Case Study 2: Symptomatic Bradycardia

Robert S. Hoffman, MD

Director

New York City Poison Center

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

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

ECG

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

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

Physiology

Physiology

Physiology

Physiology

Beta Blocker

Digoxin Toxicity

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

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

Diagnosis and Prognosis

Bismuth C, et al: Clin Toxicol 1973; 6:153-162

Composite endpoints

•Death

•Vasoactive drugs (epinephrine, etc)

•Pacemaker

22.2 mmol/L

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

Digoxin Effect

Bradycardia

Atrial Tachycardia with A-V Block

More

Bidirectional Ventricular Tachycardia

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

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

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

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

Question 5

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

General Treatment

Answer 5

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

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

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

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

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

Cardiac Energy Dynamics

• Normal Function

• Preferred Substrate– Fatty Acids

• High energy• Stable pool

Cardiac Energy Dynamics

• Sick hearts

• Convert to glucose– Immediate energy– Limited availability– Large swings– Basis for:

• Tight glucose control• High dose insulin/euglycemia therapy

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

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

Yuan TH, et al: Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J

Toxicol Clin Toxicol 1999;37:463-474

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)

Lipid Emulsion Therapy

• Mechanism of action

• 2 Prevailing hypotheses– “Lipid sink theory”– Bioenergetic theory

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

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

ACADEMIC EMERGENCY MEDICINE 2007;14:105

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

Results 1

Results 2

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

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

Results

Human Case Reports

• Bupivacaine, Levobupivacaine, Ropivacaine, Mepivacaine

• Bupropion and lamotrigine

• Beta blockers

• Haloperidol and other antipsychotics

• Calcium channel blockers

• Tricyclic antidepressants

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

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

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

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

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 ingested0.5 mg/vial

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

Summary

• Understand the physiology

• Understand the toxicology

• Define the physiology– Labs– ECG– Clinical status

• Tailor the antidotes to the physiology and toxicology

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