1. Calcium Channel Antagonists in Children Rama B. Rao, MD NYU/Bellevue Hospital Center 2007

4. Physiology of Children GI –Lower hepatic glycogen reserves –Limited enzymatic capacity –pH and motility –Chew or bite tablets altering absorption

5. Physiology of Children Respiratory –Diminished reserves Metabolic –Increased requirements

6. Management Limitations No confirmatory assay –Qualitative –Quantitative Delayed onset toxicity

7. Limitations Therapeutic interventions –No antidote –Variable outcomes –Limited data in children

9. Pharmacology of CCA Most tablets exclusively dosed for adults Often slow release Hepatically metabolized

10. Calcium Channels L type:Myocardium, sm mm, ß Islet pancreas T N PNeuronal, SR, other Q R

11. ß1ß1 GsGs AC ATP cAMP PKA Ca 2+ SR Ca 2+ 1 2 3 4 5 NORMAL MYOCARDIAL CELL

12. ß1ß1 GsGs AC ATP cAMP PKA Ca 2+ SR Ca 2+ 1 2 3 4 5 CCA Result: Negative inotropy

13. 0 1 2 3 4 Phase 2 Myocardial Cell Ca 2+ inward (with K + outward) Result CCA: Diminished contractility Contractile Cells

14. 0 1 2 3 4 Phase 2 Myocardial Cell Phase 4 Purkinje Fiber SA Node Result CCA: Altered conduction Delayed initiation Depressed movement thru Purkinje fiber Pacemaker Cells

15. Ca 2+ Vascular Smooth Muscle 11 Receptor operated Voltage sensitive Calmodulin Ca 2+ Contraction of sm mm

16. Ca 2+ CCA and Vascular Smooth MM 11 Receptor operated Voltage sensitive Calmodulin Ca 2+ Result : reduced vasoconstriction

17. CCA: Dihyrdopyridines Smooth mm: peripheral vasodilation –In mild overdose: Hypotension Tachycardia –In children and severe OD Hypotension Bradycardia

18. CCA: Verapamil, Cardizem Phenylalkylamines Greater binding at myocardial cells –Negative inotrope –Negative chronotrope Inhibit release of insulin in overdose

19. CCA: Management Assume ingestion Assess early/late or imminent* IV, ECG, monitoring *Fingerstick blood glucose?

20. Decontamination Activated charcoal: 1 gm/kg MDAC:0.5 gm/kg q4  Whole bowel irrigation?

21. Fellowship Case 30 month old male is found with an open bottle of verapamil SR 240mg tabs. New Rx : 100 tabs 94 tabs found

22. Verapamil

23. Case continued Toddler has normal vital signs Playful Running around the ED

24. Whole Bowel Irrigation PEG balanced salt solution Assess for bowel sounds NGT placement with confirmation –First AC –Follow with PEG 500* ml/hr (start at 100 ml/hr and rapidly titrate) –Q4  AC Continue until clear rectal effluent *Can give higher dose of up to 2L/hour as tolerated

25. Management Conundrums Hypotension: What can we try?

26. Ca 2+ CCA and Vascular Smooth MM 11 Receptor operated Voltage sensitive Calmodulin Ca 2+

27. CCA and Vascular Smooth MM 11 Receptor operated Voltage sensitive Calmodulin Ca 2+ NE, Phenylephrine Ca 2+

28. How does this affect cardiac output?

29. Rx: Vasodilation Agent Vasoconstriction HRCO NE++++↓↓↓ PE++++↓↓↓ HR = Heart rate; CO=Cardiac Output NE= Norepinephrine PE= Phenylephrine

30. Clinical Evaluation Mental status Peripheral circulation Urine output Lactate production Acid/base status

31. Vasodilation Crystalloid Calcium: variable efficacy Direct acting α 1 agonists –Norepinephrine –Phenylephrine Caveat need to combine with inotropes

32. Bradycardia What can we try?

33. Bradycardia Atropine and calcium –Variable efficacy ß 1 agonists* –Direct: Epinephrine, Isoproterenol –Indirect: Glucagon

34. What do these do to blood pressure?

35. Bradycardia Agent Vasoconstriction HRCO Calcium ±± ↑ ↑ Atropine ↑± Isoproterenol ↓↑±↑± Glucagon ↑±↑± Epi ±↑±↑±

36. Inotropes Critical to cardiac output Allow titration of pressors Also have caveats

37. What kind of inotropes can we try?

38. ß1ß1 GsGs AC ATP cAMP PKA Ca 2+ SR Ca 2+ 1 2 3 4 5 NORMAL MYOCARDIAL CELL

39. ß1ß1 GsGs AC ATP cAMP PKA Ca 2+ SR Ca 2+ 1 3 4 CCA Ca 2+ Epi, Dobutamine Amrinone 5’MP Glucagon 2

40. Inotropes ß 1 agonists –Direct –Indirect Phosphodiesterase inhibitors Calcium

41. Calcium 10% = 100 mg/mL Calcium chloride –1.36 mEq/mL –Central line important Calcium gluconate –0.43 mEq/mL

42. CaCl 2 10% (100 mg/mL) 20 mg/kg bolus over 3-5 minutes Repeat in 10 minutes Dilute concentration to 20 mg/mL 20-50 mg/kg/hr infusion

43. Calcium Gluconate 10% (100 mg/mL) 60-100 mg/kg bolus over 3 minutes (remember this has less mEq Ca 2+ ) May repeat in 10 minutes Dilute to 50 mg/mL Infusion 120-240 mg/kg/hr

44. Inotropes ß 1 agonists –Direct –Indirect Phosphodiesterase inhibitors Calcium

45. What do these inotropes do to blood pressure?

46. Inotropes Agent VasoconstrictionHRCO Dobutamine* ↓↑±↑ Epi ±↑↑±↑± Glucagon ↑±↑± Amrinone* ↓↑↑ Calcium ± ± ↑ * Needs pressor

47. Agent Vasoconstriction HRCO NE++++↓↓↓ PE++++↓↓↓ Calcium ±± ↑ ↑ Atropine↑± Isoproterenol ↓↑±↑± Dobutamine ↓↑±↑ Epi ± ↑↑±↑± Glucagon ↑±↑± Amrinone ↓↑↑ HR = Heart rate; CO=Cardiac Output In CCA Toxicity

48. Insulin and Dextrose Increase energy efficiency Prolongs opening of Ca 2+ channels Potential anti-inflammatory effects

49. Insulin and Dextrose Canine models –Increase lethal dose verapamil –Delayed time to death –Not necessarily change in heart rate or MAP –Compared to saline, epi, glucagon groups

50. Insulin and Dextrose Human cases –No comparative trials –Often rescue medication –None as first line therapy –?Reporting bias of success –At least a dozen survivors –Bolus vs infusion

51. ß1ß1 GsGs AC ATP cAMP PKA Ca 2+ SR Ca 2+ Myocardium under duress FFA metabolism

52. ß1ß1 GsGs AC ATP cAMP PKA Ca 2+ SR Ca 2+ Dextrose and Insulin I K+K+ Insulin/Glucose Glucose Aerobic metabolism

53. Insulin and Dextrose First fluid, calcium, other interventions Insulin 1 U/kg bolus –0.5-1 u/kg/hour infusion (some even higher) Dextrose 0.25 g/kg of D 25 for glucose <200 mg/dL Potassium supplementation < 2.5 Eq/mL

54. Insulin and Dextrose Check blood glucose and K + q 20 min x 3 Then every hour Clinical response may be within 20 – 60 minutes Call PCC: when to start, stop, outcomes

55. Invasive Therapies ECMO/VAD Exchange transfusion? Balloon pump

56. Intralipids: The Future? Used in local anesthetic toxicity Mechanism uncertain Rat and canine models are promising With lipid soluble toxin Lipidrescue.org

57. Intralipid? 20% solution 1-2 mL/kg bolus 0.25 mL/kg/hr Call PCC Lipidrescue.org

58. Case Toddler with 6 missing tablets Discussed aggressive therapy with family, PCC faculty, PICU faculty WBI started

59. Outcome All six tablets found in diapers within 7 hours of starting the WBI Baby discharged after 24 hours observation

60. Dosing (please recheck) Atropine –0.02 mg/kg q 3 minutes up to 3 mg Isoproterenol –0.05 – 2 mcg/kg/min Potassium –0.5 mEq/kg/hour prn

61. Dosing: Infusions Epinephrine –0.1- 1 mcg/kg/minute Norepinephrine –0.05 – 0.1 mcg/kg/min Phenylephrine –0.1 – 0.5 mcg/kg/min

62. Dosing Infusions Glucagon –50 mcg/kg and titrate to effective dose as bolus –If response then continue at that dose per hour as infusion Amrinone/Inamrinone –0.75 mcg/kg bolus over 3 minutes –5-10 mcg/kg/minute infusion –Should use with a vasoconstrictor