of hyperglycaemia using a modified glucose clamp to maintain BG between 5-10 mmol/l or between 20-30 mmol/l) Intervention 14 tested immediately after complete symptom resolution of mild hypo episode Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 5 Cognitive function WISC-111 subtests Outcome Neuropsych testing The effects of type 1 diabetes on cognitive function in children and adolescents. Study Puczynski 1990 19.1 No sig diff. bxn noct hypo nights and control nights Analysis of variance demonstrated as significant decrease in performance IQ when hyperglycaemic (106+/4.3 vs 112+/-4.5 IQ points, p<0.05) 8/12 had decreased IQ when hyperglycaemic, 2 remained the same and 2 had a slight increase Results Stat sig. decrease in 5/12 tasks following mild hypoglycaemic episode despite complete resolution of symptoms The same two psychologists conducted all tests and each patient was tested by the same psychologist on both occasions Blinding: Patients and the testing psychologist were blinded to the order of testing Randomisation: Method of randomisation not stated Patients were randomised to either euglycaemia or hyperglycaemia in the first instance, and then received the crossover treatment at least six months later Comments Suggests time lag in resolution of cognitive function after mild hypo Comparative RCT (crossover) Design Comparative III-2 II Level III-2 Technical Reports/Consensus Statements International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Rosen DS, Blum RW, Britto M, Sawyer SM, Siegel DM, Society for Adolescent Medicine: Transition to adult health care for adolescents and young adults with chronic conditions: position paper of the Society for Adolescent Medicine. Journal of Adolescent Health. 33:309-311, 2003 Austroads: Assessing Fitness to Drive. Guidelines and Standards for Health Professionals in Australia. Sydney, Austroads Incorporated, 2001 International Diabetes Federation. Position Statement. Diabetes and tobacco use: a harmful combination. 2003. Diabetes UK. Information. Alcohol and Diabetes. 2003. London, Diabetes UK. Ref Type: Report National Institute for Clinical Excellence. Eating Disorders: Core interventions in the treatment and management of anorexia nervosa, bulimia nervosa, and related eating disorders. 2003. London. Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 National Institute for Clinical Excellence. Type 1 Diabetes (Childhood): Diagnosis and Management of Type 1 Diabetes in Children and Young People (DRAFT). 2004. Chapter 19: School 24 25 34 57 59 60 14 Ref No 4 299 12 13 14 15 Rovet 1997 Sansbury 1997 Rovet 1999 Hannonen 2003 21 children with T1D and 10 healthy controls 16 children with type 1 diabetes 28 T1D children 100 controls (50 boys, 50 girls) mean age 13.1 +/2.5 years 103 T1D (50 boys, 53 girls), mean age 13.5+/2.3 years. T1D and one episode of severe hypo Normal controls T1D with no hypo. NEPSY (dev. Neuropsych assessment) Divided into 3 groups Memory – Digit span Phonological processes in T1D with hypos scored lower than controls (p<0.05) Hypo seizure patients scored lower (p<0.01) Attention – T1D without hypos had test scores significantly lower than controls (p<0.05) Poor met control assoc with lower vocab subtest scores. Hypo seizures more likely to have IQ decline (67% vs 14%, p<0.05) Behaviour checklist Verbal IQ Inc duration assoc with lower matching figures score. IQ poorer performance in early onset (p=0.01) Seizure history had lower verbal IQ than controls (P<0.01) but did not differ form children with diabetes who had no seizures who scored slightly below controls. Increased age assoc with decreased IQ score T1D attention scores lower (p<0.05) Reading and memory impairment in early onset groups Of 136 eligible children approached 103 agreed to participate (76%). Higher depression score after hypo night (p=0.03) IQ scores lower in early onset and longer duration Matching figures WISC-R Verbal subtests WISC-R WAIS-R MMFFT for Attention Mood assessment WISC-R Perceptual, fine motor, visuomotor, visual memory and attention WISC-R Follow up at 1, 3, 7 years 9 had hypoglycaemic seizure HbA1c Duration Age at onset Divided in 4 groups depending upon age of onset and length of duration Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 11 Holmes 1985 15 healthy controls 41 children with T1D Unclear methodology Patients and controls recruited from Hosp for Sick Children, Toronto, Canada. Comparison between controls and diabetes subjects were by t tests and ANOVA’s. Comparative Case series Case series Comparative Case series III-2 IV IV III-2 IV 300 17 18 19 Northam 1998 Northam 2001 Schoenle 2002 64 T1D children between the ages of 7 and 16 years Follow up study from Northam 98 study 90 patients (aged 6-17 years, mean 12.1 +/- 2.9) who had been previously assessed soon after Dx and 2 years later were re-evaluated 6 years after onset of diabetes. 84 controls (12.1+/-2.8 years, p=NS). 123 children (3-14 years) with recent T1D onset were compared with 129 community control subjects 40 sibling controls 63 new T1Ds Longitudinal study looking at long term metabolic control and hypoglycaemia on intellectual development. Standardized measures of general intelligence, attention, speed of processing, memory, learning, executive skills and behavioural adjustment soon after diagnosis and 2 years later. Neurocog function examined at onset and 1 year later Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents 16 Rovet 1990 Assessed at least 4 times using German version of the Hamburg Wechsler intelligence scale for preschool children, and by the Adaptive Intelligence Diagnosticum others WPPSI-R WISC-R and others WISC-R Severe hypo assoc. with lower verbal and full-scale intelligence quotient scores. Significant performance decline by 7yr and verbal IQ between age 7 and 16 years was observed in diabetic boys diagnosed before the age of 6 ( not in those diagnosed later, not in diabetic girls). Attention, processing speed, & executive skills were esp. affected when onset was before 4 yrs old. No diff No differences in T1D and controls at initial assessment within 3 months of diagnosis. After 2 years significant decrease in vocabulary IQ (P<0.01), block design P<0.05) subtests. Multivariate group differences were apparent on speed of processing (p<0.05) and learning (P<0.01) subtests, reflecting smaller developmental gains in children with IDDM when compared with control subjects. Six years after onset of diabetes, children with T1D performed more poorly than controls on verbal IQ (F=8.07, p<0.01), ful scale IQ (F=5.33.P<0.05) attention (F=2.63, P<0.05), processing speed (F=4.81,P<0.01), longterm memory (F=3.58,P<0.01), and executive skills (F=4.57,P<0.05). both T1D with & without scored lower compared with controls (p<0.01) Vocabulary decreased after 1 year (p=0.05) Prospective longitudinal study. Cohort of 64 patients analysed out of a larger group of 164 patients being followed. Selection based on having had at least 4 out of 6 longitudinally applied tests between ages 7 7 children with T1D and 17 control children were not evaluated at 2 years. prospective longitudinal case series Comparative Comparative Comparative cohort study IV III-2 III-2 III-2 301 Population Intervention Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No Insulin regimen during travel when crossing time zones. Study 21.1 Outcome Results Comments Design Level Technical Reports/Consensus Statements International Society for Pediatric and Adolescent Diabetes: ISPAD Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Medical Forum International, 2000 American Diabetes Association: Management of diabetes at diabetes camps. Diabetes Care 26 Suppl 1:S136-S138, 2003 Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Chapter 21: Travelling and Holidays 5 19 20 Ref No 3 Consensus Statements used to formulate the recommendations and principles of clinical practice. No studies were identified specifically addressing the benefits on glycaemic control of diabetes camps. 20.1 Male sex, diagnosis at a young age, metabolic condition at diagnosis and long-term metabolic control(p<0.001),, rather than experienced hypoglycaemic attacks (p=0.21) are risk factors for intellectual development. and 16 years. Technical Reports/Consensus Statements American Diabetes Association: Care of children with diabetes in the school and day care setting. American Diabetes Association. Diabetes Care 26:131-135, 2003 International Society for Pediatric and Adolescent Diabetes: Consensus Guidelines for the Management of Type 1 Diabetes Mellitus in Children and Adolescents. Zeist, Netherlands, Medforum, 2000 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Consensus Statements used to formulate the recommendations and principles of clinical practice. Chapter 20: Diabetes Camps Ref No 4 20 21 19.2 The deterioration of performance in boys diagnosed at a very young age was not associated with the occurrence of severe hypoglycaemic episodes but was correlated with the degree of metabolic deterioration at diagnosis and with high long-term average of HbA1c. 302 BD patients were advised to take between 15-20% of TDD before each meal Individually advised to adjust insulin depending on flight and regimen. Basal bolus patients were advised to continue taking short-acting insulin with each meal during travel, but no intermediate acting. Advised to increase their insulin dose if travelling west, and decrease if travelling east. Also have 2-4 units of short-acting if BGL>15 mmol/L Does not report on glycaemic control Gives very little details about what patients actually did with their intermediate acting insulin. Small numbers Dose not specify individual insulin regimens Does not mention age range. Small numbers (n=27) Case series Case series Technical Reports/Consensus Statements National Center for Complementary and Alternative Medicine (NCCAM) and NIH. What Is Complementary and Alternative Medicine (CAM)? 2003. http://www.nccam.nih.gov/ American Diabetes Association: Unproven Therapies. Diabetes Care 26:142S, 2003 Department of General Medicine, Royal Children's Hospital, and Melbourne. Use of Complementary and Alternative Medicines for Inpatients. 2003. http://www.rch.org.au/genmed/CAMguidelines.htm. Appendix 2: Evidence Tables Australian Clinical Practice Guidelines: Type 1 Diabetes in Children and Adolescents Ref No 1 10 13 Mean BGL same for east and west travel, but higher for travel days than days at home Patients were happy with this simple system and reported no problems. Eastward travel reduced insulin dose 2.6% of total daily dose per time shift hour Westward travel: increase in insulin 3.1% of total daily dose per time shift hour. Consensus Statements used to formulate the recommendations and principles of clinical practice. No Level I or II studies were identified for this chapter 22.1 BGL Patient satisfaction Total insulin dose required Technical Reports/Consensus Statements Ambler G, Barron V, May C, Ambler E, Cameron F: Caring for Diabetes in Children and Adolescents. A parent’s manual. Sydney, Combined Children's Diabetes Services of NSW, 2001 Australasian Paediatric Endocrine Group: APEG Handbook on Childhood and Adolescent Diabetes. Sydney, Australasian Paediatric Endocrine Group, 1996 Chapter 22: Complementary and Alternative Medicine Ref No 1 6 16 insulin treated patients (age range 9- 69) 2 on basal bolus regimen, and 14 on BD injections 27 T1D patients Consensus Statements used to formulate the recommendations and principles of clinical practice. 5 Jones 94 21.2 4 Sane 90 IV IV 303
