What’s New in Paediatric T1DM

1. What’s New in Paediatric T1DM TCH Paediatric Multidisciplinary Diabetes Team 10 July 2013

2. Learning objectives • Recognise clinical signs and symptoms to allow for the earliest possible diagnosis and referral of children with new-onset T1DM. • Describe current insulins and regimen options available in 2013. • Develop an understanding of the various technologies available for the management of T1DM at home. • Understand strategies for and review sick-day management plans for children with T1DM in your practice.

3. Case study1 • 4yr old boy • GP presentation: 3 week history of weight loss, polyuria and polydipsia. • 2 day history of sore throat • Woke up in the morning with ‘heavy breathing’ • Past medical and family history were unremarkable.

4. Case study2 Physical examination • Alert • GCS score 15/15 • Kussmaulbreathingpresent • PR 136 bpm, RR 44, BP 92/58 • >5% dehydration • Dry crackedlips • Weight 16kg (~3kg weightloss in 4 weeks) • Pharyngitis

5. Case study3 • At GP surgery: BGL 25mmol/L – referred to ED In ED: • Capillarybloodgas: pH 7.18, bicarbonate (HCO3) 12 mmol/L, BGL 25 mmol/L, Na 136 mmol/L (corrected = 142) , K 4.9 mmol/L Corrected Na = measured Na + 0.3 (glucose – 5.5)

6. Case study4 Management: • 10ml/kg bolus Normal saline • Re-assessed: PR 118, RR 36, BP 96/58 • IV insulin infusion: 0.1U/kg/hr • Fluids: N/S + 40mmol/L KCL at maintenance + 5% replacement over 48 hrs • Transferred to HDU – further management as per DKA protocol

7. Case study5 Atresolution of ketoacidosis: • Initiated on MDI: Levemir at bedtime; Novorapid with meals using an insulin dosing card. • DNE / Dietician / Social work involvement • Discharged home on day 5 with nightly contact with on-call Paediatric Endocrinologist for dose adjustments

8. Classification of Diabetes • Type 1 diabetes • β-cell destruction • Type 2 diabetes • Progressive insulin secretory defect • Other specific types of diabetes • Genetic defects in β-cell function, insulin action • Diseases of the exocrine pancreas • Drug- or chemical-induced • Gestational diabetes mellitus (GDM) Diabetes Care 2013;36(suppl 1):S11.

9. Criteria for diagnosis of Diabetes Diabetes Care 2013;36(suppl 1):S13; Table 2.

10. Criteria for Prediabetes *For all three tests, risk is continuous, extending below the lower limit of a range and becoming disproportionately greater at higher ends of the range. Diabetes Care 2013;36(suppl 1):S13; Table 3.

11. Pathogenesis of T1DM • Autoimmune destruction of the pancreatic islet cell • Hallmark = lymphocytic infiltration of islets • Progresses over years • Leads to insulin deficiency • Glucagon production is preserved but impaired action

12. Incidence of T1DM in Australia • Australian incidence (NDR) in children 0-14 years between 2000-2006 Diabetic Medicine 2009; 26(6): 596-601

13. Genetics of T1DM 1 • Susceptibility to T1DM is an inheritable trait BUT >85% cases occur in the absence of first-degree relative • Lifetime risk: first-degree relative (5%) vs general population (0.3%)

14. Genetics of T1DM 2 • Twin concordance: monozygotic (30-50%) vs dizygotic (6-10%) • Risk increases with early age at diagnosis: 3-5 fold increase risk if first degree relative diagnosed <5 years age

15. Genetics of T1DM 3 Susceptibility loci: HLA-DR3 and HLA-DR4 • At least one locus: 95% T1DM vs 3% general population Protective loci: HLA-DR2, HLA-DR5, and HLA-DQB1*0602 • 1 in 15,000 people with HLA-DQB1*0602 develop T1DM

16. Environmental factors in T1DM • Cow’s milk protein exposure (bovine serum albumin and β-lactoglobulin) • Vitamin D deficiency • Viruses: coxsackieA or B, enterovirus, rubella, cytomegalovirus, ECHO virus, EBV, mumps, retrovirus • Drugs & toxins: egalloxan-like or streptozotocin- like agents that induce oxidant beta-cell damage • Stress The Environmental Determinants of Diabetes in the Young (TEDDY) study

17. Islet-specific autoantibodies1 • Islet cell autoantibodies (ICA) • Glutamicacid decarboxylase autoantibodies (GADA) • Insulinoma-associated 2 autoantibodies (IA-2A) • Insulin autoantibodies (IAA) • Zinc transporter autoantibodies (ZnT8A). Multiple and specific combinations of autoantibodies more predictive Diabetes Care 2009;32:2269-74

18. Islet-specific autoantibodies2 • Not causative • Present months to years before onset of symptoms • Persist for varying duration after onset • 90-95% T1DM have at least one at diagnosis Cell Mol Life Sci 2007;64:865-72 Ann Intern Med 2004;140:882-6 J ClinEndocrinolMetab 2004;89:3896-902. Diabetes 1999;48:460-8

19. The Pathogenesis of T1DM Atkinson MA & Eisenbarth GS. Lancet 2001; 358; 221-229

20. Normal glucose homeostasis Meal

21. Insulin secretion

22. Fasting blood glucose is not an appropriate screen test for T1DM

23. Clinical Presentation • Polyuria – 95% • Weight loss – 61% • Fatigue – 52% Polyuria is often missed on history The EURODIAB study Diabetologia2001;44(Suppl 3):B75-80.

24. Goals of T1DM Management • Utilize intensive therapy aimed at near-normal BG and A1C levels • Prevent diabetic ketoacidosis and severe hypoglycemia • Achieve the highest quality of life compatible with the daily demands of diabetes management • In children, achieve normal growth and physical development and psychological maturation • Establish realistic goals adapted to each individual’s circumstances

25. DCCT and EDIC Findings • Intensive treatment reduced the risks of retinopathy, nephropathy, and neuropathy by 35% to 90% compared with conventional treatment • Absolute risks of retinopathy and nephropathy were proportional to the A1C • Intensive treatment was most effective when begun early, before complications were detectable • Risk reductions achieved at a median A1C 7.3% for intensive treatment (vs 9.1% for conventional) • Benefits of 6.5 years of intensive treatment extended well beyond the period of most intensive implementation(“metabolic memory”) Intensive treatment should be started as soon as is safely possible after the onset of T1DM and maintained thereafter DCCT/EDIC Research Group. JAMA. 2002;15;287:2563-2569.

26. Principles for Good Glycaemic Control

27. The Multidisciplinary Team Approach • Paedaitric Endocrinologist • Diabetes Nurse Educator / Nurse Practitioner • Dietician • Social Worker • Psychologist • Age-appropriate clinics ISPAD Clinical Practice Consensus Guidelines 2006–2007

28. Contributors to good glycaemic control • Education for parents / child (age appropriate) • Correct insulin regimen • Contact in between clinics for adjustments • Good relationship with GP ISPAD Clinical Practice Consensus Guidelines 2006–2007

29. Pharmacokinetics of insulin Products Rapid (Humalog, Novorapid, Apidra) Insulin Level Short (Humalin R, Actrapid) Intermediate (NPH, Protaphane) Long (glargine) Long (detemir) 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours N Engl J Med. 2005;352:174-183.

30. Increased Complexity Better control Less Hypoglycaemia Pre-mix Twice-daily MDI CSII

31. Insulin dosing advice INSULIN DOSING CARD Ezy-BICC SMART-METER Accu-Chek Aviva Expert INSULIN DOSING APP Insulin Pro

32. DKA

33. Risk factors for DKA at diagnosis of T1DM • Younger age • Ethnic minority • No first degree relative • Low SES/poor medical access/uninsured • Lack of community health screening • Lower weight SDS at diagnosis Rates of DKA inversely related to prevalence of T1DM Diabet Med 2013. doi: 10.1111/dme.12252 Pediatr Clin N Am 2011; 58 : 1301–1315

34. DKA criteria • Hyperglycemia BG > 11 mmol/l (young or partially treated children, pregnant adolescents may present with “euglycemic ketoacidosis”) • Venous pH <7.3 and/or bicarbonate <15 mmol/L • mild DKA pH <7.3 bicarbonate <15 • moderate pH <7.2 bicarbonate <10 • severe pH <7.1 bicarbonate < 5 • Glucosuria and ketonuria/ketonemia (β-HOB) ISPAD Clinical Practice Consensus Guidelines 2006–2007

35. Pathophysiology of DKA ISPAD Clinical Practice Consensus Guidelines 2006–2007

36. DKA Clinical Manifestations 1 • Feeling unwell for a short period, often less than 24 hours • Polyuria, polydipsia and increased thirst, nocturia • Polyphagia • Weight loss • Nausea and vomiting, vomitus can have coffee-ground colour due to haemorrhagicgastritis • Abdominal pain, due to dehydration and acidosis • Weakness ISPAD Clinical Practice Consensus Guidelines 2006–2007

37. DKA Clinical Manifestations 2 • Neurologic signs: restlessness, agitation,lethargyand drowsiness, coma. Increased • Osmolality is the main factor that contributes to altered mental status • Visual disturbances due to hyperglycaemia • Deep and rapid breathing, known as Kussmaul breathing, may have acetone odouron breath. ISPAD Clinical Practice Consensus Guidelines 2006–2007

38. DKA Clinical Manifestations 3 • Signs of dehydration due to fluid loss through polyuria, vomiting and breathing: reduced skin turgor, dry mucous membranes • Signs of hypovolaemia: tachycardia, hypotension, postural hypotension ISPAD Clinical Practice Consensus Guidelines 2006–2007

39. DKA Clinical Manifestations 4 • Mild hypothermia due to acidosis-induced peripheral vasodilation, warm dry skin. • Fevers are rare despite infection. Severe hypothermia is a poor prognostic sign ISPAD Clinical Practice Consensus Guidelines 2006–2007

40. Measurement of Ketone bodies

41. Hypoglycaemia

42. Hypoglycaemia 1 Adrenergic Neuroglycopenic • Diaphoresis • Tachycardia/Palpitations • Shakiness • Tingling • Pallor • Confusion • Irritability • Behavoural changes • Difficulties concentrating • Headache • Visual disturbance • Slurred speech • Altered consciousness • Seizures

43. Hypoglycaemia 2 • Check BGL if symptoms: <4.0mmol/L • To increase BGL by 3-4mmol/L: <30kg child use 10g ≥30kg child use 15g • Re-check BGL every 10-15 mins and repeat treatment if necessary ISPAD Guidelines Pediatric Diabetes 2009: 10(Suppl. 12): 134–145

44. Hypoglycaemia 3 • Check 20-30 mins after resolution to ensure BGL maintained • Solid food should be avoided until BGL ≥ 4mmol/L (impairs absorption of fast-acting CHO) • Severe hypoglycaemia: IM Glucagon – 0.5mg in <12 years; 1.0mg in ≥ 12 years ISPAD Guidelines Pediatric Diabetes 2009: 10(Suppl. 12): 134–145

45. Cognitive Effects of Hypoglycemia in Children • Repeated and early exposure to severe hypoglycemia has been reported to reduce long-term spatial memory in children with type 1 diabetes • Early exposure to hypoglycemia may be more damaging to cognitive function than later exposure Diabetes Care. 2005;28:2372-2377.

46. Incidence of Severe Hypoglycemia: T1DM Exchange Garg S, et al. Presented at 5th International Conference on Advanced Technologies & Treatment for Diabetes, Barcelona, 2012.

47. Causes of Hypoglycemia in Toddlers and Preschoolers • Unpredictable food intake and physical activity • Imprecise administration of low doses of insulin • Frequent viral infections • Inability to convey the symptoms of low blood sugar J Pediatr. 2002;141:490-495.

48. Glucose Variability and Health Outcomes: Direct and Indirect Pathways Glucose variability Fear of hypoglycemia Reluctance to intensify therapy Quality of life High A1C Severe hypoglycemia Complications Morbidity Mortality Controversial Health Psychol. 1992;11:135-138 Diabetes Care. 1996;19:876-879;Diabetes TechnolTher. 2008;10:69-80.

49. MEDTRONIC DEXCOM HYPOMON

50. Sick Day Management