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Managing Hyperglycemia in Inpatients: Ensuring Success Hospitalizations Account for Largest Portion of Direct Cost of Diabetes Care Current Guidelines and Evidence for Inpatient Hyperglycemic Control 2012 Total direct cost: $176 billion Hospitalizations Nursing home 31% Curtis L. Triplitt, Pharm.D., CDE Associate Director Diabetes Research Center Texas Diabetes Institute Associate Professor Department of Medicine, Division of Diabetes University of Texas Health Science Center at San Antonio San Antonio, Texas Office visits 43% ER visits 5% Outpatient clinics 4% 9% 8% Outpatient meds and supplies American Diabetes Association. Diabetes Care. 2013; 36:1033-46. Enlargement on page 6 At what glucose level does your ICU implement an IV insulin protocol, and what is the glycemic target? Guidelines from Professional Organizations on ICU Blood Glucose (BG) Goal Year Patient Population Organization BG Treatment Threshold (mg/dL) BG Target (mg/dL) BG Hypoglycemia Definition (mg/dL) Updated since NICESUGAR, 2009 <70 Yes 2009 AACE and ADA ICU patients 180 140–180 2013 Surviving Sepsis Campaign ICU patients 180 <180 2009 Institute for Healthcare Improvement ICU patients 180 <180 <40 Yes 2012 American College of Critical Care Medicine (ACCM) ICU 150 <150 (Trauma) <180 (Stroke+) <70 Yes 2013 American College of Physicians ICU patient Not stated 140–200 Not stated Yes American Heart Association ICU patients with ACS 180 90–140 2008 Kavanagh BP et al. N Engl J Med. 2010; 363:2540-6. Qaseem A et al. Ann Intern Med. 2011; 154:260-7. Not stated Not stated a. b. c. d. e. f. Yes No Jacobi J. Crit Care Med. 2012; 40:3251-76. Finfer S et al. N Engl J Med. 2009; 360:1283-97. 2009 AACE/ADA Target Inpatient Glucose Levels and Hypoglycemia Definitions BG Value BG >200 mg/dL, target 80-110 mg/dL BG >200 mg/dL, target 80-140 mg/dL BG >180 mg/dL, target 140-180 mg/dL BG in 200s mg/dL, target 140-180 mg/dL Have protocol, but none of these fit Have no ICU protocol or I don’t know Definition Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients (ACCM) Implications >140 mg/dL Hyperglycemia* Premeal levels persistently above this level may necessitate treatment >180 mg/dL Hyperglycemia No random blood glucose levels should be, in general, above this goal <70 mg/dL Hypoglycemia Standard definition in outpatients, correlates with the initial threshold for release of counterregulatory hormones <40 mg/dL Severe hypoglycemia Increased mortality risk, cognitive impairment begins at 50 mg/dL in normal individuals In the population of critically ill injured (trauma) ICU patients, we suggest that BG ≥ 150 mg/dL should trigger initiation of insulin therapy, titrated to keep BG < 150 mg/dL for most adult trauma patients and to maintain BG values absolutely < 180 mg/dL, using a protocol that achieves a low rate of hypoglycemia (BG ≤ 70 mg/dL) to achieve lower rates of infection and shorter ICU stays in trauma patient Hypoglycemia We suggest that a BG ≥ 150 mg/dL triggers initiation of insulin therapy for most patients admitted to an ICU with the diagnoses of ischemic stroke, intraparenchymal hemorrhage, aneurysmal subarachnoid hemorrhage, or traumatic brain injury, titrated to achieve BG values absolutely < 180 mg/dL with minimal BG excursions <100 mg/dL, to minimize the adverse effects of hyperglycemia *Reassess insulin regimen if BG levels fall below 100 mg/dL Occasional patients may be maintained with BG below and/or above these cut-points AACE = American Association of Clinical Endocrinologists ADA = American Diabetes Association Moghissi ES et al. Endocr Pract. 2009; 15:353-69. Jacobi J et al. Crit Care Med. 2012; 40:3251-76. 1 Managing Hyperglycemia in Inpatients: Ensuring Success Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients (ACCM) Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients (ACCM) We suggest that BG ≤ 70 mg/dL are associated with an increase in mortality, and that even brief severe hypoglycemia (BG ≤ 40 mg/dL) is independently associated with a greater risk of mortality and that the risk increases with prolonged or frequent episodes We suggest continuous insulin infusion (1 unit/mL) therapy should be initiated after priming new tubing with a 20-mL waste volume Subcutaneous (SC) insulin may be acceptable in the ICU if BG goals are maintained Test and adjust BG every 1-2 hours - this has not been studied prospectively Jacobi J et al. Crit Care Med. 2012; 40:3251-76. Jacobi J et al. Crit Care Med. 2012; 40:3251-76. Surviving Sepsis: Guidelines Differences Surviving Sepsis Campaign 1. A protocolized approach to BG management in ICU patients with severe sepsis commencing insulin dosing when Initiate at 180 mg/dL, but no lower threshold for glycemic control except hypoglycemia 2 consecutive BG levels are >180 mg/dL This protocolized approach should target an upper BG ≤180 mg/dL rather than an upper target BG ≤110 mg/dL (grade 1A) No evidence for 140-180 mg/dL range versus 110-140 mg/dL range except for hypoglycemia 2. BG values should be monitored every 1–2 hr until glucose values and insulin infusion rates are stable and then every 4 hr thereafter (grade 1C) 3. Glucose levels obtained with point-of-care testing of capillary blood should be interpreted with caution, as such measurements may not accurately estimate arterial blood or plasma glucose values (this statement is ungraded) Although all evidence taken into account, NICE-SUGAR is the main trial that influences Dellinger RP et al. Crit Care Med. 2013; 41:580-637. Dellinger RP et al. Crit Care Med. 2013; 41:580-637. American College of Physicians American College of Physicians Recommendation 1: ACP recommends not using intensive insulin therapy to strictly control blood glucose in non-surgical intensive care unit (SICU)/medical intensive care unit (MICU) patients with or without diabetes mellitus (Grade: strong recommendation, moderate-quality evidence) Recommendation 2: ACP recommends not using intensive insulin therapy to normalize blood glucose in SICU/MICU patients with or without diabetes mellitus (Grade: strong recommendation, highquality evidence) Current evidence does not show a mortality benefit associated with use of IIT to achieve a target of normoglycemia (blood glucose levels of 4.4 to 6.1 mmol/L [80 to 110 mg/dL]) Current evidence does not support 80 to 180 mg/dL compared with higher or unspecified targets using a variety of intensive insulin therapy regimens for patients with myocardial infarction, stroke, or acute brain injury or those under perioperative care A nonsignificant reduction in the incidence of infection has been observed Although the target blood glucose levels in the current trials ranged widely, avoiding targets less than 7.8 mmol/L (<140 mg/dL) should be a priority because harms are likely to increase at lower blood glucose targets Evidence from some studies showed an increase in mortality associated with IIT and hypoglycemia. Data on the effects of IIT targeted to normoglycemia on reduction in length of ICU stay are mixed IIT = intensive insulin therapy Qaseem A et al. Ann Intern Med. 2011; 154:260-7. 2 Qaseem A et al. Ann Intern Med. 2011; 154:260-7. Managing Hyperglycemia in Inpatients: Ensuring Success American College of Physicians Striking the Right Balance Recommendation 3: ACP recommends a target blood glucose level of 7.8 to 11.1 mmol/L (140 to 200 mg/dL) if insulin therapy is used in SICU/MICU patients (Grade: weak recommendation, moderate-quality evidence) Summary - poorly controlled glucose worsens outcomes Evidence is not sufficient to give a precise range for blood glucose levels Hyperglycemia Hypoglycemia 140 to 200 mg/dL is associated with similar mortality outcomes as intensive insulin therapy targeted at blood glucose levels of 80 to 110 mg/dL and is associated with a lower risk for hypoglycemia Current studies do not provide enough information to determine whether allowing blood glucose levels to increase above 10.0 to 11.1 mmol/L (180 to 200 mg/dL) is associated with similar outcomes to those seen at lower target levels Qaseem A et al. Ann Intern Med. 2011; 154:260-7. NICE-SUGAR: Baseline Characteristics NICE-SUGAR Study Multicenter-multinational randomized, controlled trial (Australia, New Zealand, and Canada; N=6104 ICU patients) − Intensive BG target: 4.5-6.0 mmol/L (81-108 mg/dL) − Conventional BG target: <10.0 mmol/L (180 mg/dL) Primary outcome: Death from any cause within 90 days after randomization Patient population − − − − Age: ~60 years Gender: ~36% female Diabetes: ~20% (BMI ~28 kg/m2) Interval, ICU admission to randomization: 13.4 hr Reason for ICU admission − Operative* ~37% − Non-operative† ~63% Sepsis: ~22% Trauma: ~15% Mean APACHE II score: ~21; APACHE >25: 31% Reason for ICU admission: surgery: ~37%, medical: 63% History of DM: 20% (T1DM: 8%, T2DM: 92%) At randomization: sepsis: 22%, trauma: 15% *No significant number of cardiothoracic surgery patients †No significant number of CCU patients Finfer S et al. N Engl J Med. 2009; 360:1283-97. Finfer S et al. N Engl J Med. 2009; 360:1283-97. Enlargement on page 6 Intensive Glycemic Control in Critically Ill Adults: Severe Hypoglycemia Risk NICE-SUGAR Study Outcomes Intensive Group Conventional Group Morning BG (mg/dL) 118 ± 25 145 ± 26 Hypoglycemia (BG ≤ 40 mg/dL) 206/3016 (6.8%) 15/3014 (0.5%) 28-Day mortality (P=0.17) 22.3% 20.8% 90-Day mortality (P=0.02) 27.5% 24.9% Outcome Measure Meta-analysis of 26 Randomized Controlled Trials (13,567 patients) Study Severe Hypoglycemia (≤ 40 mg/dL) Favors IIT Favors conventional control Van den Berghe et al.8 Henderson et al.31 Bland et al.25 Van den Berghe et al.9 Mitchell et al.35 Azevedo et al.22 De La Rosa Gdel et al.12 Devos et al.13 Oksanen et al.36 Brunkhorst et al.11 Iapichino et al.32 Arabi et al.10 Mackenzie et al.33 NICE‐SUGAR18 Overall 0.1 1 10 Risk Ratio (95% CI) Griesdale DE et al. CMAJ. 2009; 180:821-7. Finfer S et al. N Engl J Med. 2009; 360:1283-97. 3 Managing Hyperglycemia in Inpatients: Ensuring Success Pharmacists Need to Clearly Understand Guidelines from Professional Organizations: Non-ICU Goals Treatment goals Treatment options Treatment protocols Potential medication errors and methods to reduce errors Their important role on multidisciplinary team in ensuring safe and effective management of hyperglycemia in the hospital setting Year Organization Patient Population 2009 AACE and ADA Consensus Statement Noncritically ill patients 2012 Endocrine Society Clinical Practice Guideline Noncritically ill patients BG Treatment Threshold BG Target Premeal 180 mg/dL <140 mg/dL Premeal 180 mg/dL <140 mg/dL BG Definition of Hypoglycemia Updated since NICESUGAR <70 mg/dL (Reassess treatment if <100 mg/dL) Yes (Reassess treatment if <100 mg/dL) Yes Moghissi ES et al. Endocr Pract. 2009; 15:353-69. Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16-38. Adapted from Kelly JL. Am J Health-Syst Pharm. 2010; 67(Suppl 8):S9-16. Discharge Planning: New Hyperglycemia Transition to Outpatient Status Begin discharge planning early A1C Obtain A1C for discharge planning if result not available from previous 2 to 3 months <5.7% − A1C can now also be used as a means to make the diagnosis of diabetes − This is often missed by inpatient team 5.7% to 6.4% Patient has pre-diabetes (at risk); follow up advisable; consider diabetes prevention strategies 6.5% to 7% Patient has diabetes; can be treated with lifestyle and consider metformin 7% to 9% Stabilize blood glucose before discharge General Guidelines Patient does not have diabetes nor pre-diabetes >9% Patient has diabetes and pharmacotherapy is indicated Most patients would likely benefit from basal-bolus insulin regimen at discharge Society of Hospital Medicine Glycemic Control Task Force. Workbook for Improvement. URL in ref list. Discharge Planning: Diagnosed Diabetes A1C <7% 7% to 8% Transition from Hospital to Home Reinstitute preadmission insulin regimen or oral and non-insulin injectable antidiabetic drugs at discharge for patients with acceptable preadmission glucose control General Guidelines Continue pre-admission diabetes management therapy plan Increase dose of preadmission diabetes medications and/or add a second or third oral agent or basal insulin at bedtime >8% If on 2 diabetes medications, add basal insulin at bedtime >9% to 10% Most patients should be on basal-bolus insulin at discharge Initiate insulin administration in those for whom it is indicated at least one day before discharge to allow assessment of efficacy and safety of this transition Provide patients and their families or caregivers with both oral and written instructions regarding glycemic regimen Society of Hospital Medicine Glycemic Control Task Force. Workbook for Improvement. URL in ref list. 4 Managing Hyperglycemia in Inpatients: Ensuring Success “Survival Skills” to Teach Before Discharge How and when to take medication or insulin − What to expect from the medication − Confirm insurance reimbursement How and when to test BG − What are target glucose levels Basics on meal planning How to treat and prevent hypoglycemia Conclusion Hyperglycemia − Common in critically ill patients, both with and without diabetes − Predictor of adverse outcomes, including mortality Sick-day management plan Date and time of follow-up visits − Including diabetes education Good, but not stringent, glucose control is most common strategy among different guidelines When and who to call on the health care team Hypoglycemia should be avoided, as adverse mortality consequences may result − Schedule follow up with clinician (timely manner) − Emergency numbers − Available community resources Pharmacists can and should be part of multidisciplinary glycemic control team and discharge planning in their institution Moghissi E et al. Endocr Pract. 2009; 15:353-69. Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16-38. 5 Managing Hyperglycemia in Inpatients: Ensuring Success Guidelines from Professional Organizations on ICU Blood Glucose (BG) Goal Year Patient Population Organization BG Treatment Threshold (mg/dL) BG Target (mg/dL) BG Hypoglycemia Definition (mg/dL) Updated since NICESUGAR, 2009 <70 Yes 2009 AACE and ADA ICU patients 180 140–180 2013 Surviving Sepsis Campaign ICU patients 180 <180 2009 Institute for Healthcare Improvement ICU patients 180 <180 <40 Yes 2012 American College of Critical Care Medicine (ACCM) ICU 150 <150 (Trauma) <180 (Stroke+) <70 Yes 2013 American College of Physicians ICU patient Not stated 140–200 Not stated Yes 2008 American Heart Association ICU patients with ACS 180 90–140 Kavanagh BP et al. N Engl J Med. 2010; 363:2540-6. Qaseem A et al. Ann Intern Med. 2011; 154:260-7. Not stated Not stated Yes No Jacobi J. Crit Care Med. 2012; 40:3251-76. Finfer S et al. N Engl J Med. 2009; 360:1283-97. Intensive Glycemic Control in Critically Ill Adults: Severe Hypoglycemia Risk Meta-analysis of 26 Randomized Controlled Trials (13,567 patients) Study Severe Hypoglycemia (≤ 40 mg/dL) Favors IIT Favors conventional control Van den Berghe et al.8 Henderson et al.31 Bland et al.25 Van den Berghe et al.9 Mitchell et al.35 Azevedo et al.22 De La Rosa Gdel et al.12 Devos et al.13 Oksanen et al.36 Brunkhorst et al.11 Iapichino et al.32 Arabi et al.10 Mackenzie et al.33 NICE‐SUGAR18 Overall 0.1 1 10 Risk Ratio (95% CI) Griesdale DE et al. CMAJ. 2009; 180:821-7. 6 Managing Hyperglycemia in Inpatients: Ensuring Success Enlargement on page 13 Types of Insulin Practical Approach to Inpatient Glycemic Control Kevin W. Box, Pharm.D. Senior Clinical Pharmacist UC San Diego Health System San Diego, California Diabetes Education Online: Diabetes Teaching Center at the University of California, San Francisco. Table of insulin action. URL in ref list. Used with permission. HPI: 54 y/o, 100-kg man with T2DM x 8 yr admitted with diabetes-related foot infection, eating regular meals Outpatient Meds On admission what would you do? a. Continue home regimen of metformin, glipizide, and NPH b. Continue metformin and glipizide at half of outpatient dose c. Withhold oral meds; start glargine 30 units daily, lispro 10 units qac, and moderate correctional scale d. Withhold oral meds; start high correctional scale only Pertinent Labs − Glipizide 10 mg po daily − Metformin 1000 mg po twice daily − NPH insulin 20 units subcutaneously at bedtime − A1C 10% − BG in ED 240 mg/dL Stepwise Approach to Physiologic Insulin Dosing Withhold All Oral Agents Non-insulin agents are inappropriate in most hospitalized patients Moghissi ES et al. Diabetes Care. 2009; 32:1119-31. 7 Step 1 Estimate amount of insulin patient would need over one day, if getting adequate nutrition = total daily dose (TDD) Step 2 Assess patient’s nutritional situation Step 3 Decide which components of insulin the patient will require and percentage of TDD each should represent Step 4 Assess blood glucose at least daily, adjusting insulin doses as appropriate Managing Hyperglycemia in Inpatients: Ensuring Success STEP 1: Estimate the amount of insulin the patient would need over one day, if getting adequate nutrition = TDD Our Patient Calculate TDD Insulin drip-based estimate (for patients treated with an insulin infusion) For patients already treated with insulin, consider the patient’s preadmission subcutaneous regimen and glycemic control on that regimen Weight-based estimate − No drip − On orals and NPH as outpatient − Weight 100 kg (0.6 units/kg) = 60 units 100 kg (0.5 units/kg) = 50 units − TDD = 0.4 units/kg x Wt in kg − Adjust down to 0.3 units/kg x Wt in kg for those with hypoglycemia risk factors, including kidney failure, type 1 diabetes (especially if lean), frail/low body weight/ malnourished elderly, or insulin naïve patients − Adjust up to 0.5-0.6 units/kg (or more) x Wt in kg for those with hyperglycemia risk factors, including obesity and high-dose glucocorticoid treatment Enlargement on page 13 Which pattern of nutrition does your patient fit into? STEP 2: Assess the patient’s nutritional situation Eating meals or receiving bolus tube feedings Eating Eating meals but with unpredictable intake Getting continuous tube feedings Getting tube feedings for only part of the day Getting parenteral nutrition NPO Tube feedings NPO STEP 3: Decide which components of insulin the patient will require and percentage of TDD each should represent Our Patient Eating regular meals Basal insulin can generally be estimated to be half of the TDD Nutritional insulin makes up remaining half of the TDD 50:50 8 Managing Hyperglycemia in Inpatients: Ensuring Success STEP 3: Decide which components of insulin the patient will require and percentage of TDD each should represent Our Patient Step 1: TDD − Weight 100 kg (0.6 units/kg) = 60 units In most cases, basal insulin should be provided Step 2: Nutrition pattern When a patient is not receiving nutrition, nutritional insulin should not be given Step 3: Insulin components and ratio − Eating regular meals Nutritional insulin needs must be matched to the actual nutritional intake − 50:50 In most cases, well-designed corrective insulin regimens should be provided − Bolus – lispro 10 units qac − Basal – glargine 30 units − Correction scale - lispro qac and qhs (moderate-high) qac = before every meal qhs = at bedtime Enlargement on page 14 Correction Insulin Low Dose Correction STEP 4: Assess blood glucose at least daily, adjusting insulin doses as appropriate Moderate Dose Correction Blood glucose targets can only be achieved via continuous management of the insulin program 1:50 >150 mg/dL qac and >200 mg/dL qhs High Dose Correction 1:25 >150 mg/dL qac and >200 mg/dL qhs There is no “autopilot” insulin regimen for a hospitalized patient! 1:25 >150 mg/dL, starting at 3 units qac and >200mg/dL, starting at 4 units qhs What insulin regimen would you use now? Our Patient Overnight the patient decompensated on the floor (blood pressure 98/55 mm Hg), and a rapid response was called a. Continue current glycemic regimen b. Withhold all subcutaneous insulin and start IV insulin infusion c. Restart home NPH of 20 units subcutaneous at bedtime d. 2 units regular insulin every 1 hour subcutaneous until BG <150 mg/dL − Transferred to ICU, started on norepinephrine drip at 10 mcg/min, and intubated Blood glucose levels during the night − 201 mg/dL (2400) − 248 mg/dL (0600) 9 Managing Hyperglycemia in Inpatients: Ensuring Success Enlargement on page 14 Our Patient: Glucose Management Report Our Patient Patient extubated, off pressors Team would like recommendations to transfer off insulin drip so he can go to floor Transition Step 1 Our Patient: IV Insulin Administration BG (mg/dL) Insulin infusion rate (units/hr) Is the patient ready for transition? Patient is not critically ill or requiring pressors Blood glucose in target range all of last 6 hours Transition Step 2 No Yes Continue Insulin Drip Continue to step 2 Transition Step 3 Does patient need scheduled subcutaneous insulin? Calculate total daily dose insulin requirement (TDD) No Patients with no history of diabetes and A1c <6% Yes All patients with T1DM Patients with T2DM and insulin rate >1 unit/hour Patients with A1c >6% TDD = (average drip rate)_____ units/hr x 20 hr Note: approximately 80% of 24 hr = 20 hr No Yes Transition to correction scale only Continue to Step 3 10 Managing Hyperglycemia in Inpatients: Ensuring Success Transition Step 3 Approximate 6-hour total = 14.7 units BG (mg/dL) Insulin infusion rate (units/hr) Calculate total daily dose insulin requirement (TDD) 14.7 units / 6 hours = 2.5 units/hour TDD = (average drip rate) 2.5 units/hr x 20 hr TDD = 50 units Transition Step 4 Full Nutrition Full nutrition: Patient is currently eating >50% of his/her meals, on goal parenteral nutrition or tube feedings, dextrose IV fluid >50 mL/hr • Patient currently eating >50% of his/her meals • On goal TPN or tube feeds • Dextrose IV fluid >50 mL/hr Minimal nutrition: Patient is currently NPO, eating <50% of his/her meals, is on a zero carbohydrate clear liquid diet, or 6 hours used in step 3 calculation is a period of fasting (overnight) Minimal Nutrition: Our Patient: Designing Transition Regimen Calculated insulin = basal insulin • Patient currently NPO or eating<50% of his/her meals • Zero carbohydrate clear liquid diet • 6 hours used in step 3 calculation is period of fasting (overnight) • Give 50% of TDD as basal insulin 2 hr before stopping infusion • Give 50% of TDD as nutritional insulin divided TID if tolerating meals (lispro) or every 6 hr if on continuous tube feeds (regular) • Correction scale Transition step 1: Patient is ready to transition Transition step 2: A1C 10%, patient needs scheduled insulin Transition step 3: TDD = 50 units (weight based 50-60 units) • Give 100% TDD as basal insulin 2 hr before stopping infusion • Add nutritional insulin when clinically indicated • Correction scale Transition step 4: Eating regular meals Insulin components and ratio 50:50 − Basal – glargine 25 units − Bolus – lispro 8 units qac − Correction scale – lispro qac and qhs (moderate) 11 Managing Hyperglycemia in Inpatients: Ensuring Success Transition Step 5 Conclusion Protocols every institution should have Assess blood glucose values at least daily, adjusting insulin doses as appropriate − How to initiate a basal-bolus insulin regimen − Continuous IV insulin infusion − Transition from IV insulin infusion to a basal bolus regimen − Hypoglycemia − Nutrition on hold unexpectedly − Diabetic ketoacidosis − Continuous quality improvement monitoring 12 Managing Hyperglycemia in Inpatients: Ensuring Success Types of Insulin Diabetes Education Online: Diabetes Teaching Center at the University of California, San Francisco. Table of insulin action. URL in ref list. Used with permission. Which pattern of nutrition does your patient fit into? Eating Tube feedings NPO 13 Managing Hyperglycemia in Inpatients: Ensuring Success Correction Insulin Low Dose Correction 1:50 >150 mg/dL qac and >200 mg/dL qhs Moderate Dose Correction High Dose Correction 1:25 >150 mg/dL qac and >200 mg/dL qhs 1:25 >150 mg/dL, starting at 3 units qac and >200mg/dL, starting at 4 units qhs Our Patient: Glucose Management Report 14 Managing Hyperglycemia in Inpatients: Ensuring Success Overview Issues and Special Populations for Inpatient Glycemic Management Identify controversies in goal glucose values in patient specific populations Determine whether patients in specific situations are at greater or lesser risk of hyperglycemia or hypoglycemia Examine approaches for managing hyperglycemia in special populations of hospitalized patients Paul M. Szumita, Pharm.D., BCPS Clinical Pharmacy Practice Manager Director, Critical Care Pharmacy Residency Brigham and Women’s Hospital Boston, Massachusetts What is your opinion on the goal glucose in critical care setting? a. Guidelines have it right on the money b. Would like goal glucose higher than current guideline c. Would like goal glucose lower than current guideline d. Would like another large RCT to put controversy to bed ICU Goal Glucose Controversy Hypoglycemia and Mortality: Australian Database Analysis Hyperglycemia and Mortality: Stamford Hospital Analysis 45 Mortality Rate (%) 40 Hypoglycemia 35 Incidence (%) Hospital Mortality (%) Adjusted OR (95% CI)* 30 None 92.9 15.7% 1.0 25 < 73 mg/dL 6.2 29.5% 1.5 (1.3-1.6) < 40 mg/dL 0.9 57.4% 2.6 (2.1-3.2) 20 15 *Covariate adjustment for age, sex, surgical status, primary diagnosis, comorbid illness, APACHE II, mechanical ventilation, acute kidney injury, and hospital site 10 5 0 80–99 100–119 120–139 140–159 160–179 180–199 200–249 250–299 Similar trends were seen when patients were stratified by MICU, SICU, cardiothoracic ICU, and sepsis > 300 Mean Glucose Value (mg/dL) Database analysis of 24 Australian ICUs and 66,184 adult ICU admissions for >24 hours from January 1, 2000, to December 31, 2005 Single center retrospective analysis of 1,826 consecutive MICU/SICU patients, whole blood glucose values during ICU stay, October 1, 1999 - April 4, 2002 Krinsley JS. Mayo Clin Proc. 2003; 78:1471-8. Bagshaw SM et al. Crit Care Med. 2009; 37:463-70. 15 Managing Hyperglycemia in Inpatients: Ensuring Success Enlargement on page 23 Leuven I Leuven II VISEP Glucontrol NICE SUGAR SICU MICU Sepsis Mixed ICU Mixed Protocol Heterogeneity Mixed Centers 1 1 18 19 42 Sample size 1548 1200 488/537 1011 ~6030 Diabetic ~13% ~17 ~30% ~19% ~20% Excluded 14 863 1,612 ? 34,067 Stopped early No No Yes Yes No Primary diet TPN 85% TPN 85% 60% TPN 27% TPN 25% TPN APACHE II ~9 ~23 ~20 ~15 ~21 Mortality ICU: ~ 7% Hos: ~10% ICU: ~25% Hos: ~40% 28 Day: ~27% ICU: ~16% Hos: ~22% 28 Day: ~21% Hypoglycemia IIT: 5% Control: 2% IIT: 18.7 % Control: 3.1% IIT: 17% Control: 4.1 % IIT: 9.8 Control: 2.7% IIT: 6.8 % Control: 0.5% Protocol Leuven Leuven Leuven Variable ? NICE Target (mg/dL) 80-110 80-110 80-110 80-110 81-108 Control (mg/dL) Timing Duration < 180 < 180 < 180 140-180 144-180 ICU admit ICU admit < 12 hrs ? < 24 hrs ICU stay ICU stay ICU/ 21 days ICU or 56 days Eating or 90 days Mortality in RCTs Targeting 80-110 mg/dL 30 Mortality Rate (%) ICU 25 5 Mortality Rate (%) 27.5 24.9 25.6 8 4.8 P = 0.31 P = 0.74 Leuven MICU* VISEP** P = 0.5 P = 0.02 P < 0.04 Glucontrol* NICESUGAR*** van den Berghe G et al. N Engl J Med. 2001; 345:1359-67; van den Berghe G et al. N Engl J Med. 2006; 354:449-61; Brunkhorst FM et al. N Engl J Med. 2008; 358:125-39; Preiser JC et al. Intensive Care Med. 2009; 35:1738-48; Finfer S et al. N Engl J Med. 2009; 360:1283-97. Intensive Insulin Therapy in Critically Ill Surgical Patients 38.1 31.3 Mortality Sepsis Dialysis Blood Transfusion Polyneuropathy 22.122.3 20.2 10.6 Not available P = 0.05 Reduction (%) Not available P = 0.95 34% Leuven SICU Leuven MICU > 5days* > 3 days* 31% of cohort Control 16.7 15.2 10 Mortality in Patients with Extended ICU Stay *ICU Intensive Control P = 0.005 24.7 15 Leuven SICU* van den Berghe G et al. N Engl J Med. 2001; 345:1359-67; van den Berghe G et al. N Engl J Med. 2006; 354:449-61; Brunkhorst FM et al. N Engl J Med. 2008; 358:125-39; Preiser JC et al. Intensive Care Med. 2009; 35:1738-48; Finfer S et al. N Engl J Med. 2009; 360:1283-97. **28 day ***90 day Intensive 26.8 24.2 20 0 IIT = intensive insulin therapy 45 40 35 30 25 20 15 10 5 0 *ICU **28 day ***90 day 63% of cohort VISEP > 5 days** Glucontrol* NICESUGAR*** 41% 46% 44% 50% 92% of cohort van den Berghe G et al. N Engl J Med. 2001; 345:1359-67; van den Berghe G et al. N Engl J Med. 2006; 354:449-61; Brunkhorst FM et al. N Engl J Med. 2008; 358:125-39; Preiser JC et al. Intensive Care Med. 2009; 35:1738-48; Finfer S et al. N Engl J Med. 2009; 360:1283-97. van den Berghe G et al. N Engl J Med. 2001; 345:1359-67. Intensive Insulin Therapy in Medical ICU Patients NICE SUGAR: More Morbidity = More Mortality? Mortality Morbidity Outcome - Significantly reduced in patients in ICU ≥ 3 days Days mechanical ventilation, mean ± SD Morbidity significantly reduced in all patients - Decreased weaning time from mechanical ventilation - Decreased time to discharge from ICU - Decreased time to discharge from the hospital Intensive n=3014 Conventional n=3011 P Value 6.6 ± 6.6 6.6 ± 6.5 0.56 (+) Blood culture 12.8% 12.4% 0.57 Renal-replacement therapy 15.4% 14.5% 0.34 Red blood cell transfusion 42.1% 41.3% 0.56 Polyneuropathy not reported What is the mechanism behind the small, but statistically significant increase in mortality with intensive insulin therapy at 90 days in NICE SUGAR? van den Berghe G et al. N Engl J Med. 2006; 354:449-61. Finfer S et al. N Engl J Med. 2009; 360:1283-97. 16 Managing Hyperglycemia in Inpatients: Ensuring Success Glycemic Separation in “Good” RCTs Targeting 80-110 mg/dL Intensive Hypoglycemia in RCTs Targeting 80-110 mg/dL Control Hypoglycemia defined < 40 mg/dL 153 160 153 151 140 120 100 80 103 P < 0.001 112 111 P < 0.001 P < 0.001 147 145 119 118 P < 0.001 P < 0.001 % Patients Mean glucose (mg/dL) 180 60 40 20 71 vs. 33 units/day 59 vs. 10 units/day 32 vs. 5 units/day 43 vs. 10 units/day 50 vs. 17 units/day Leuven MICU* VISEP* Glucontrol NICESUGAR* 0 Leuven * AM glucose SICU* Intensive Control 18.7 17 All variables P < 0.001 9.8 6.8 5 2 3.1 4.1 2.7 0.5 Leuven SICU Leuven MICU VISEP Glucontrol NICE-SUGAR van den Berghe G et al. N Engl J Med. 2001; 345:1359-67; van den Berghe G et al. N Engl J Med. 2006; 354:449-61; Brunkhorst FM et al. N Engl J Med. 2008; 358:125-39; Preiser JC et al. Intensive Care Med. 2009; 35:1738-48; Finfer S et al. N Engl J Med. 2009; 360:1283-97. van den Berghe G et al. N Engl J Med. 2001; 345:1359-67; van den Berghe G et al. N Engl J Med. 2006; 354:449-61; Brunkhorst FM et al. N Engl J Med. 2008; 358:125-39; Preiser JC et al. Intensive Care Med. 2009; 35:1738-48; Finfer S et al. N Engl J Med. 2009; 360:1283-97. Barriers to Inpatient Glucose Management No Ideal Protocol in the Literature Many have been described Few have been rigorously evaluated Few published protocols were ever designed to reach blood glucose goal of 80-110 mg/dL Heath care system and workers No consensus regarding goals No published “how to” No standardized approach to testing and treatment Inadequate insulin drip protocol Lack of compliance Fear of hypoglycemia Culture Accuracy of point-of-care testing (POCT) Lack of education Poor communication Lack of health care resources 20 18 16 14 12 10 8 6 4 2 0 Anger KE et al. Pharmacotherapy. 2006; 26:214-28. Examples of Published IV Insulin Protocols Yale1 Markovitz2 Leuven3 Portland4 Texas Diabetes Council5 The “Fixed” Protocol Blood Glucose (mg/dL) DIGAMI6 University of Washington7 Krinsley8 Rush University Protocol9 Northwestern University10 < 50 1Goldberg PA et al. Diabetes Care. 2004; 27:461-7. 2Markovitz LJ et al. Endocr Pract. 2002; 8:10-8. 3van den Berghe G et al. N Engl J Med. 2001; 345:1359-67. 4Furnary AP et al. Endocr Pract. 2004; 10(Suppl 2):21-33. 5Texas Diabetes Council. October 25, 2007. URL in ref list. 6Malmberg K et al. Circulation. 1999; 99:2626-32. 7Ku SY et al. Jt Comm J Qual Patient Saf. 2005; 31:141-7. 8Krinsley JS. Mayo Clin Proc. 2004; 79:992-1000. 9Donaldson S et al. Diabetes Educ. 2006; 32:954-62. 10DeSantis AJ et al. Endocr Pract. 2006; 12:491-505. Action • Stop insulin; give 25 mL of 50% dextrose; recheck BG in 30 minutes • When BG >75 mg/dL, restart with rate 50% of previous rate 50 – 75 • Stop insulin; if previous BG >100 mg/dL, then give 25 mL of 50% dextrose; recheck BG in 30 minutes • When BG >75 mg/dL, restart with rate 50% of previous rate 76 –100 • If <10 mg/dL lower than last test, decrease rate by 0.5 units/hr • If >10 mg/dL lower than last test, decrease rate by 50% • If ≥ last test result, maintain same rate 101 – 150 • Same rate 151 – 200 • If 20 mg/dL lower than previous test, same rate • If higher than previous test, increase by 0.5 units/hr > 200 • If ≥30 mg/dL lower than last test, use same rate • If <30 mg/dL lower than last test (OR if higher than last test), increase rate by 1 unit/hr Furnary AP et al. Endocr Pract. 2004; 10(Suppl 2):21-33. 17 Managing Hyperglycemia in Inpatients: Ensuring Success Multiplication Factor Concept “Multiplier” Protocol Concept: A Simple Calculation CURRENT RATE X ADJUSTMENT FACTOR (Blood glucose – 60) X multiplication factor = new insulin infusion rate for that hour - The multiplication factor used in the equation changes depending on the rate of change in glucose value over time (this factor based on rate of change in BBG over time) = NEW RATE Osburne RC et al. Diabetes Educ. 2006; 32:394-403. Davidson PC et al. Diabetes Care. 2005; 28:2418-23. BBG = bedside blood glucose What is your opinion on the importance of the diagnosis of diabetes on goal glucose? Non-Diabetics vs. Diabetics Adaptive mechanisms developed in the setting of chronic hyperglycemia in diabetic patients may decrease morbidity and mortality associated with stress-induced hyperglycemia a. All patients should have the same goal (regardless of diagnosis of diabetes) b. Patients with diabetes should have lower goal c. Patients without diabetes should have lower goal Krinsley JS et al. Curr Opin Clin Nutr Metab Care. 2012; 15:151-60. Krinsley JS et al. Crit Care. 2013; 17:R37. Association Between Mean Blood Glucose and In-Hospital Mortality No diabetes 0.8 Without Diabetes 0.4 All patients Diabetes 0.2 0 With Diabetes 50 50 Percentage Mortality 0.6 Percentage Mortality Mortality Rate Patients With Diabetes vs. Patients Without Diabetes 25 0 80-110 110-140 140-180 Mean BG (mg/dL) >180 25 0 80-110 110-140 140-180 >180 Mean BG (mg/dL) Mean Glucose (mg/dL) Krinsley et al. Crit Care. 2013; 17:R37 (adapted). Kosiborod M et al. Circulation. 2008; 117:1018-27 (adapted). 18 Managing Hyperglycemia in Inpatients: Ensuring Success Diabetes vs. No Diabetes 2013 DM vs. No-DM in ICU Diabetics Trial design 0.16 Mortality Probability - Multi-center, retrospective, cohort analysis from 12 ICUs in eight different hospitals part of the Intermountain Healthcare system - Approved by the Intermountain investigational review board 0.14 80-110 mg/dL 0.12 0.10 0.08 90-140 mg/dL 0.06 0.04 0.02 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Days Post ICU Admission Lanspa MJ et al. Chest. 2013; 143:1226-34. Lanspa MJ et al. Chest. 2013; 143:1226-34 (adapted). Insulin Needs in Special Patient Populations Diabetes vs. No Diabetes Non‐diabetics Mortality Probability 0.16 Patients receiving high dose steroids Patients receiving enteral or parenteral nutrition Patients undergoing surgery 90-140 mg/dL 0.14 0.12 0.10 0.08 80-110 mg/dL 0.06 0.04 0.02 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Days Post ICU Admission Lanspa MJ et al. Chest. 2013; 143:1226-34 (adapted). Optimizing Care of the Inpatient with Hyperglycemia Is Challenging! Case Scenario: Steroids 78-year-old woman hospitalized for worsening dyspnea and cough Inpatient situations are unstable No single algorithm is suitable for all patients Many scenarios require increased monitoring and possible adjustments in insulin dose Chronic obstructive pulmonary disease (COPD) since age 55 No prior history of diabetes - A1C 6.2% Started on methylprednisolone 40 mg IV every 6 hr BG on day 2 climbs to 210 mg/dL 19 Managing Hyperglycemia in Inpatients: Ensuring Success Basal Bolus Therapy with Emphasis on Nutritional Insulin Hyperglycemia and Steroids Common complication of glucocorticoid therapy - Prevalence 20-50% among patients without prior history of diabetes Medium-dose glucocorticoids (40-60 mg/day) tend to cause minimal increase in FPG and marked elevation in PPG Results from - Increases in hepatic glucose production - Impairment of glucose uptake in peripheral tissues All of this contributes to increases in postprandial glucose Predictors - Total glucocorticoid dose - Duration of glucocorticoid therapy - Increasing age FPG = fasting plasma glucose PPG = postprandial plasma glucose Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16-38. Clore JN et al. Endocr Pract. 2009; 15:469-74. Clement S et al. Diabetes Care. 2004; 27:553-91. Moghissi ES et al. Endocr Pract. 2009; 15:353-69. Hyperglycemia and Glucocorticoid Therapy: Summary Case Scenario: Total Parenteral Nutrition (TPN) Institute glucose monitoring for at least 48 hours in all patients 55-year-old obese man admitted for hemorrhagic pancreatitis, no prior history of diabetes BG 200 mg/dL on admission A1C 7.5% (previously unrecognized DM) Patient not eating, anticipated he will not be able to eat for one week Total parenteral nutrition started - Add or adjust insulin regimen based on monitoring results During initiation and tapering of steroid therapy, proactive adjustment of insulin therapy can help avoid uncontrolled hyperglycemia and hypoglycemia Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16-38. Moghissi ES et al. Endocr Pract. 2009; 15:353-69. General Recommendations: Hyperglycemia Associated with Parenteral Nutrition (PN) TPN, Glucose, and Patient Mortality Study Hyperglycemia Definition (mg/dL) For patients receiving PN, regular insulin administered as part of PN formulation can be both safe and effective Subcutaneous correction-dose insulin is often used in addition to insulin mixed with the PN - When starting PN, the initial use of a separate insulin infusion can help in estimating the required total daily dose of insulin Separate IV insulin infusions may be needed to treat marked hyperglycemia during PN Mortality Odds Ratio Cheung (2005) > 164 10.9 Lin (2007) Sarkisian (2010) > 180 ≥ 180 5.0 7.22 Pasquel (2010) > 180 2.80 Olveira (212) > 180 5.6 Cheung NW et al. Diabetes Care. 2005; 28:2367-71. Lin LY et al. Am J Med Sci. 2007; 333:261-5. Sarkisian S et al. Can J Gastroenterol. 2010; 24:453-7. Pasquel FJ et al. Diabetes Care. 2010; 33:739-41. Olveira G et al. Diabetes Care.35 2013; 36:1061-6. Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16-38. Moghissi ES et al. Endocr Pract. 2009; 15:353-69. 20 Managing Hyperglycemia in Inpatients: Ensuring Success Case Scenario: Tube Feedings Complications of Enteral Nutrition Prospective and observational study in 64 patients (mean age 76.2 yr) receiving EN on internal medicine inpatient unit Percent of patients 70-year-old woman admitted with a stroke Prior history of type 2 diabetes mellitus - Controlled on oral agents BG 150 mg/dL on admission, A1C 7% Currently unable to swallow Continuous enteral nutrition started on hospital day 2 60% 50% 40% 30% 20% 10% 0% 49% Most frequent complications 46% 35% 33% 30% 20% 13% 3% Should blood glucose levels be checked in patients receiving enteral nutrition? Pancorbo-Hidalgo PL et al. J Clin Nurs. 2001; 10:482-90. Glycemic Management of the Patient Receiving Enteral Nutrition Case Scenario: Surgery 60-year-old woman with type 2 diabetes mellitus treated with insulin is admitted for hip fracture Continuous enteral nutrition (EN) - Basal: 40-50% of TDD as long- or intermediate-acting insulin given once or twice a day - Short-acting insulin 50-60% of TDD given every 6 hr - Admission glucose = 180 mg/dL Cycled enteral nutrition - Intermediate-acting insulin given together with a rapid- or short-acting insulin with start of tube feeding - Rapid- or short-acting insulin administered every 4-6 hr for duration of EN administration - Correctional insulin given for BG above goal range Bolus enteral nutrition - Rapid-acting or short-acting insulin given prior to each bolus feeding Umpierrez GE et al. J Clin Endocrinol Metab. 2012; 97:16-38. Basal-Bolus vs. Sliding Scale Insulin in RABBIT 2 Surgery Study Basal-Bolus Superior to Sliding Scale Insulin (SSI) Treatment for Inpatient Hyperglycemia Mean BG (mg/dL) 240 Achievement of Glucose Goals 220 * 200 * * 180 † † † † 140 Basal-bolus insulin 120 100 2 3 4 5 6 7 8 9 10 Days of Therapy No differences in rate of hypoglycemia or hospital length of stay *P Hospital Complications* BG <70 mg/dL BG <40 mg/dL Basal bolus 8.6% 23.1% 3.8% Sliding scale 24.3% 4.7% 0% P value 0.003 < 0.001 0.057 SSI 160 Admit 1 Outcomes and Hypoglycemia *Composite of postoperative complications including wound infection, pneumonia, bacteremia, respiratory, and acute renal failure < 0.01, †P < 0.05. Error bars denote standard deviation. Insulin glargine + glulisine: 0.4 units/kg for BG 140-200 mg/dL; 0.5 units/kg for BG 201-400 mg/dL (1/2 daily dose given as basal insulin) SSI = regular insulin 4 times daily for BG > 140 mg/dL Umpierrez GE et al. Diabetes Care. 2007; 30:2181-6. Umpierrez GE et al. Diabetes Care. 2011; 34:256-61. 21 Managing Hyperglycemia in Inpatients: Ensuring Success Example Hypoglycemia Protocol Essential Part of Insulin Therapy: Hypoglycemia Protocol If patient CAN safely swallow without aspirating Clear definition of hypoglycemia If patient CANNOT safely swallow or patient has NPO status - (BG < 70 mg/dL) Nursing order to treat without delay - Stop insulin infusion (if patient on one - unless type 1 diabetes mellitus) - Oral glucose (if patient able to take oral) - IV dextrose or glucagon (if patient unable to take oral) - Repeat BG monitoring 15 min after treatment for hypoglycemia and repeat treatment if BG not up to target - Directions for when and how to restart insulin If BG 50-69 mg/dL: Give 4 oz. juice or regular soda If BG 50-69 mg/dL: Give D50W 25-50 mL (12.5-25 g dextrose) IV push If BG ≤49 mg/dL: Give 8 oz. juice or regular soda If BG ≤ 49 mg/dL: Give 1 mg glucagon IM • Recheck BG in 15-20 min. If BG <70 mg/dL, then continuously repeat until BG ≥70 mg/dL and notify provider. • Once BG >70 mg/dL, repeat BG monitoring in 1 hour and check again in 2 hours. Notify provider of insulin adjustments and changes in BG monitoring. Look for cause of hypoglycemia and determine if other treatment changes are needed • If BG level has not remained ≥70 mg/dL for both BG checks, notify provider for further insulin adjustments and changes in BG level monitoring. Moghissi ES et al. Endocr Pract. 2009; 15:353-69. Roe ED et al. Hosp Pract (1995). 2012; 40:116-25. Daily Dose Adjustment Conclusion “Best” blood glucose goal for ICU patients is yet to be established Not All IV insulin protocols are created equal (regardless of the goal) Non-diabetes patients MAY BE different from patients with diabetes and may benefit from tight glycemic control Large prospective, RCT of non-diabetic patients following tight glycemic control with multiplication factor protocol intervention is warranted All efforts to reduce hypoglycemia are warranted • Determine yesterday’s total insulin dose actually administered • Review yesterday’s glycemic control • Calculate today’s scheduled insulin dose – Some BG values < 90 mg/dL 80% of yesterday’s total – BG values 90-179 mg/dL 100% of yesterday’s total – Some BG values ≥ 180 mg/dL, no BG < 90 mg/dL 110% of yesterday’s total McDonnell ME et al. Supplement to ACP Hospitalist. December 15, 2009: pages 24-30. URL in ref list. 22 Managing Hyperglycemia in Inpatients: Ensuring Success Leuven I Leuven II VISEP Glucontrol Sepsis Mixed ICU Mixed NICE SUGAR Centers Protocol Heterogeneity Mixed 1 1 18 19 42 Sample size 1548 1200 488/537 1011 ~6030 Diabetic ~13% ~17 ~30% ~19% ~20% Excluded 14 863 1,612 ? 34,067 ICU Stopped early SICU MICU No No Yes Yes No Primary diet TPN 85% TPN 85% 60% TPN 27% TPN 25% TPN APACHE II ~9 ~23 ~20 ~15 ~21 Mortality ICU: ~ 7% Hos: ~10% ICU: ~25% Hos: ~40% 28 Day: ~27% ICU: ~16% Hos: ~22% 28 Day: ~21% Hypoglycemia IIT: 5% Control: 2% IIT: 18.7 % Control: 3.1% IIT: 17% Control: 4.1 % IIT: 9.8 Control: 2.7% IIT: 6.8 % Control: 0.5% Protocol Leuven Leuven Leuven Variable ? NICE Target (mg/dL) 80-110 80-110 80-110 80-110 81-108 144-180 Control (mg/dL) Timing Duration < 180 < 180 < 180 140-180 ICU admit ICU admit < 12 hrs ? < 24 hrs ICU or 56 days Eating or 90 days ICU stay ICU stay ICU/ 21 days IIT = intensive insulin therapy van den Berghe G et al. N Engl J Med. 2001; 345:1359-67; van den Berghe G et al. N Engl J Med. 2006; 354:449-61; Brunkhorst FM et al. N Engl J Med. 2008; 358:125-39; Preiser JC et al. Intensive Care Med. 2009; 35:1738-48; Finfer S et al. N Engl J Med. 2009; 360:1283-97. 23