1. Case Study 2: Symptomatic Bradycardia Robert S. Hoffman, MD Director New York City Poison Center

2. Objectives Understand the differential diagnosis of drug-induced bradycardia Explain the use of the laboratory in cases of unknown bradycardia Discuss the treatment of patients with known and unknown causes of bradycardia

3. Differential Diagnosis A 42 year old man presents to the hospital complaining of weakness and dizziness following an intentional drug overdose –He is pale and diaphoretic appearing but awake –Blood pressure 62/30 mm Hg –Pulse 40/minute; slightly irregular –Physical examination otherwise normal

4. ECG

6. Question 1 The most likely etiology of this patient’s toxicity is: –A. Digoxin –B. Calcium channel blocker –C. Beta blocker –D. Clonidine –E. Organophosphate

7. Answer 1 You can not be certain at this point: –A. Digoxin –B. Calcium channel blocker –C. Beta blocker –D. Clonidine Sedation –E. Organophosphate Muscarinic and nicotinic findings

8. Physiology

12. Beta Blocker

13. Digoxin Toxicity

15. Question 2 Which laboratory tests might be useful to help narrow the differential diagnosis –A. Glucose –B. Calcium –C. Potassium –D. Sodium –E. Both A and C

16. Answer 2 Which laboratory tests might be useful to help narrow the differential diagnosis –A. Glucose –B. Calcium –C. Potassium –D. Sodium –E. Both A and C

17. Diagnosis and Prognosis Bismuth C, et al: Clin Toxicol 1973; 6:153-162

18. Composite endpoints Death Vasoactive drugs (epinephrine, etc) Pacemaker

20. 22.2 mmol/L

22. Question 3 Which ECG finding is MOST characteristic of digoxin toxicity: –A. Scooped ST segment –B. Sinus bradycardia –C. Atrial tachycardia with high degree A-V block –D. Bidirectional ventricular tachycardia –E. Slow atrial fibrillation

23. Digoxin Effect

24. Bradycardia

25. Atrial Tachycardia with A-V Block

26. More

27. Bidirectional Ventricular Tachycardia

28. Answer 3 Which ECG finding is MOST characteristic of digoxin toxicity: –A. Scooped ST segment –B. Sinus bradycardia –C. Atrial tachycardia with high degree A-V block –D. Bidirectional ventricular tachycardia –E. Slow atrial fibrillation

30. Question 4 Which rhythm is inconsistent with digoxin toxicity –A. Sinus tachycardia –B. Rapid atrial fibrillation –C. Supraventricular tachycardia at 150/min –D. Multifocal atrial tachycardia –E. All of the above

31. Answer 4 Which rhythm is inconsistent with digoxin toxicity –A. Sinus tachycardia –B. Rapid atrial fibrillation –C. Supraventricular tachycardia at 150/min –D. Multifocal atrial tachycardia –E. All of the above

32. More Case Information ECG: As shown previously Glucose: 300 mg/dL (16.16 mmol/L) Serum potassium: 4.8 mmol/L A fluid bolus of 1L of saline is given without response –Blood pressure 72/40 mm Hg –Pulse 45/min

34. Question 5 Which of the following therapies is most appropriate at this point? –A. Digoxin antibodies –B. Epinephrine –C. Glucagon –D. Calcium –E. Milrinone

35. General Treatment

36. Answer 5 Which of the following therapies is most appropriate at this point? –A. Digoxin antibodies –B. Epinephrine –C. Glucagon –D. Calcium –E. Milrinone

37. Kline JA, Tomaszewski CA, Schroeder JD, Raymond RM: Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine. J Pharmacol Exp Ther 1993;267:744- 50

38. More Case Information A serum digoxin concentration is reported as non-detectable. The patient is given the following with little improvement: –3 grams of calcium chloride –Escalating doses of glucagon (up to 10 mg) –Amrinone –Dopamine continuous infusion

40. Question 6 Which therapies might be indicated next: –A. Hemodialysis/hemoperfusion –B. Pacemaker –C. Intra-aortic balloon pump –D. High-dose insulin euglycemia therapy –E. Intravenous fat emulsion

41. Answer 6 Which therapies might be indicated next: –A. Hemodialysis/hemoperfusion –B. Pacemaker –C. Intra-aortic balloon pump –D. High-dose insulin euglycemia therapy –E. Intravenous fat emulsion

42. Cardiac Energy Dynamics Normal Function Preferred Substrate –Fatty Acids High energy Stable pool

43. Cardiac Energy Dynamics Sick hearts Convert to glucose –Immediate energy –Limited availability –Large swings –Basis for: Tight glucose control High dose insulin/euglycemia therapy

44. Kline JA, Tomaszewski CA, Schroeder JD, Raymond RM: Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine. J Pharmacol Exp Ther 1993;267:744- 50

45. Kline JA, et al. Cardiovasc Res 1997;34:289-298

46. Yuan TH, et al: Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol 1999;37:463-474

47. Technique Bolus 1 unit/kg of regular insulin Follow with a continuous infusion –0.5-2.0 units/kg/hour of regular insulin Add glucose as necessary –0.5-1 gm/kg/hr Allow mild hypokalemia (only mild)

48. Lipid Emulsion Therapy Mechanism of action 2 Prevailing hypotheses –“Lipid sink theory” –Bioenergetic theory

49. Lipid Emulsion Therapy Lipid sink theory –Intralipid partitions the drug into a lipid phase creating a concentration gradient for removal of the drug from the target organ Weinberg GL: Reg Anesth Pain. 2006;31:296

50. Tebutt S: Intralipid prolongs survival in a rat model of verapamil toxicity. Acad Emerg Med 2006;13:134

51. ACADEMIC EMERGENCY MEDICINE 2007;14:105

52. Methods 14 dogs instrumented extensively Verapamil toxicity, defined as a 50% decrease in MAP All dogs got atropine and calcium chloride (15 mg/kg q 5min) Randomized –IFE (7 mg/kg of 20%) IV –Or equivalent volumes of 0.9% normal saline

53. Results 1

54. Results 2

55. Ann Emerg Med. 2007;49:178-185.

56. Methods 30 sedated and ventilated clomipramine poisoned rabbits At 50% MAP given –0.9% NaCl 12 mL/kg –OR 8.4% sodium bicarbonate 3 mL/kg –OR 20% Intralipid 12 mL/kg

57. Results

58. Human Case Reports Bupivacaine, Levobupivacaine, Ropivacaine, Mepivacaine Bupropion and lamotrigine Beta blockers Haloperidol and other antipsychotics Calcium channel blockers Tricyclic antidepressants

59. Lipid Emulsion Weinberg Protocol Bolus –1.5 mL/kg over one minute –Repeat every 3-5 minutes –Maximum 8 mL/kg Infusion –0.25 mL/kg/min until hemodynamic recovery –Can increase to 0.5 mL/kg/min if needed

60. Indications For Digibind In Acute Overdose Serum potassium over 5.0 mEq/L Any life-threatening dysrhythmia –Redefine for digoxin A digoxin level over 10-15 ng/mL Need for prolonged ICU observation Mixed overdose with calcium calcium channel blocker

62. Question 7 What is the correct dose of digoxin- specific Fab in an adult patient with an acute overdose and severe toxicity? –A. 1 vial –B. 2 vials –C. 5 vials –D. 10 vials –E. 20 vials

63. Answer 7 What is the correct dose of digoxin- specific Fab in an adult patient with an acute overdose and severe toxicity? –A. 1 vial –B. 2 vials –C. 5 vials –D. 10 vials –E. 20 vials

64. Digibind Dosing Empiric dose –10 to 20 vials in acute overdose Amount ingested known –Each vial binds 0.5 mg of digoxin –Assume 100% bioavailability –Divide: mg ingested 0.5 mg/vial

65. Digibind dosing Level known: [ ]=d/Vd; d=[ ] X Vd level (ng/mL) X Wt (Kg) X 5.6 L/kg 0.5 mg/vial X 1000 ~ level (ng/mL) X wt (kg) 100

67. Summary Understand the physiology Understand the toxicology Define the physiology –Labs –ECG –Clinical status Tailor the antidotes to the physiology and toxicology

68. Clinical Clues Blood pressure –Preserved with digoxin Mental status –Preserved with CCB Electrolytes –K+ increased with digoxin, less so with beta blockers –Glucose increased with calcium channel blockers