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UNIVERSITY OF ILLINOIS AT CHICAGO PEDIATRIC ENDOCRINE MANAGEMENT PROTOCOLS Prepared by Dr. S. Pang , Dr. Ize-Ludlow ,and Dr. Shindu Kannan, and Nipapat V Updated June –Aug /2010 Contents I. ADRENAL CRISIS(ALL UPDATED) ........................................................................................................... 2 II. CALCIUM DISORDERS(UPDATE IN PROGRESS/THIS IS UNUPDATED VERSION) ..................... 6 HYPOCALCEMIA ........................................................................................................................................................ 6 HYPERCALCEMIA .................................................................................................................................................... 11 III. GLUCOSE DISORDERS(ALL UPDATED) ................................................................................................ 14 HYPOGLYCEMIA........................................................................................................................................................ 14 DIABETES MELLITUS ............................................................................................................................................... 24 A. Diabetic Ketoacidosis .............................................................................................................................. 24 B. Diabetic Ketosis Only.............................................................................................................................. 30 C. Nonketotic Hyperglycemic Hyperosmolar state--------------------------------------------------------------30 D. Surgical Management of the Diabetic Patient ...................................................................................... 32 VI. THYROID DISORDERS(ALL UPDATED) ................................................................................................ 33 Congenital Hypothyroidism ....................................................................................................................................... 33 Myxedema Coma ........................................................................................................................................................ 34 Hyperthyroid Storm ................................................................................................................................................... 35 Neonatal Grave's Disease (Thyrotoxicosis)............................................................................................................... 36 V. PERSITENT DYSFUNTIONAL BLEEDING IN ADOLESCENT FEMALE(NEW)------------------------38 MANAGEMENT OF SEVERE DYSFUNCTIONAL UTERINE BLEEDING(UPDATED) ................................ 388 VI. MANAGEMENT OF DIABETES INSPIDUS( IN PREPARATION)---------------------------------------Division of Pediatric Endocrinology. University of Illinois Hospital (UIH) and Daytime UIH Office # (312)996-1795 Evening/Weekend UIH Call Service # (312)649-2639 –updated Call attending who is on service (pls refer to call schedule) I. ADRENAL CRISIS Emergency Management for Adrenal Insufficiency Adrenal Crisis - Signs and symptoms: Dehydration Vomiting Hypotension Lethargy Diarrhea Shock Tachycardia Fever Adrenal crisis may be triggered by infection, trauma or surgery. Immediately draw blood sample while starting an IV and send for stat electrolytes, glucose, pH, CO2 HCO3, BUN, CBC and differential In addition to the above blood sample: - For suspected adrenal insufficiency, send blood for: cortisol and aldosterone (3cc in red top tube) plasma renin activity (PRA) (2.5cc chilled) ACTH (purple top tube) - For suspected congenital adrenal hyperplasia (CAH), send blood for: 17-hydroxyprogesterone and androgen levels (2-3 cc in red top tube) - Do EKG. This is a medical emergency that requires prompt recognition and treatment. It may be precipitated in the hypofunctional adrenal cortical conditions (e.g., CAH, Addison's Disease), when patients are not yet diagnosed, are noncompliant with therapy, or are stressed with trauma or bacterial infection or during surgery in adrenal insufficient patients. There may be significant hyponatremia, hyperkalemia, hypoglycemia and dehydration with shock. 1. Glucocorticoid replacement: Administer hydrocortisone sodium succinate (Solu-Cortef) in a stat dose of 2.0 mg/kg IV push or IM. One may estimate the emergency dose of hydrocortisone by IV bolus as follows: for an infant, give 25 mg; for a small child, 50 mg; a larger child or adolescent, 100-150 mg. After the initial dose of Solu-Cortef use hydrocortisone at 100 mg/m2/day as continuous IV infusion or q6 hours by IV bolus or IM (if an IV line cannot be established). For continuous IV infusion: In children < 2 years of age: mix 50 mg Solu-Cortef in 100 ml NS and infuse at a rate of 4 ml/hr. IV piggyback. In children > 2 years of age: mix 100 mg Solu-Cortef in 100 ml NS and infuse at a rate of 4 ml/hr. IV piggyback. If the patient's condition does not improve or deteriorates another bolus infusion of Solu-Cortef may be given. 2. Fluid replacement: a) In children who are severely dehydrated and hypotensive, give normal saline in 5%dextrose at 20 ml/kg over 1 hour. This dose may be repeated if needed for 1 more hour. If in shock, give colloid 10 cc/kg over 50 - 60 minutes until stabilized and switch to D5½NS. b) Thereafter, administer IV fluid to correct deficit + maintenance + ongoing losses as per the degree of dehydration. Calculate 24-hour fluid requirements as follows: Use NS or ½NS in 5-10% dextrose: - For 10% dehydration: Deficit: 100 ml/kg, wt./day (except adolescents & adults) + Maintenance: 100 ml/kg, wt. for up to 1-10 kg 50 ml/kg, wt. for up to 11-20 kg 20 ml/kg, wt. for up to >20 kg + Ongoing losses. Administer ½ of the total fluid requirement during the first 8 hours (this includes the amount given as bolus in the first 1-2 hours), and administer ½ over the next 16 hours. - For children with mild (5%) or moderate (5 - <10%) dehydration: Calculate the maintenance fluid requirement and administer 1.5 (5%) and 2 (5-10%) times maintenance respectively over 24 hours as NS or ½NS in 5-10% dextrose, half within the first 8 hours and half in the next 16 hours. - For children without dehydration: Administer 1.5 maintenance equally over 24 hours as ½NS in D5-10% dextrose. c) Do not add K to IV fluids until K level is <5 meq/L and the patient is urinating and administer only daily maintenance K requirement. 3. Replacement of mineralocorticoids: Pharmacologic doses of hydrocortisone and fluid/electrolyte therapy are usually sufficient for initial management of adrenal crisis: When the child is tolerating oral fluids, Florinef (9α- fludrocortisone) should be given orally at maintenance (0.05 0.1 mg/day) or double or triple maintenance (0.1 - 0.3 mg) if necessary until the crisis is over (make sure patients' BP is not hypertensive either). 4. In the child with hypoglycemia: Give IV bolus of 2-4 ml/kg of 25% dextrose. (In neonates the dose is 2 ml/kg of 10% dextrose). Thereafter the parenteral glucose should be administered at a rate sufficient to maintain the plasma glucose level at a range of 60-100 mg/dl 5. Hyponatremia: Calculate Na+ requirement as follows: Deficit: (Normal serum Na+- observed serum Na+) x body weight(kg) x 0.6 Maintenance: 2-3 meq/kg/24 hours. Replace half the deficit over 8-12 hours along with the maintenance for that period of time. 6. Hyperkalemia: May cause cardiac arrhythmia and cardiac arrest, every patient must have an EKG and a cardiac monitor. Periodic EKG rhythm strips should be run to detect the cardiac effects of hyperkalemia. Management of patients with hyperkalemia: a) If serum K+ > 6 meq/L: Kayexalate may be given by enema. Each 1 g Kayexalate will decrease the K+ level by 1 meq/L. If serum K+ is 7 meq/L give 3g of Kayexalate to reduce serum K+ to 4 meq/L. This may be repeated at 4-6 hours if necessary. b) If serum K+ > 7 meq/L add: Sodium bicarbonate 2-3 meq/kg infusion by IV. c) In an emergency you may use IV regular insulin with excessive glucose in IV solution but watch to avoid hypoglycemia. d) If the EKG shows changes related to hyperkalemia (peaked T waves, prolonged PR intervals, bradycardia, disappearance of P waves (sinoventricular rhythm), widened QRS complex, a full blown sine wave pattern that can lead to ventricular fibrillation and asystole) then administer 10% Ca Gluconate by IV at a rate of 0.5 cc/kg over 10 minutes (monitor heart rate closely). e) If all of the above fail to correct hyperkalemia, perform dialysis. 7. Do not overtreat the patient either. Overtreatment may lead to sodium and fluid overload with resulting hypertension, hypernatremia, edema, congestive heart failure, and hypokalemia, with muscle weakness. Monitor the patient's clinical condition, weight, input/output, blood pressure, EKG, and serum electrolytes very closely. As the patient recovers and is able to tolerate liquids: Taper IV fluids and medications over a few days to a maintenance glucocorticoid and Florinef replacement dose. -3- - Maintenance dose: Hydrocortisone: 12.5-25 mg/m2/day in 2-3 doses. Florinef: 0.05 - 0.2 mg/day Management of Non-crisis Stress in Patients with Chronic Adrenal Insufficiency 1. For febrile illness: a) Double or triple hydrocortisone dose depending on the condition of the patient. b) If the child cannot tolerate oral therapy, as with severe vomiting or if she/he is rapidly becoming sleepy or unconscious, the drug must be given parenterally (IV or IM). Stress dose of parenteral hydrocortisone is 50 mg in small children and 100 mg in older children or adults one time for coverage. c) Continue the above-stress dose for the duration of the illness. 2. For surgery: a) Elective surgery: Give 2-3 times the evening maintenance dose of glucocorticoid orally or IM the night before surgery. In the morning on-call for surgery: Give Solu-Cortef or cortisone acetate 50 mg/m2/dose IM and establish an IV line for fluid administration. In the operating room: Give 75-100 mg/m2 by continuous IV infusion of Solu-Cortef before general anesthesia is started, and continue throughout surgery. Post-operatively: Give Solu-Cortef 100-150 mg/m2/day in 3-4 divided doses IV or IM. As patient recovers, usually 1-2 days post-op, gradually taper the dose or frequency until maintenance dose is reached. Hydrocortisone may be given orally if the patient is allowed and can tolerate oral food intake. b) Emergency surgery: Administer hydrocortisone 50 mg IV or IM on-call to operating room for a small child and 100 mg IV or IM for larger child or adolescent, and continue same management during and post-surgery as above. 3. During trauma: Give 2-3 times maintenance dose of hydrocortisone depending on the patient's condition. If surgery is required, follow surgical stress management. -4- - In all stress conditions (febrile illness, trauma or surgery), Florinef dose generally is the same as long as the patient is able to eat and drink well. However, if the patient vomits or is having diarrhea, the patient must be given IV fluid therapy. - Reference normative data differ between the labs. Refer to the assay lab normative data. Age Cortisol (μg/dL) 1-14 d --- 17d-5.75m --- 6m-7y --- >7y --- Tanner I --- Tanner II-III --- Tanner IV-V --- For all ages 8AM level: 8-26 4PM level: 3-12 Midnight: 1-4 NORMATIVE STEROID LEVEL (Male) SERUM Aldo 17-OHP* DHEA DHEA-S (ng/dL) (ng/dL) (ng/dL) (μg/dL) 100 35-211 <10-2000 <10-200 (<10-300) 20 14-105 <10-200 <10-80 (<10-150) 60 35 14 10-79 +40 +24 +16 60 11-69 ----+40 63 46 41 (7-140) (5-154) (7-148) 63 171 140 10-62 (30-150) (63-457) (56-240) 110 400 185 (25-200) (80-800) (80-350) --- --- --- --- 17-OHCS (mg/d) 0-2 yr = 1.1-6.8 2-10 yr = 6.6-10.9 10-14 yr = 4.1-14.2 --- URINE 17-KS (mg/d) P’triol (mg/d) --- --- --- --- 1.62 +1.2 1.62 +1.2 1.62 +1.2 2.6 +1.0 9.3 +4.4 0.06 +0.06 0.06 +0.06 0.10 +0.08 0.13 +0.05 1.11 +0.62 --- --- Age Cortisol (μg/dL) 1-14 d --- 17d-5.75m --- 6m-7y --- >7y --- Tanner I --- Tanner II-III --- Tanner IV-V --- 8AM level: 8-26 4PM level: 3-12 Midnight: 1-4 *Acceptable range of treated CAH: BL: Blank CHEA: Dehydroepiandrosterone DHEA-S: Dehydroepiandrosterone-Sulfate 17KS: 17-Ketosteroid For all ages NORMATIVE STEROID LEVEL (Female) SERUM Aldo 17-OHP* DHEA DHEA-S (ng/dL) (ng/dL) (ng/dL) (μg/dL) 100 35-211 <10-2000 <10-200 (<10-300) 20 14-105 <10-200 <10-80 (<10-150) 60 43 16 10-79 +40 +38 +17 60 11-69 ----+40 63 46 41 (7-140) (5-154) (7-148) 76 257 115 10-62 (40-182) (51-414) (41-211) 93 343 180 (20-260) (72-741) (71-340) --- --- --- --- 17-OHCS (mg/d) 0-2 yr = 1.1-6.8 2-10 yr = 6.6-10.9 10-14 yr = 4.1-14.2 --- 300-800 ng/dL Aldo: Aldosterone 17-OHP: 17-hydroxyprogestrone 17-OHCS: 17-hydroxycorticosteroid P’trial: Pregnanetriol POTENCIES OF GLUCOCORTICOID PREPARATIONS Glucocorticoid Potency Equivalent Steroid (hydrocortisone) Glucocorticoid Dose Short-Acting Cortisol 1.0 20 Cortisone 0.8 25 Prednisone 3.5 5 Prednisolone 4.0 5 Intermediate Triamcinolone 5.0 4 Long-Acting Betamethasone 25.0 0.6 Dexamethasone 30 (may be 100) 0.75 -5- URINE 17-KS (mg/d) P’triol (mg/d) --- --- --- --- 1.1 +0.03 1.1 +0.03 1.1 +0.03 2.0 +0.8 10 +5 0.06 +0.06 0.06 +0.06 0.10 +0.08 0.19 +0.4 0.69 +0.25 --- --- II. CALCIUM DISORDERS (this section is currently being updated and the below is un-updated version as of 2010-when updated this notation will not appear) - HYPOCALCEMIA Definition: Total serum calcium concentration generally < 8.6 mg/dl in the presence of a normal serum albumin concentration* or as an ionized serum calcium concentration generally < 4.5 mg/dl or as per UIH lab's normative calcium level as of October 96 (<4.2 mg/dl). * The total serum calcium concentration decreases approximately 0.8 mg/dl for each 1 gm/dl decrease in serum albumin concentration. Work-up in Hypocalcemic Patients Neonates: Family Hx of calcium disorder: Pregnancy Hx: Maternal: Ca^ level, hyperparathyroidism, diabetes mellitus Perinatal Hx: Gestational age, intra-partum events Neonatal Hx: Check intake of high phosphorous formula such as PM 60/40 formula Physical symptoms: - Jitteriness, seizures, apnea, tremors - Low Ca++ level may be associated with prematurity, birth asphyxia, congenital heart disease, infant of diabetic mother Work-up: Obtain blood for: 1. Ca (total and ionized), P, Mg, total protein, Cr, BUN, pH. 2. PTH level 3. VitD level (25-OH vit D) 4. Chromosomal analysis for 22 q 11 deletions to rule out DiGeorge syndrome (CATCH 22 syndrome) 5. EKG: QT internal increase in hypocalcemia, decrease in hypercalcemia 6. Chest X-ray: Thymic shadow, aortic arch position to look for DiGeorge syndrome (CATCH 22 syndrome) Older Children Check for: - Chvostek's sign - Trousseau signs (carpopedal spasm) - Danger of laryngospasm - Look for signs of pseudohypoparathyroidism (obesity, short stature) Work-up: Obtain blood for: 1. Ca (total and ionized), P, Mg, total protein, A/G ratio, Cr, BUN, pH, alkaline phosphatase, SGOT, SGPT, electrolytes. 2. T4 level 3. Cortisol level ┐to look for autoimmune 4. Anti-adrenal/parathyroid antibodies ┘endocrine failure 5. Obtain 24-hr urine for creatinine and phosphorous excretion 6. Skull X-ray or flat plate of abdomen to look for ectopic calcification 7. Ophthalmologic examination with slit lamp to look for ectopic calcification Symptomatic Hypocalcemia (GUIDELINE) -6- Neonates and Older Children - Use slow IV infusion of: 10% Ca Gluconate (1 ml = 9.3 mg of Ca++) 1-2 ml/Kg BW (up to 10 ml total/hr) in diluted solution with equal amount of DW - For convulsion: 10% Ca gluconate (CG) IV (2 ml/Kg) very slowly (at least over 10 minutes) until seizure ends (max 1020 cc in older children) - Maintain IV Ca at 2-3 mg Ca++/Kg/Hr = 50-70 mg Ca++/Kg/day - Reduce IV rate by 50% over 2 days - Do not add to IV solution containing NaHCO3 or phosphate (may cause precipitation) - Use a freely running IV-line to avoid extravasation and tissue necrosis - Monitor heart rate and discontinue Ca++ for bradycardia - Serial Ca level to assess the need - If serum Ca level does not return to normal, a coexisting Mg deficiency may be present. If Mg level < 1.5 mg/dl Add Mg Supplement - SEVERE: Mg sulfate 50% IM 0.2 ml/Kg q 8-12 hours - MILD: Mg sulfate 0.2-1.2 mL/Kg/day P.O. - Start oral Ca and vit D supplement as soon as patient tolerates oral intake. Symptomatic/Asymptomatic/Mild Hypocalcemia (GUIDELINE) Maintain Oral Elemental Ca - In neonate: Ca++ 75 mg/Kg/day divided q 4-6 hours - In older infants and children: Ca++ 50 mg/Kg/day Ca Gluconate (9% Ca++) 10% CG 10 CC = 1 GM CG = 93 mg Ca++ 1 Tab = 500 mg CG = 46 mg Ca++ - Neo-Calglucon Syrup (6.3% Ca++) 5 CC = 1.8 GM Neo-Calg =115 mg Ca++ - HYPEROSMOLAR - WATCH FOR DIARRHEA Calcium Lactate (13% Ca++) 1 Tab = 325 mg CL = 42 mg Ca++ = 650 mg CL = 84 mg Ca++ -7- Vitamin D Preparation: Compound (Trade name) Cholecalciferol (D3) (= Delta D) Calciferol (D2) (= Drisdol) Dihydrotachysterol (DHT) (= Hytakerol) Calcitrol Onset of Action (hrs) Calcium Increases Significantly Peak Activity (wks) Blood Half Life Duration of Biological Activity 8-24 in 2 wks 4-8 30 days 4-16 wks 8-24 in 2 wks 4-8 30 days several months (4-16 wks) in a few days-1 mos. 1-2 ---- 1-2 wks ---- 5-16 hrs up to 20 days in 1-4 days with 0.3 g/kg/day <4-6 PO=1.25 cholecalciferol (Active D3 = Rocalcitrol) IV=If malabsorptionIV (Calcijex) .01-.05 g/kg/day PRN or 3 times/wk Short-term onset Calcidriol = calcifediol ------2-4 15 days 4-12 wks (25 OH D3 = Calderol) Extracted from references: Peds 57:729, 1976; JCEM 45:457, 1977; J of Peds 88:177, 1976; JCEM 55:238, 1982; Harrison and Harrison, Disorders of Ca and Phosphate Metabolism in Childhood and Adolescence, 1979, p. 71. Recommended dose of Vitamin D preparation in Infants and Children: Compound Cholecalciferol (Vit D3) Calciferol Dihydrotachysterol (DHT) Calcitriol = 1,25-(OH)2-D3 = 1,25-OH-cholecaeciferol = active vit D3 =Rocaltrol 1-OH3 (synthetic analog of active Vit D3 Calcidriol (25 OH D3) =Calderal -8- During Hypocalcemic Time Adjust Dose for Maintenance as per Ca++ Level --- --- 0.125 mg (5,000 U) /kg/day Maximum 50,000 IU/day 1000-5000 IU/day Start with high maintenance or with higher than maintenance dose. 0.05-0.2 mg infant/day 0.2-1.5 mg child/day 0.01-0.02 mg/kg/day 0.25 g/capsule 0.5 g/capsule Gradual increase in dose 0.25-0.5 g/day as starting dose or 0.03 g/kg/day 0.25-1 g/day --- Not well established Not well established 20 g/capsule 50 g/capsule ---- 50-200 g/day Dose 400 U/Tab or 1000 U/Tab 1.25 mg/Tab = 50,000 U * 8,000 U/mL 0.125 mg/Tab 0.2 mg/Tab 0.4 mg/Tab 0.2 mg/5 ml 0.125 mg/capsule 0.25 mg/ml (crystalin/mg/ml of vegetable oil can be prepared) Extracted from reference: J. of Endo 91:1006, 1977; JCEM 45:456, 1977; Harrison & Harrison Disorders of Calcium Metabolism in Childhood and Adolescence, 1979, p.71. Aims of Treatment in Hypocalcemic Patients (Patients Receiving Vitamin D Supplement) The primary goal is to abolish hypocalcemic symptoms and normalize Ca++ levels and avoid hypercalcemia. Biochemical 1. To maintain serum calcium level 8.5-9.0 mg/dl. If serum calcium >10.5 mg/dl, discontinue treatment temporarily until serum calcium level <9.5 mg/dl. ↑ fluid intake, ↓ food intake high in Ca. 2. To maintain urine calcium excretion <3 mg/kg/24h or spot urine Ca/Cr < 0.1. If >3 mg/kg/day, or spot urine Ca/Cr > 0.2, then reduce the dose to maintain lower serum calcium level without hypocalcemic symptoms. Clinical Follow-up 1. Serial determination of serum Ca, P: pm or at least every 3 months. 2. Serial determination of urine calcium excretion: pm or at least every 6 months - 1 year. 3. Serial determination of creatinine clearance: pm or at least every 1 year. 4. Ophthalmology examination for band keratopathy and lenticular opacities (cataracts): pm or every 1 year. NORMAL RANGE IN SERUM GROUP TOTAL Ca (mg/dl) P (mg/dl) Other UIHLab Other UIHLab Other UIHLab Premature 7-11 8.6-10.4 5.4-10 4.5-6.5 100-400 100-400 Full-Term 7-11 8.6-10.4 3.5-8.6 4.5-6.5 100-400 100-400 Infant 9-11 8.6-10.4 4.5-6.7 4.5-6.5 100-400 ↑↑ 100-400 8.8-10.5 8.6-10.4 4.5-5.5 4.5-6.5 100-400 ↑ 100-400 Puberty (>10yrs.) 8.5-10.4 8.6-10.4 3.0-4.5 3-4.5 100-400 ↑↑↑ 100-400 Adult(>18yrs.) 8.5-10.4 8.6-10.4 3.0-4.5 3-4.5 57-154 40-125 Childhood -9- ALKALINE PHOSPHATASE N-METAPHENYL PHOSPHATE (u/L) Laboratory Data in the Differential Diagnosis of Hypocalcemia* 25Resistance to Hydroxyvitamin Chronic PseudoVitamin D 1,25Hypoparathyroidism Hypomagnesemia D3- 1αRenal hypoparathyroidism Deficiency Dihydroxyvitamin Hydroxylase Disease D3 Deficiency Total ↓ Calcium Ionized ↓ Calcium Phosphorus ↑ Magnesium N↓ Alkaline N phosphatase Parathyroid ↓ hormone 25-OH-D3 N 1,25(OH)2D3 N↓ * ↓ = decreased; ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑ N ↑ ↓ ↓ N ↓ N ↓ N ↑ N↑ N N ↑ ↑ ↑ ↑ ↑ ↓ ↑ ↑ ↑ ↑ N N ↓ ↓N↑ N ↓ N ↑↑↑ N ↓ N N↓ ↑ = increased; N = normal Biochemical Abnormalities in Various Types of Rickets* Alkaline Type of rickets Ca++ Phosphate HCO3PTH Phosphatase Nutritional ↓ ↓N↑ ↑ N ↑ 1α-Hydroxylase deficiency ↓ ↓ ↑ N ↑ Calcitriol resistance ↓ ↓ ↑ N ↑ Familial hypophasphatemic N ↓ ↑ N N↑ HHRH N ↓ ↑ N ↓ Tumor rickets N ↓ ↑ N N McCune-Albright syndrome N ↓ ↑ N N Uremia ↓N↑ ↑ ↑ ↓ ↑↑ Fanconi syndrome N ↓ ↑ ↓ ↑ Hypophosphatasia N ↑ ↓ N N Epiphyseal dysplasia N N N N N -10- Calcifediol Calcitriol ↓ N N N N N N N N N N ↓N↑ ↓ ↑ N ↑ ↓N N ↓ ↓N N N HYPERCALCEMIA Definition: A child or infant can be considered to be hypercalcemic if serum total calcium concentration is >10.8 mg/L or when ionized calcium (= Ca++) concentration is >5.6 mg/L. To Determine Nature of Underlying Disorder Neonatal Hypercalcemia - Phosphate deficiency Parenteral nutritional deficiency Very low birth-weight infants fed human milk or (less commonly) standard formula - Hypervitaminosis D Excessive maternal vitamin D intake - Hyperparathyroidism Congenital parathyroid hyperplasia Maternal hyperparathyroidism Maternal and neonatal renal tubular acidosis - Mutations in Ca++-sensing receptor gene Neonatal, severe (primary) hyperparathyroidism Familial, hypocalciuric hypercalcemia - Uncertain pathophysiological mechanism Idiopathic infantile hypercalcemia Severe infantile hypophosphatasia Subcutaneous fat necrosis Blue diaper syndrome - Chronic maternal hypercalcemia (?) Thyrotoxicosis Chronic thiazide diuretic, lithium therapy Vitamin A intoxication Causes of Hypercalcemia in Children and Older Subjects - Hyperparathyroidism Congenital Autosomal recessive/dominant Multiple endocrine neoplasia types I, IIA, (IIB) Acquired (adenoma or hyperplasia) Secondary (post-renal transplantation) - Familial hypocalciuric hypercalcemia - Hypervitaminosis D Nutritional Granulomatous/inflammatory diseases (sarcoidosis, leprosy, tuberculosis) - Immobilization - Neoplasia Secreting Parathyroid hormone-like protein Osteoclast activating factor(s) - Others Hyperproteinemia Hypophosphatemia Drugs (thiazides, lithium, vitamin A) Hyperthyroidism -11- History: - Age of patient, growth and developmental milestones - Vit D and A ingestion, medications, dietary history, ingestion of milk and alkali - History of hypothermia - History of renal failure - History of muscle injury, other associated disorders - History of maternal hypoparathyroidism - History of chronic maternal hypercalcemia: thyrotoxicosis, chronic thiazide diuretics, lithium treatment, vit A intoxication, excessive maternal vit D intake - Familial history Physical examination: - Features of patient congenital heart disease (William's syndrome) - Subcutaneous fat necrosis - Lymph node enlargement, hepatosplenomegaly - Thyroid enlargement Laboratory tests for differential diagnosis: - Major differential test: serum PTH, serum vit D metabolites, alkaline phosphatase - Ancillary differential tests: serum phosphorus, spot sample for urinary phosphorus, calcium excretion, and creatinine concentration (urinary Ca/Cr >0.2 is hypercalciuria) - Skeletal and soft tissue X-rays: bone resorption vs increased density, soft tissue ectopic calcification, osteosclerosis - Selective tests as needed: 1. Sonogram and radionuclide studies, selective venous catheterization for differential diagnosis of primary hyperparathyroidism vs. ectopic parathyroidism or parathyroid secreting malignancy 2. Cortisone suppression test: vit D vs. non-vit D mediated etiology 3. Abdominal sonogram for nephrocalcinosis 4. CT scan and MRI of parathyroid glands if hyperparathyroidism is proven. Treatment of Severe and Symptomatic Hypercalcemia Treat for symptomatic hypercalcemia or when total calcium exceeds 13 mg/dl. 1. No calcium or vitamin D ingestion 2. Increase calcium excretion - Hydration more than 2-3 times maintenance with normal renal function. Use NS or D5½NS or 2/3 Ringers lactate. - Na diuresis: Use Lasix 1-2 mg/kg/dose every 4-6 hours until Ca decreases to 12 mg/dl. * Fluid balance should always be on the positive side after correcting deficit and on-going deficit. * Replace on-going Na and K loss every 4-6 hours. * High sodium diet promotes continued renal calcium excretion after correction of acute hypercalcemia. 3. Decrease calcium absorption - Glucocorticoid: Cortisone 10 mg/kg/day - 300 mg/day. IV daily X3-5 days. - Prednisone: 1-2 mg/kg/day, up to 60 mg/day. (* Most effective in vit D toxicity, sarcoidosis, or idiopathic hypercalcemia.) 4. Inhibition of bone resorption: Most effective treatment a) Calcitonin: 2-3 U/kg q12h IV, SC or IM. It also increases urinary excretion of calcium, and has a potent analgesic action. - Check calcium level q2h in the first 6 h. - Refractory phenomenon may occur - Mobilization ASAP b) Bisphosphonates: (Etiodronate and Pamidronate) - Etiodronate: 7.5 mg/kg q4h IV infusion for 3-7 days. Discontinue Tx if Ca level has fallen by 2-3 mg/dl after -12- 1st 2-3 doses. - Pamidronate: More potent. 14-45 mg IV infusion up to 6 days or single 24 h. infusion of 45, 60, 90 mg. c) Mithramycin: IV bolus or 25 µg/kg BW over 4-6 hours. Can be repeated q 24-48. Extravasation can be irritating locally and lead to cellulitis. - Watch toxicity (nausea, anorexia, hemorrhage, liver, renal damage, proteinuria, azotemia, thrombocytopenia) - Do not use in patients with hematological, liver, or renal disease. - Phosphate: not recommended. May cause precipitation of Ca and P salts in the vascular system and kidneys. Use only in severe hypercalcemia when all other measures have failed d) Calcium Nitrate: The ultimate action is to inhibit osteoclast function. - IV: dose = 200 mg/m2 in 1 L of fluid daily for 5 days. - It is a nephrotoxic agent. - Can cause associated reduction in serum phosphate concentration and hemoglobin concentration. e) Dialysis: use in patients with renal failure. 5. Investigate etiology and removal of primary etiology. 6. Parathyroidectomy should be strongly considered for hyperparathyroidism due to progressive skeletal mineral loss and the adverse effects of long-term hypercalcemia on the kidneys. General Guidelines for the Management of Hypercalcemia 1. Mild hypercalcemia: Establish diagnosis, correct underlying problem. 2. Moderate hypercalcemia: Hydration and mobilization while establishing Dx and reassessment of Tx. 3. Severe Hypercalcemia: MEDICAL EMERGENCY. Draw blood for PTH, vit D metabolism, biochemical screening and assess kidney function. Start intense medical treatment ASAP. -13- III. GLUCOSE DISORDERS - HYPOGLYCEMIA This protocol deals with cases of recurrent or persistent hypoglycemia in the pediatric age group in the form of a decision tree (algorithm). This algorithm is meant to be an aid to the physician dealing with the hypoglycemic child to help in choosing the appropriate laboratory studies in every step of the evaluation of the patient in order to facilitate diagnosis and treatment. Definition of Hypoglycemia - may be controversial Newborn: plasma glucose level < 50 mg/dl is conventionally used for diagnosing hypoglycemia *whole blood glucose blood glucose concentrations are 10-15% lower than plasma glucose* Infant and child: 2 different definitions are used 1) Diagnostic level: plasma glucose < 50mg/dl 2) Therapeutic level: plasma glucose > 70mg/dl (lowest level acceptable during therapy for hypoglycemia) Evaluation in the Newborn History: - AGA, SGA, LGA - Feeding history - Maternal history (DB, diabetic mother, blood group incompatibility, maternal IV glucose - Treatment, maternal medication (chlorpropamide, benzthiazide, diuretics, salicylate and/or ethanol ingestion, eclampsia, pre-eclampsia). Signs and symptoms: - Apnea/tachypnea/Cyanotic episodes - Abnormal cry/ tachypnea / hypotonia - Lethargy/Apathy/Poor cry/Poor feeding - Hypothermia/Hypotension - Irritability/Tremors/Seizures - Cardiac arrest Physical exam: 1) Look for macrosomia ( large size) for hyperinsulinemia 2) Beckwith Wiedemann Syndrome (large tongue, umbilical hernia, macrosomia) 3) Galactosemia: Jaundice and cataracts 4) Glycogen storage disease: hepatomegaly 5) Hypopituitarism : micropenis, midline defects, cleft lip and cleft palate Evaluation in Older Infants to Children History: - Perinatal history, birth weight, apgar score - Relationship of symptoms to feeding or meals or the introduction of new foods - Prior history of hypoglycemia episodes - History of condition associated with hypoglycemia (e.g., diabetes mellitus) - Family history of hypoglycemia, inborn errors, early infant deaths, reye syndrome - Age of onset of symptoms -14- Toxic ingestions ( e.g., alcohol intoxication, salicylate poisening) Relationship of symptoms to acute illness or starvation Information about growth development Dietary factors: dietary intake before the event, fed or fasting at the time of hypoglycemia, symptoms after ingestion of milk product or fructose Signs and symptoms: - Autonomic response, primarily catecholamine-mediated Hunger, Nausea Sweating Tachycardia Feeling of anxiety/nervousness/weakness Tremors - Neuroglycopenia, primarily related to effects of hypoglycemia on the brain Disordered consciousness (lethargy, tiredness, apathy, somnolence, stupor, coma) Behavioral abnormalities (irritability, sleep disorders, anger/manic behavior, depression, confusion) Headache Staring spells Seizures Important points in physical examination: 1) Height, head circumference, weight 2) Complete neurological examination 3) Midline defects 4) Fundus examination 5) Pigmentation 6) Hepatosplenomegaly, signs of hepatic disease, e.g., jaundice 7) Size of genitalia 8) Omphalacele, Macroglossia, Visceromegaly (cardinal features of Beckwith Wiedemann Syndrome) 9) Chubby features 10) Doll’s face 11) Muscle tonus 12) Scoliosis 13) Suspected Reye Syndrome 14) Infections 15) Cataracts - Etiologies of Hypoglycemia by Most Common Age of Initial Occurrence NEWBORN TO 1 YEAR * Small for gestational age * Premature * Twins * Infections/Sepsis * Cold stress * Infants of diabetic mothers * Beckwith-Wiedemann * Maternal Toxemia * Maternal drugs, e.g. Propranolol, ß-tocolytics * Rh incompatibility * Exchange transfusions * Umbilical artery malposition * Congenital heart disease/failure * Transient ß cell hyperinsulinism due to perinatal stress event * Hyperinsulinism due to islet cell dysplasia (hypertrophy, adenoma) * Congenital hyperinsulinism (peristent hyperinsulinemia of the infancy) -15- * Inborn errors of carbohydrate metabolism (glycogen storage diseases, galactosemia, hereditary fructose intolerance) * Inborn errors of fatty acid oxidation or ketogenesis +/- increase insulin level * Cortisol and/or growth hormone deficiency (hypopituitarism, congenital adrenal hyperplasia) * Prolonged fasting * Carbohydrate malabsorption * Hepatic failure * Inborn errors of amino acid metabolism * Inborn errors of gluconeogenesis (specific enzyme defects, galactosemia, hereditary fructose intolerance) * Toxins: Salicylate, 1-propyl alcohol 1 YEAR TO ADOLESCENCE * Prolonged fasting (ketotic hypoglycemia) or malnutrition Hepatic failure * Fevers, infections * Toxins: Salicylate, ethanol, hypoglycemic drugs * Reye syndrome * Cortisol and/or growth hormone deficiencies * Islet cell adenomas * Exogenous insulin excess (diabetes mellitus treatment, child abuse) Etiologies of Hypoglycemia A. Increased glucose utilization. Impaired conservation of glucose 1. Conditions of Insulin excess a. ß cell hyperplasia: Beckwith-Wiedemann, Rh incompatibility b. Familial hyperinsulinism ( also known as persistent hyperinsulinemia hypoglycemia of infancy or congenital hyperinsulism) including 3 genetic forms - Loss of function mutation in the ß-cell plasma membrane ATP potassium channel - Gain of function mutations of the mitochondrial enzyme glutamate dehydrogenase, also known as hyperinsulinism-hyperammonemia - Gain of function mutation of islet glucokinase c. ß cell adenoma d. Reactive hypoglycemia: umbilical artery catheter, short bowel e. Ingestion of hypoglycemia agents: maternal or child f. Exogenous insulin excess 2. Excessive tissue demands A) Tumors B) Infections C) Cold stress D) Exercise 3. Impaired ketogenesis/ketone utilization (Inadequate conservation of glucose) a. Inadequate fat stores: premature, SGA, malnutrition b. Inadequate fat mobilization: insulin excess, cortisol deficiency, growth hormone deficiency, propranolol c. Inadequate fatty acid oxidation 1. Carnitine deficiency (primary or secondary) 2. Decreased CPT-I activity 3. Decreased Acyl CoA dehydrogenase activity: inherited or secondary e.g., "hypoglycin" inhibition (Jamaican vomiting sickness) d. Inadequate ketogenesis: decreased HMG-CoA synthase/lyase activity -16- e. Inadequate ketone utilization: decreased ß-ketothiolase activity B. Decreased glucose production I. Deficiency of substrate or its mobilization a. Glycogen: diminished stores: prematurity, SGA, neonatal stress, malnutrition, growth hormone or cortisol deficiency b. Glycerol: fat stores or glycerokinase deficiency II. Defective recycling of lactate or alanine a. Substrate deficiency: ketotic hypoglycemia III. Disorder of glycogenolysis Glycongen synthetase deficiency, Glucose- 6 phosphatase deficiency, Debranching enzyme, Phospholyrase deficiency, Phosphorylase kinase IV. Disorder of gluconeogenesis a. Hepatic enzyme deficiency: Fructose-1,6-diphosphatase deficiency, Phosphoenolpyruvate carboxykinase (PEPCK) deficiency, Glucose-6-phosphatase, pyruvate carboxkinase b Toxins: ASA, ethanol, other alcohols V. Other enzyme defect: a. Galactosemia (galactose-1 -phosphate uridyl transferase deficiency) b. Hereditary fructose intolerance (aldolase deficiency) VI. Hereditary disorders of ammo acid and organic acid metabolism: maple urine syrup disease, methylmalonic aciduria, proprionic acidemia C. Hormone deficiencies or decreased action of hormones 1. ACTH/Cortisol: hypopituitarism, congenital adrenal hyperplasia, ACTH unresponsiveness, Addison disease, acute steroid withdrawal 2. Growth hormone: hypopituitarism, isolated growth hormone deficiency 3. Epinephrine: propranolol administration 4. Glucagon deficiency, but well documented cases have only rarely been described D. Hepatic failure Work up for Hypoglycemia in the Newborn Draw the following blood sample when hypoglycemia is present or 3-4 hours after the last feeding: 1) Draw critical blood sample for glucose, cortisol, insulin, growth hormone, acetone and if sufficient sample, please send Free fatty acid, cortisol, T4 and TSH levels. 2) Consider evaluating pH, lactate, pyruvate and ketones if hepatomegaly is present. 3) Do urine ketone test. 4) Send urine for organic acid analysis 5) Newborn screening (errors of metabolism, include aminoacidemia, urea cycle disorders, organic aciduria, and fatty acid oxidation disorders) Endocrine dynamic tests such as glucagon challenge test or GH stimulation tests or ACTH provocative tests are reserved for confirmation of suspected diagnosis. As per the suspected diagnosis, glucagon may be used for diagnosis (Glycemic response to glucagon) Significant rise in blood glucose more than 30 mg/dl above baseline after glucagon administration (1mg IV), suggestive of hyperinsulinism Treatment Both oral and IV caloric administration should be provided simultaneously. If the child tolerates oral feeding, -17- oral administration of nutrients such as 5% dextrose or formula as frequent intermittent boluses or continuous feeding should be maintained. Parenteral IV glucose treatment may be given at 6-15 mg/kg/minute and tapered as per baby's response. Glucose infusion rate may need to increased as high as 15 to 25 mg/kg/min in hyperinsulinemia. For the relief of acute hypoglycemic symptoms (i.e., seizures) administer 10% dextrose 2 ml/kg at a rate of 1 ml/ minute, followed by continuous parental infusion at the rate of 6-15 mg/kg/min. The continuous parenteral glucose treatment should be continued based on the blood glucose level in the baby. While waiting for the random or dynamic test results you may consider a trial of glucocorticoids (Hydrocortisone 5 mg/kg/dose x 2-3 doses oral or IV), or growth hormone (0.1 mg/kg/dose 1-2 doses SQ) Glucagon (Emergency treatment only in case of insulin induced hypoglycemia) 1 mg IM or IV but watch for rebound hypoglycemia Treatment for congenital hyperinsulinsim will be discussed later in this protocol Work up for hypoglycemia in older infants and children At the time of hypoglycemia draw a blood sample for glucose, lactate, acetoacetic acid, ß-hydroxybutyrate, free fatty acids, insulin, growth hormone, cortisol, liver function tests and ACTH (Chilled tube). Do urine ketone test. In patients suspected of having endogenous hyperinsulinism, measure plasma glucose, insulin, C-peptide, βhydroxybutyrate (at UIC, acetone has been used instead of β-hydroxybutyrate), and circulating oral hypoglycemic agents during an episode of hypoglycemia. If there is no spontaneous hypoglycemia then perform a 24 hour fasting until the child become hypoglycemic and at the time of hypoglycemia draw a blood sample for the above tests. Give glucagon stimulation test to check blood glucose response when hypoglycemic. I. Presence of Ketonuria/Ketonemia: Ratio of glucose/insulin > 4 1) Cortisol > 10 mcg/dl and GH >10 ng/ml, elevated blood lactate and poor blood glucose response to glucagon suggest: Disorders of glycogen metabolism (specific enzyme deficiencies), galactosemia, hereditary fructose intolerance or Disorders of gluconeogenesis (specific enzyme deficiencies, fructose 1,6-biphosphatase), errors in ammo acid metabolism. 2)Cortisol < 10 mcg/dl and/or GH < 10 ng/ml. Suspect hypopituitarism and/or adrenal insufficiency *** please note that premature newborn has limited capacity of cortisol secretion despite normal H-P-A ( hypothalamic- pituitary-adrenal ) axis therefore cortisol < 10 does not always mean cortisol deficiency *** II. Absence of Ketonuria/Ketonemia 1) Ratio of glucose/insulin <4 ( in hypoglycemic state, any detectable insulin is inappropriate) Cortisol > 10 mcg/dl, GH > 10 ng/ml. Lack of elevation of free fatty acids or lactate, and increase in blood glucose by > 30 mg/dl over baseline after glucagon suggest hyperinsulinism. Features of Hyperinsulinism in the Newborn Glucose infusion rate >10 mg/kg/min needed to sustain normoglycemia Large for gestational age Mild hepatic enlargement (glycogen) 2) Glucose: insulin ratio <4 during hypoglycemia ( in hypoglycemic state, any detectable insulin is inappropriate) Non-ketotic hypoglycemia Absence of ketonemia, "acetonemia" (ketonuria may be seen) -18- Absence of elevated free fatty acids or lactate in the blood Rise in blood glucose >30 mg/dl above baseline 30-40 minutes after glucagon administration Features of Hyperinsulinism in the older Children Glucose infusion rate >5 mg/kg/min or >3 mg/kg/min in young child or adolescent respectively. Mild hepatic enlargement (glycogen) Glucose: insulin ratio <4 during hypoglycemia ( in hypoglycemic state, any detectable insulin is inappropriate) Non-ketotic hypoglycemia Absence of ketonemia, "acetonemia" (ketonuria may be seen) Absence of elevated free fatty acids or lactate in the blood Rise in blood glucose >30 mg/dl above baseline 30-40 minutes after glucagon administration 2) Ratio of glucose/insulin > 4, Cortisol > 10 mcg/dl, GH >10 ng/ml, elevated free fatty acids. Do serum camitine and urine organic acid profile. Defects in fatty acid ß-oxidation Carnitine deficiency Carnitine palmitoyl transferase deficiency Acyl CoA dehydrogenase deficiency Other work up may be indicated as necessary: - Radiologic imaging for congenital hyperinsulinism 1) 18F-DOPA PET scan, that is injected intravenously and concentrates in insulin cells for detection in a PET scanner. However, 18F-DOPA is not yet FDA approved, so the test is being done under a research protocol. 2) Pancreatic arterial calcium stimulation of insulin secretion, not to be specific as originally reported 3) CT scan, MRI, and ultrasound, have not been successful in identifying Focal KATP hyperinsulinism - Molecular genetic testing: 5 genes are known to be associated with familial hyperinsulinsm 1) ABCC8 2) KCNJ11 3) GLUD1 4) GCK 5) HADH - Radiologic imaging for insulinoma 1)Selective pancreatic angiography, may be used to detect insulinoma 2) Helical or multi slice CT scan or MRI - Tissue specimen (liver, fibroblasts, blood cells) for enzyme analysis, histology - Toxic screen (ASA, ethanol) - Reducing substances in the urine (galactosemia ) -19- Clinical and Differential Diagnoses in Childhood Hypoglycemia *Key: N — normal; 0 = absent: ↑ = low increase: ↑ ↑ = great increase; ↓ = some decrease; ↓ ↓ = marked decrease Serum Glycemic Urinary response ketones Hepato to Hypoglycemi (K) or Condition Uric glucagon a reducing Lipid megaly aci sugars s d Fe Faste (S) d d Normal 0 0 0 N N ↑↑ ↑ Hyperinsulinemi Recurrent N or 0 0 N ↑↑ ↑↑ a severe ↓ Severe with Ketotic missed K+++ 0 N N ↑ 0-↑ hypoglycemia meals Moderate with Hypopituitarism K++ 0 N N ↑ 0-↑ missed meals Severe with Adrenal missed K++ 0 N N ↑ 0-↑ insufficiency meals Enzyme deficiency Glucose-6Severe K+++ ++++ ↑ ↑ ↑↑ 0 0 phosphatase constant Moderate Debrancher with K++ + N N ↑ 0 fasting Mild to Phosphorylase K++ + N N 0-↑ 0 moderate Fructose-1,6Severe with diphosphatase fasting Galactosemia Fructose Intolerance Carnitine Deficiency Carnitine Palmitoyl Transferase 1 Deficiency Acetyl CoA Dehydrogenase -20- Effect of 24 – 36 h fast on plasma Glucos Insuli Ketone Alanin Lactat e n s e e ↓ ↓ ↑ ↓ N ↓↓ ↑↑ ↓↓ N N ↓↓ ↓ ↑↑ ↓↓ N ↓↓ ↓ ↑↑ ↓↓ N ↓↓ ↓ ↑↑ ↓↓ N ↓↓ ↓ ↑↑ ↑↑ ↑↑ ↓↓ ↓ ↑↑ ↓↓ N ↓ ↓ ↑↑ ↓↓ N ↑↑ ↑↑ ↑ 0 ↓↓ ↓ ↑↑ ↑↑ ↑↑ 0-S+++ +++ N N ↑ 0 ↓ ↓ ↑ ↓ N After fructose 0-S+++ +++ N N ↑ 0-↑ ↓ ↓ ↑ ↓ N Moderate to severe with fasting ↓ N ↑ 0 ↓ ↓ ↓ N N-↑ After milk or milk products K++++ 0 ++++ 0-+ Lab data in individuals with hyperinsulinemic hypoglycemia or hypoglycemia caused by other mechanisms Symptoms, signs, or both Glucose (mg/dl) Insulin (µU/ml) C-peptide (nmol/liter) -Hydroxybutyrate (mmol/liter) Glucose increase after glucagon (mg/dl) Circulating oral hypoglycemic agent No <50 <2 <0.2 2-4 <30 No Normal Yes <50 >1 <0.2 <2 >30 No Exogenous insulin Yes <50 >1 ≥0.2 <2 >30 No Endogenous insulin Yes <50 >1 ≥0.2 <2 >30 Yes Oral hypoglycemic agent Diagnostic interpretation Treatment of Hypoglycemia in Older Children Use frequent oral feedings if tolerated and IV glucose of 10% dextrose to maintain blood sugar level in the normal range. While waiting for the random or dynamic test results you may administer the following as per suspected diagnosis: Medication - Glucocorticoids: HC dose: 5 mg/kg/dose x 2-3 doses/day orally or IV for suspected adrenal insufficiency. - Growth hormone 0.1 mg/kg/dose SQ 1-2 doses/day for suspected GH deficiency. In all above treatments when the decision is made to stop treatment, IV fluids and medication should be tapered and discontinued over a few days to prevent hypoglycemia, and in the case of corticosteroid treatment, to prevent adrenal crisis. Treatment for familial hyperinsulinism Medication - Diazoxide: 5-20 mg/kg/day (usually ineffective in children with KATP channels forms of Hyperinsulinism) - Somatostatin analog such as octreotide ( 2-10 μg/kg/day initially divided every 12 hours; increase dosage depending upon patient response by either using a more frequent interval ( q 6-8 hr ) or larger dose as well as the use of continuous subcutaneous injection using a portable pump greatly enhances clinical efficacy - Calcium chanel blocker such as Nifedipine (0.25-0.7 mg/kg/d PO divided q8h) are another alternative therapy, but the use of calcium chanel blocker for familial hyperinsulinsm has not been evaluated in controlled trial - Glucagon ( Emergency treatment only in case of insulin induced hypoglycemia) 1 mg IM or IV Dietary therapy - Frequent high carbohydrate meals and the ingestion of uncooked cornstarch (1-2gm/kg/dose) - Surgical treatment - Surgical exploration is warranted in children older than several weeks of age in whom hyperinsulinism is proven and pharmacologic therapy fails to control hypoglycemia - Long term treatment and prognosis depend upon whether the pancreatic pathology at the time of surgical exploration is focal or diffuse - Focal anomalies : selective resection is often curative - Diffuse lesion : require subtotal pancreatectomy, in which 95-99 percent of the pancreas is removed SEE ALSO NEXT PAGE FOR algorithm) : This protocol deals with cases of recurrent or persistent hypoglycemia in the pediatric age group in the form of a decision tree (algorithm). This algorithm is meant to be an aid to the physician dealing with the hypoglycemic child to help in choosing the appropriate laboratory studies in every step of the evaluation of the patient in order to facilitate diagnosis and treatment. -22- This algorithm is meant to be an aid to the physician dealing with the hypoglycemic child to help in choosing the appropriate laboratory studies in every step of the evaluation of the patient in order to facilitate diagnosis and treatment. -23- DIABETES MELLITUS A) DIABETIC KETOACIDOSIS Diabetic Ketoacidosis is a state of hyperglycemic, hypertonic dehydration and ketotic academia . It exists when: 1.The glucose is >200 mg/dl => 11mmol/L. 2. Ketonemia is present, ketones strongly positive at >1:2 dilution of serum and ketonuria is present. 3. The pt is acidotic (pH < 7.3 & bicarbonate < 15 meq/L for inpatient therapy). Rapid initial evaluation is needed to confirm the diagnosis and assess the extent of metabolic abnormality. This should be followed by starting the initial phase of treatment. Initially, treatment is very vigorous to halt and start to reverse the metabolic disturbances, but once the situation is more controlled, over-vigorous medication can produce too rapid changes in glucose, osmolarity and pH and possibly contribute to development of hypoglycemia and cerebral edema. Treatment must be cautiously aggressive. Emergency Management I. History: It is especially important to note: - usual insulin dose - time and amount of last insulin dose - recent blood and urine tests - history of vomiting, sign of inter-current illness/infection II. Physical Examination: - assess degree of dehydration (baseline weight, pulse, BP, skin, mucous membranes, oliguria; most diabetics in moderate to severe ketoacidosis are 10% dehydrated) - assess acidosis (Kussmaul breathing if present serum CO2 is likely to be <10) - focus of infection - assess neurologic status (mental status, neurologic exam) III. Initial Laboratory Assessment: - differentiate DKA from nonketotic hyperglycemic coma - do a bedside chemstrip. At the same time send stat blood sample to lab for: venous pH, glucose, serum osmolarity and ketones, lytes, BUN, creatinine, calcium, phosphate and CBC with differential, urine ketones. - for new onset diabetics, also send blood sample for insulin level or C-peptide level and islet cell antibody. - ECG with standard limb leads and special attention to T-wave size - other lab tests, cultures (e.g. blood, urine, sputum), x-rays, etc., if suspect precipitating cause such as infection IV. Treatment: This guideline is modified version from the reference recommendations based on actual practice experience by the Pediatric Endocrine service at UIH. This is not intended as a rigid prescription, but is offered only as a GUIDELINE. Each case should be individually and frequently reassessed Initial Management I. Fluids: Begin a flow sheet and monitor strict I &O. Consider patient 10% dehydrated. Infuse normal saline 20 cc/kg for the first hour and calculate fluid replacement volume (described below ) while infusing normal saline (NS). If in shock, give 10 cc/kg colloid over 50-60 minutes until stabilized. After the first hour add 40 meq/L of K in IVF with 20 meq KCl /L and 20 meq KP04 /L provided that: - the patient has voided urine - there are no peaked T-waves on ECG done with standard limb leads - serum potassium is not high or less than 6.0 -if serum phos level is not high If serum phos level high, start w/ KCL and then switch to KCl/KP04 when phos level is not high. -if serum K level is low, use 25 meq/L of KCl and 25 meq/L KP04 and consider use of IV K rider with 10 meq/hr x 1-4 hrs depending on the degree of hypokalemia. II. Insulin ( types of insulin used for IV : regular or humalog or novolog) : DECREASE BLOOD SUGAR BY APPROXIMATELY 100 MG% EVERY HOUR. IV insulin solution is to be made up of 50 units regular insulin in 250 cc of normal saline to yield a solution containing 1 unit of insulin/5 cc (or 100 units in 500 cc) to be infused piggyback in IV tubing via pump or via separate IV line via pump. Allow 50 cc to run through tubing to saturate insulin-binding sites before starting infusion. 1. In general, for blood glucose > 500 mg% with moderate to severe acidemia (venous pH < 7.25): a) Do not give bolus IV insulin as the fluid bolus administration during the first hour is likely to decrease blood glucose level even without insulin. b) Start separate IV line for insulin infusion therapy (if possible) apart from IV line for hydration. Amount of insulin may be at 0.05-0.1 U/kg/hr depending on blood glucose level, ketosis and acidosis degree. Example: 10 kg patient, 0.1 U x 10 = 1 unit/hr = 5 cc of insulin-saline solution/hr. c) If blood glucose declines rapidly (> 100 mg/hr) then decrease insulin dose to 0.05 U/kg/hr, or if necessary readjust the insulin dose. d) When blood glucose level reaches approximately <300 and at about 250 mg%, add glucose (D5 or D10) in IV solution while continuing and adjusting IV insulin infusion rate which will maintain blood glucose level 100-200 mg%. 2. For blood glucose level < 500 mg% or if acidemia is mild (venous pH > 7.25) despite blood glucose level > 500 mg%, bolus insulin at 0.05 unit/kg only may be given, but it may not be necessary. For insulin infusion: a) If significant acidemia (venous pH < 7.25) is present despite blood glucose level < 500 mg%, then infuse insulin dose of 0.1 U/kg/hr. b) If acidemia is mild and blood glucose level is > 500 mg%, infuse insulin dose at 0.1 U/kg/hr. c) If acidemia is mild, and blood glucose level is < 500 mg%, infuse insulin dose at 0.05-0.1 U/kg/hr. In all cases, when blood glucose level reaches approximately 250 mg%, add glucose (D5 or D10) in IV solution while continuing and adjusting IV insulin infusion rate which will maintain blood glucose level 100200 mg%. 3. Remember to: a) Make up fresh solution q 24 hours (keep it in the refrigerator when not in use). b) Regulate infusion with a pump. This is imperative if insulin infusion is piggy backed into other IV fluids. Prepare separate IV for insulin. III. Bicarbonate: IN GENERAL , DO NOT GIVE OR PUSH BICARBONATE-GIVING BICARBONATE HAS BEEN REPORTED TO BE ASSOCIATED W/ A RISK FACTOR FOR WORSENING OR AIDING CEREBARAL EDEMA OR METABOLIC ENCEPHALOPATHY IN DKA PTS. May give only in the presence of severe acidosis (venous pH < 6.9), or if patient is hemodynamically unstable may give bicarbonate 0.5 meq/kg diluted with equal amount of sterile water over 1-2 hours, or calculate base deficit to -25- correct HC03 to 14 meq/L (base deficit x 0.6 x kg) ÷ 4 = for quarter correction only or continue drip until pH 7.1 only. Example: If serum HCO3 10 meq/L and patient weight 30 kg (14-10 x 0.6 x 30 kg) ÷ 4 = 18 meq HCO3 to be infused over 1-2 hours Or use Bicarbonate dose at 1-2 mmol/kg over 60 min. Subsequent Management * BRAIN HERNIATION is a life threatening and often unpredictable complication of DKA. Recent studies indicate that some degree of cerebral edema commonly occurs during the course of DKA. Also, plasma vasopressin is inappropriately elevated in patients with DKA. Therefore, fluid replacement should be as follows: - MANNITOL SHOULD BE AT THE PATIENTS BEDSIDE THROUGHOUT THE FIRST 24 HOURS OF THERAPY FOR SEVERE DKA, AND SHOULD BE GIVEN FOR CLINICAL DETERIORATION IN MENTAL STATUS INDICATIVE OF OR SUSPICION OF CEREBRAL EDEMA. Monitoring: 1. Accucheck glucose level q 1 hour while on insulin infusion until patient is stable for 4 hours on unchanged insulin infusion and fluid/glucose intake, then accuchecks may be done q 2 hours. 2. Blood glucose, electrolytes and venous pH q 2 hours initially, then q 4 hours. 3. Serum ketone dilutions q 4-6 hours initially then q 12 hours. I. Fluid and Electrolyte Management: 1. Calculation of Required Fluids and Electrolytes: a) In DKA, assume a minimum of 10% dehydration, and calculate the deficit volume at 100 cc/kg of weight. b) Maintenance daily fluid requirements: 100 cc/kg for 1st 10kg ┐ nd 50 cc/kg for 2 10 kg ├ Do not exceed total fluid 4L/m2/day 20 cc/kg for > 20 kg ┘ Example for 30 kg child Deficit/Episode 10% dehydration for 48 hrs replacement Maintenance/24 and 48 hrs Total 48 HRS (Deficit + Maintenance) H2O=100 cc/kg x 30 kg =3000 cc 100 cc/kg x 1st 10kg = 1000 cc 50 cc/kg x 2nd 10 kg = 500 cc 20 cc/kg x 3rd 10 kg = 200 cc = 1700 cc/24 hr = 3400 cc/48 hr 3000 cc+3400= 6400 cc/48 hr Na+ 6 meq/kg = 180 meq 3-5 meq/kg/d = 90-150 meq/24 hr = 135-225 meq/36 hr = 180-300 meq/48 hr 270-330 meq/24 hr 315-405 meq/36 hr 360-480 meq/48 hr K+ 5 meq/kg = 150 meq 1-2 meq/kg/d = 30-60 meq/24 hr = 45-90 meq/36 hr = 60-120 meq/48 hr 180-210 meq/24 hr 195-240 meq/30 hr 210-270 meq/48 hr PO4 3 mM/kg = 90 mM 0.5-1 mM/kg/d = 15-30 mM/24 hr = 22-45 mM/36 hr = 30-60 mM/48 hr 105-120 mM/24 hr 112-135 mM/36 hr 120-150 mM/48 hr -26- 1st hr bolus at 20 cc/kg 600 cc If given 2nd hr bolus given at 10 cc/kg 300 cc = Infusion Rate = If no 2nd bolus: 6400 -600 cc= 5800 cc/47 hr = 123 cc/hr if 2nd bolus given: 6400 – 900cc= 5500cc/46 hr =119 cc/hr 2. Fluid replacement method after 1st hour bolus treatment: a) For patients with significant CNS symptoms (drowsiness, sleepiness, unsatisfactory mental orientation, hypertension, headache, etc.); to help prevent cerebral swelling, replace the required volume evenly over 46-47 hours (48 hr correction). DO NOT replace urine loss (* Reference: Journal of Pediatrics 1988; 113: 10-14,) b) For patients with clear mental state and no significant CNS symptoms, replace the volume over 24-36 hr period evenly. 3. Electrolyte replacement: a) For 47 hr fluid replacement following IV fluid bolus, use 1/2 rate as 0.9 NS and 1/2 infusion rate as 0.45 NS initially to avoid rapid osmolarity shift. If serum NA level is > 150 meq/L, then switch IV solution to 1/2 NS for the remaining replacement hours. b) For 23 hr fluid replacement following IV fluid bolus, you may use ½ infusion rate as 0.9 NS and ½ infusion rate as 0.45 NS initially. If serum Na level is > 150 meq/L, you may switch IV solution to 0.45 NS for the remaining hours, provided NA level does not decline below 135 meq/L. c) WHEN THE PATIENT HAS VOIDED AND THE POTASSIUM LEVEL IS not high (< 6.0 meq/L), start 40 meq potassium/L in IV solution initially. If K+ level declines < 4.0 meq/L, then increase K+ to 50 meq/L in IV solution without delay. If phosphate is normal or low, give ½ as KCl and ½ as K 2PO4. If using phosphate, check Calcium level, as there is a risk of hypocalcemia. Also, obtain PO4 levels before starting treatment and after infusion at 24 and 48 hours. However, if patient has NOT voided, but serum K+ level is < 3.5 meq/L or below normal and insulin infusion has begun, 20-30 meq KCl/L may be given in the IVF. Check serum K + level hourly to determine the direction of serum K+. If declining further, change it to 20meq/L KCl and 20 meq/L K2PO4. If K+ level is moving toward 5 meq/L or above, discontinue or decrease amount of K+ in the IVF and re-check K+ level in 1-2 hrs regardless of voiding history. II. Insulin: 1. Continue insulin infusion, adjusting as necessary depending on the blood glucose level and the degree of acidosis. When blood glucose is 250-300 mg% or less and there is still ketonemia, add D5-D12.5% glucose in IV. The insulin dose may range 0.05-0.2 U/kg/hr. If blood sugar level decreases rapidly despite IV glucose, increase glucose to D10% or D12.5 % or decrease the rate of insulin infusion, and maintain blood sugar level at 100-200 mg % until ketonemia clears. 2. When the blood glucose is < 250 mg%, venous pH is > 7.30 + HCO3 is > 15 meq/L serum ketone is negative at dilution of < 1:2. Insulin infusion may be discontinued, subcutaneous insulin should be given at the time of discontinuation of the insulin infusion. 3. Guideline of Subcutaneous insulin regimen is to be developed by Pediatric endocrine team : Both long acting insulin( Lantus, Levemir or NPH) to provide basal insulin need (or this by insulin pump basal rate of short acting -27- insulin) and rapid/short acting insulin is used to cover carbohydrate meal dose and high blood glucose level correction dose at meal times and or as PRN dose for non-meal time snack or for non meal time hyperglycemia. a) For new diabetics or known diabetic with poor oral intake or on NPO: The patient needs both calories via IV .This is to be used only as a GUIDELINE. Long-acting insulin already "on-board" must be considered, as well as other factors, which would alter the requirement, i.e., stress, hydrocortisone administration, infection, etc. The child must be carefully monitored, and insulin dose adjusted depending upon response. You may increase or decrease insulin dose with a reasonably consistent glucose administration. Review of General Principles in Management of DKA 1. The patient is insulin-deficient regardless of the blood glucose level. Therefore, ALWAYS MAINTAIN INSULINIZATION. If the blood glucose falls too fast, decrease insulin dose or increase the IV glucose. Use D10/D12.5% in IVF if necessary. REMEMBER THAT TO REVERSE THE METABOLIC DERANGEMENTS, THE PATIENT NEEDS INSULIN, FLUIDS, ELECTROLYTES, AND CALORIES. If the patient is off IV insulin he/she must be given subcutaneous regimen. 2. Clinical decisions are based on data. These include physical findings and laboratory data. Therefore, THE PATIENT MUST BE CHECKED AT FREQUENT INTERVALS - i.e., CLOSE MONITORING OF CHANGES IN MENTAL STATUS, VITAL SIGNS, pH, GLUCOSE, ELECTROLYTES, FLUID BALANCE. 3. To properly integrate the data and make proper clinical decisions, AN UP-TO-THE-MINUTE FLOW SHEET MUST BE MAINTAINED. 4. Every patient in DKA will need a lot of IV fluids, therefore, A STABLE, LARGE IV LINE IS ESSENTIAL (not a 25g Butterfly in a tiny peripheral vein). IF A GOOD IV LINE CANNOT BE STARTED, CALL PICU ATTENDING. 5. IV INSULIN MUST BE GIVEN VIA AN INFUSION PUMP. DO NOT ALLOW IV INSULIN TO "DRIP." 6. Always think about what you are treating while you closely follow your patient. A PROTOCOL IS A GUIDELINE ONLY, NOT A SUBSTITUTE FOR "CEREBRATION". Each patient's DKA management must be individualized, based on the patient's mental, physical, and biochemical findings. 7. If there are any problems, do not hesitate to call the Pediatric Endocrine Services for help. 8. SEE NEXT PAGE FOR EXAMPLE OF DIABETIC KETOACIDOSISFLOW-SHEET References: -J of Pediatr 1988; 113: 10-14, -Glaser at al Risk factorsfor cerebral edema in chidren with diabetic ketoacidosis N Engl J Med 2001:344:264269 -Dunger et al European sodiety for Pediatric endocrinology/Lawson Wikins Pediatirc Endocrine society consensus statement on diabetic ketoacidosis in children and adolescents. Pediatrics 2004: 113: e133-e140 and Arch DisChild. 2004:89:188-194 -Wolfsdorf et al ISPAD Clinical Practise consensus Guideline 2006-2078. Pediatric Diabetes 2007,8:28-43 -Green et al failure of bicarbonate to improve outdome in severe DKA. Ann Emerg Med. 1998, 31-41-48 -28- NAME: HOSP. #: DATE DIABETIC KETOACIDOSIS FLOW-SHEET : TIME (hrs) 0 CLOCK TIME CLINICAL Vital Signs Mental Status Weight INSULIN THERAPY IV Infusion (u/hr) (cc/hr) SUB Q FLUID INTAKE (u) Fluid Type IV #1 Volume Fluid Type IV #2 Volume Fluid Type Oral Volume FLUID OUTPUT Urine Emesis Other LABS Accucheck, BS Blood Glucose Serum Ketones Urine Ketones pH Na/K Cl/CO2 Ca/PHOS Other -29- 1 2 3 4 5 6 7 8 B) DIABETIC KETOSIS only Rx of diabetic hyperglycemia with or without ketosis, but not in frank DKA, this applies to both emergency room outpatients and in hospital management: This may not require insulin infusion and ICU, but still requires close attention, and fluid and insulin treatment. The general approach and initial tests are the same as given for DKA. 1. 2. 3. Fluids calculated on Maintenance and Deficit, estimate of percent dehydrated. Can take PO fluids if not vomiting. Hydration is an essential part of therapy. Insulin: a) May use continuous low dose IV insulin infusion (regular insulin 0.025-0.05 unit/kg/hr), or give one initial IV bolus regular insulin 0.05-0.1 U/kg to begin metabolic repair and give SC regular insulin dose, at the same time which is absorbed slowly (SC insulin based on sliding scale). b) May need to adjust, if long-acting insulin recently taken, but if hyperglycemia and ketosis are present, then by definition, is insulin-deficient and needs short-acting insulin every 4-6 hours. You must check Accucheck q 1 hr during or following (3 hrs) IV insulin administration. C) NONKETOTIC HYPEROSMOLAR HYPERGLYCEMIC STATE (Guideline for the Pediatric Patient) This condition is characterized by severe hyperglycemia (usually > 600 mg/dl) hyperosmolarity (> 320 mOs), Arterial pH >7.3, HCO3 > 15 meq/L, plasma ketone absent or < 1:2 dilution or beta-hydroxybutyrate 1+-0.2 mmol/L and dehydration, stupor or coma. Although it is usually a complication of NIDDM, it can occur in IDDM at any age if enough insulin is present to prevent ketoacidosis, but is insufficient to control the blood sugar. This condition is rare in pediatric age patients, however, it can occur in patients on diuretics, steroid treatment and acute illness (infection, trauma, bums, etc). Severe dehydration is thought to be the pathogenic factor. The principles of treatment are: (1) fluid replacement, (2) insulin to be added if fluid replacement alone for the first 2 hours does not decrease blood glucose level, and (3) treatment for underlying problem (infection, trauma, etc). The following is our guideline for patients with non-ketotic hyperosmolar coma, and was modified from that of adult patient management protocol. Fluid Replacement Therapy Too rapid a fall of plasma glucose level should be avoided in order to prevent dangerous fluid shifts, with a rapid and marked reduction in ECF Osmolarity, fluid moves from ECF to ICF This may lead to cerebral edema. Step 1: Do all the chemistry and hematological studies as in DKA patients. Step 2: While waiting for lab data, initiate fluid therapy and call neurologist for a thorough neurologic examination. First Two Hours: Fluids - Normotensive patient - 2/3 NS or normal saline should be infused at the rate of 15-20 cc/kg/hr - Hypotensive patient - use normal saline. - Severe Hypotensive patient - use colloid same as in DKA. - Insulin: none - Calculate fluid requirement as in DKA: 10% dehydration + maintenance fluid/24 hrs. -30- Hour 2-24 Fluids - If serum sodium level < 135 always use normal saline. - If serum sodium level > 135-145 use 2/3 NS or NS Administer 2/3 of total amount of fluid for 10% dehydration correction plus maintenance fluids evenly distributed over the first 24 hours. - Carefully evaluate neurological status and blood glucose levels every hour and other blood chemistry every two hours. - Insulin Therapy. - At 2 hours after initiating fluid treatment, IV insulin treatment should be started if the plasma glucose level has not decreased appreciably and is > 700 mg% (generally patients with non-ketotic hyperosmolar coma are sensitive to insulin). Thus, use smaller dose of insulin than used in treatment of DKA, e.g. 0.03-0.05 units/kg/hr rather than the 0.1 unit/kg/hr. - Bolus injection of insulin prior to insulin drip may or may not be needed in hyperosmolar non-ketotic coma. If the patient has voided, potassium (KCl/K phosphate) must be added in IV fluid (20-40 meq/L of IV fluid) as insulin infusion begins. This is the same as DKA management. - If plasma glucose level has not decreased by 50-100 mg% two hours after insulin treatment, insulin infusion rate should be doubled. - When plasma glucose level is 200-300 mg%, glucose containing solution (D5NS) may be substituted for the saline. - Make sure IV insulin is not prematurely discontinued. - Prior to discontinuation IV insulin administer SQ insulin 0.1-0.2 unit/kg of regular insulin at least 20-30 minutes prior to D/C IV insulin. Step 3: During hours 2-8, evaluate the precipitating and associated conditions of the patients and other supportive procedures. Step 4: If the patient is alert and able to retain fluid, then gradually switch IV fluid intake to oral fluid intake. Remember that electrolytes, phosphate and magnesium are depleted in these patients. These could be replaced orally over the next several days. Sliding scale, SC. Insulin should be administered at least 30 minutes prior to meal ingestion . Reference for adult patients: Gerich, J.E. Hyperosmolar non-ketotic coma. In: Current Therapy in Endocrinology and Metabolism. Bardin (ed.). B.C. Decker, Philadelphia, 1988. Reference for Pediatric patients for definition and short brief for HHS: Wolfsdorf et al Pediatric Diabetes 2006-2007,ISPAD clinical; practice consensus guideline 2006-2007- DKA. -31- D) SURGERY GUIDELINES-revised based on most recent guideline as of 8/2010 by the UIH. 1. If non-emergency, schedule surgery in the morning hours and when patient is in reasonable diabetic control. 2. On day of surgery on NPO - Fluids: use D5 electrolyte solution, for adequate hydration give maintenance to 1½ maintenance. - Insulin: - NO INSULIN INFUSION TO B E USED DURING SURGERY Give 1/2 daily dose of long acting or intermediate insulin ( lantus, levemir or lente, NPH). and if high bg , may give one time 1/3 or ½ of short acting insulin before surgery. - Following surgery in the recovery room, PRN short/rapid acting insulin (Novolog /Humalog) per sliding scale every 3-4 hrs may be administered SQ to correct high blood glucose level >250 and to prevent severe hyperglycemia and ketosis or use SC insulin infusion by insulin pump device with glucose in IVF or use IV insulin infusion with glucose in IVF to maintain bg level<250. 3. Postoperatively after leaving recovery room: - May need additional PRN short/rapid acting insulin to be administered SQ per sliding scale every 3-4 hrs or SC insulin infusion by pump or IV insulin infusion with D5 NS % in IVF to achieve blood glucose level 150-200 mg/dL - Once patient is able to eat and tolerate po, then resume usual insulin regimen but modify the dose as per po intake 4. Management - Electrolytes, BUN, blood glucose, pre and post-operatively, and every 2-4 hours thereafter in immediate postoperative period. Various methods of management of diabetes during surgery may include: 1. 2. -32- Use of intravenous glucose with 1/2 of patient's usual morning dose of NPH, Lente, lantus with 1/3 to ½ short acting insulin given SQ prior to surgery. Use of intravenous glucose with the usual dose SQ NPH or Lente prior to surgery with or without prn base .sliding scale of short acting insulin before and after surgery. VI. THYROID DISORDERS - CONGENITAL HYPOTHYROIDISM (CH) Suspected CH I. Clinically: May be present in 10-15% of hypothyroid newborns. 1. Most frequent: a. Patient posterior fontanelle and widely opened cranial sutures. b. Umbilical hernia. 2. Less frequent: a. LGA babies b. Feeding or sucking difficulties c. Prolonged jaundice, constipation d. Hypotonia, hoarse cry, skin mottling II. Abnormal Newborn Screening Test Results: 1. Elevated TSH, low T4 a. Primary hypothyroidism ┬ Retest and immediate treatment with L-Thyroxine b. Transient hypothyroidism ┘ 2. Elevated TSH and normal T4: Compensated primary hypothyroidism. 3. Normal TSH, low T4 a. Transient hypothyroxinemia of the newborn: Euthyroid clinically. b. Congenital thyroxine binding globulin deficiency: Euthyroid clinically. c. Hypopituitary-hypothalamic hypothyroidism: Clinically suspected hypothyroidism. Suspect in newborns with hypoglycemia, diabetes insipidus, persistent jaundice, micropenis, midline craniofacial defects, ocular abnormalities. Investigate for panhypopituitarism. d. Low birth weight infants. Work-up for Suspected CH Ultimate goal is detection and early treatment of all infants to ensure normal neurologic and somatic development. I. If Confirmatory Testing Shows the Following: 1. Low T4, elevated TSH: Immediate replacement treatment with L-Thyroxine. 2. Low T4, normal TSH: Do TBG, T3RU. free T4 levels a. Normal free T4, low TBG = TBG deficiency, no treatment. Low free T4, normal TBG = possible TSH deficiency. Immediate replacement treatment with L-Thyroxine. 3. Normal T4, elevated TSH = Compensated hypothyroidism. Treat based on clinical picture. If TSH is quite high, treat the patient with L-Thyroxine. 4. Normal T4, normal TSH a. Normal birth weight = Transient hypothyroidism of the newborn of undetermined etiology. Follow-up the patient's growth development on no treatment b. History of low birth weight = Transient hypothyroidism. No treatment for a or b. II. Bone Age: Do this only in confirmed hypothyroid cases. III. Technician Scan or Thyroid Ultrasound: To be done either immediately or later (do not delay treatment for this). IV. TSH blocking receptor AB: In infants born to mothers with history of autoimmune thyroid disease (can cause transient hypothyroidism in the newborn). -33- Therapy Principles of therapy should be to ensure a prompt rising of serum T4 or free T4 concentration to the upper normal range, and suppression of serum TSH to a normal level. May begin with L-Thyroxine 10-15 µg/kg/day. Dose adjustment based on follow-up T4 and TSH levels. L-Thyroxine Dosage Schedule for Hypothyroidism of Infancy and Childhood Age Dosage (µg/kg/day) Range of Dose Birth to 6 mo 10 25-50 6-12 mo 6-10 50-75 1 - 5 yr 5-6 75-100 6 - 12 yr 3-5 75-125 > 12 yr 2-3 100-150 MYXEDEMA COMA Definition: The end stage of severe thyroid hormone deficiency when patients develop failure of multiple organ systems and laps into stupor and even death. Causes Onset is often precipitated by additional stress: 1. Infection 2. Ingestion of sedatives or narcotics It is very rare in children, encountered more frequently: 1. In the winter months 2. In the elderly 3. In women 4. In those with a history of goiter, autoimmune thyroid disorder or thyroid abnormality. 5. In those who have discontinued thyroid hormone treatment. Diagnosis Clinical: Biochemical: Prognosis: Work-up: Non-pitting edema Hypothermia Hypoventilation Stupor, cardiomyopathy, convulsion Very low serum T4 and high TSH serum levels Depends on duration of myxedema coma. Early substitution of both general supportive treatments and specific thyroid hormone replacement. Serum TSH, free T4 or total T4 CBC, U/A, lytes, BUN, Cr, CK SGOT. Blood gases, blood culture, chest X-ray, EKG Monitoring of body temperature and BP, and serum cortisol level. Principles of Treatment 1. Stabilization of vital body functions: airway, ventilation, circulation and temperature. 2. Hyponatremia is often present. May need to give hypertonic saline and limit the volume of water in the infusion fluid. 3. Thyroid hormone replacement: To replace thyroid hormone deficit quickly and to saturate the large binding capacity on the thyroxine binding proteins in order to provide an effective circulating level of free T4. - Use T4 IV only or T4 IV and T3 IV. -34- - Loading dose of T4: 2 µg/kg IV over 5 min., then 1.5 µg/kg daily by IV, then oral when able to eat 4. Glucocorticoid Treatment: Many patients with autoimmune thyroid diagnosis may have adrenal insufficiency, and hydrocortisone metabolism is decreased in myxedema coma. So hydrocortisone stress dose may be given at the beginning and repeated thereafter q 8 hrs. HYPERTHYROID STORM Causes 1. Withdrawal of antithyroid medications in a patient with severe hyperthyroidism. 2. Administration of radioactive iodine (short term). 3. Infection (pneumonia). 4. Surgery and anesthesia. 5. DKA and insulin reaction. 6. Vigorous palpations of the thyroid gland. 7. Trauma 8. Dental extraction. 9. Mental stress. Clinically Significant Fever Cardiac: - Tachycardia (out of proportion to the fever.) - Atrial fibrillation. - Increased pulse pressure. CNS: - Altered mental status: Restlessness, severe tremors, agitation, psychosis, inability to concentrate, stupor, coma GI: - Nausea, vomiting, diarrhea, abdominal pain. Other: - Pre-renal failure, hepatic failure Lab Evaluation - Free T4 Total T4, T3 RIA all elevated - TSH suppressed. - Serum lytes, renal function tests, liver function tests to manage fluid and electrolyte imbalance. Management This is an emergency, rare in childhood. All dosages are for adolescents - adults and dose to be adjusted for children . Treatment should be initiated at the earliest suspicion.. 1. Blockade of Thyroid Hormone Synthesis a) Thionamides: Antithyroid drugs (in all cases) - Methimazole=Tapazole: 30 mg every 6 hours for adolescents and 5-15 mg every 6 hours in children depending on age. - Use until crisis resolves. PTU has been reported to cause infrequently but severe hepatitis in children that may be fatal and is no longer recommended for use in children . 2. Blockade of Release of Thyroid Hormone, T4, from the Gland (in all cases) a. Iodides: Should delay until 1-3 hours after initiation of thionamides NaI by IV: 0.5 mg q12 hours Lugol’s solution: 10 drops orally q8 hours or saturated solution of KI: 3 drops orally q8 hours If NaI by IV is not available and patient cannot take oral medications, use 10 drops of -35- Lugol’s solution added to IV fluid. b. Lithium: 600 mg orally as initial dose then 300 mg q6 hours (in some cases). 1. Monitor serum level of lithium and keep < 1.5 meq/L 2. Do not use in heart failure, renal failure or arrhythmia. 3. Inhibition of T4 and T3 conversion: a. Dexamethasone sodium phosphate: 2 mg IV then 2 mg orally q6 hours (in all cases). b. The iodinated cholecystographic contrast agents (iopanoic acid and ipodate). They may be used as a substitute for both inorganic iodide. They also release inorganic iodide. 4. Control of sympathetic and adrenal medullary effects: a. p.o. Propranolol: 20 mg tid for adolescents, 15 mg tid for children; 10 mg tid for young children. It also decreases peripheral T4 and T3 conversion: If signs of heart failure occur digitalization. 5. Control of body temperature if necessary: Artificial cooling: Ice packs, cooling blankets CNS blockade with IV phenothiazines and narcotic analgesic (to prevent shivering, assist in restoring body temperature). Chlorpromazine 25-50 mg (q4-6 hours) Meperidine 25-50 mg If hypothermia persists Dantrolene 100 mg by IV Addendum for thyrotoxicosis management using 131I therapy: 1. Set up an appointment with nuclear medicine for an uptake study on Day 1 and to receive 131I treatment on Day 2 as an outpatient. 2. Then discontinue all anti–thyroid agents for 5-7 days prior to the uptake testing date. 3. Inform the patient’s family of temporary thyrotoxic symptoms following 131I treatment and tell them that there is a 90% chance of developing permanent hypothyroidism after 131I. 4. Take precautions when treating any hyperthyroid patient with radioactive iodine as an outpatient and when there is a child < 6 yrs old in the house. a. If the dose of radioactive iodine is < 12 millicuries: stay away from the child in the same house for 24 hours. b. If the dose of radioactive iodine is 12-29 millicuries: Isolation for 24 hours. Any child < 6 yrs old should not stay in the house for 24 hours. NEONATAL GRAVE’S DISEASE (THYROTOXICOSIS) Occurs in 1% of infants of mothers with Graves' Disease via transplacental passage of TS Ab from the mother to the infant. Clinical Features Prematurity Goiter Exophthalmos Tachycardia Hyperirritability Congestive Heart Failure -36- Jaundice Hepatosplenomegaly Thrombocytopenia - Disease becomes evidently active for 5-10 days after birth if the newborn was exposed to maternal antithyroid medication in utero. - Mortality rate: 15-20% - Clinical sequela: Craniosynostosis IQ impairment Treatment Very mild thyrotoxicosis: Mild thyrotoxicosis: Moderate thyrotoxicosis: Severe thyrotoxicosis: Close observation and no-specific therapy. Tapazole=Methimazole 0.5-1 mg q 8 hrs PO Iodide drop (Na or K): 1 drop q 8 hrs + Methimazole 1 mg q 8 hrs Iodide 1 drop q 8 hrs + Methimazole 1 mg q 8 hrs + Propranolol 2 mg/kg/d BID to TID - Don't use propranolol alone in neonatal hyperthyroidism due to its complication and hazard to the neonate Supportive care includes use of oxygen, digitalis, and antibiotics if indicated. - If large goiter is present, prevent tracheal obstruction to maintain airway. -37- VII. PERSITENT DYSFUNTIONAL BLEEDING IN ADOLESCENT FEMALE 1. Administer Necon 1/35 OCP- 1 tab po t id every 8 hrs x 3 days - 1 tab po bid every 12 hrs x 2 days - 1 tab po per day x 1 day 2. Then start OCP (ie. Trphasil 28) 3. Do CBC baseline and then begin Ferinsol 325 mg pot id or ferrous sulfate 300 mg po daily x 1-2 months and folic acid 1 mg po daily x 1 month. Retest CBC at 1 month and 2 months. Medical Curettage method for severe uterine dysfunctional bleeding in adolescent women 1. Administer Aygestin 10 mg (two 5mg tabs) PO hourly until bleeding completely stops. Begin FerInSol 325mg po tid and folic acid 1 mg po qd continuously. 2. Then continue Aygestin 10 mg po bid x 1 month. Some spotting may occur, but this will get lighter and will stop eventually Gyn consult and uterine ultrasound would be necessary during 1 and 2 phases 3. Discontinue Aygestin at 1 month. This will cause presumably normal amount of withdrawal bleeding. 4. Thereafter, menstrual pattern can be observed or one may go on a monthly OCP Rx or monthly Provera treatment for 5 days for regulation of menstrual cycle. -38-