Case Study 2: Symptomatic Bradycardia

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Case Study 2 Symptomatic Bradycardia

• Robert S. Hoffman, MD
• Director
• New York City Poison Center

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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

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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

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ECG
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EAPCCT Investigation of the Poisoned
Patient-Case Studies
Bordeaux, May 2010
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Question 1

• The most likely etiology of this patients
  toxicity is
• A. Digoxin
• B. Calcium channel blocker
• C. Beta blocker
• D. Clonidine
• E. Organophosphate

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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

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Physiology
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Physiology
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Physiology
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Physiology
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Beta Blocker
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Digoxin Toxicity
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EAPCCT Investigation of the Poisoned
Patient-Case Studies
Bordeaux, May 2010
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

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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

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Diagnosis and Prognosis
Bismuth C, et al Clin Toxicol 1973 6153-162
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• Composite endpoints
• Death
• Vasoactive drugs (epinephrine, etc)
• Pacemaker

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22.2 mmol/L
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EAPCCT Investigation of the Poisoned
Patient-Case Studies
Bordeaux, May 2010
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

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Digoxin Effect
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Bradycardia
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Atrial Tachycardia with A-V Block
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More
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Bidirectional Ventricular Tachycardia
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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

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EAPCCT Investigation of the Poisoned
Patient-Case Studies
Bordeaux, May 2010
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

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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

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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

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EAPCCT Investigation of the Poisoned
Patient-Case Studies
Bordeaux, May 2010
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

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General Treatment
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Answer 5

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

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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
1993267744-50
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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

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EAPCCT Investigation of the Poisoned
Patient-Case Studies
Bordeaux, May 2010
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

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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

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Cardiac Energy Dynamics

• Normal Function
• Preferred Substrate
• Fatty Acids
• High energy
• Stable pool

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Cardiac Energy Dynamics

• Sick hearts
• Convert to glucose
• Immediate energy
• Limited availability
• Large swings
• Basis for
• Tight glucose control
• High dose insulin/euglycemia therapy

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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
1993267744-50
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Kline JA, et al. Cardiovasc Res 199734289-298
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Yuan TH, et al Insulin-glucose as adjunctive
therapy for severe calcium channel antagonist
poisoning. J Toxicol Clin Toxicol 199937463-474
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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)

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Lipid Emulsion Therapy

• Mechanism of action
• 2 Prevailing hypotheses
• Lipid sink theory
• Bioenergetic theory

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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. 200631296
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Tebutt S Intralipid prolongs survival in a rat
model of verapamil toxicity. Acad Emerg Med
200613134
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ACADEMIC EMERGENCY MEDICINE 200714105
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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

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Results 1
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Results 2
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Ann Emerg Med. 200749178-185.
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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

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Results
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Human Case Reports

• Bupivacaine, Levobupivacaine, Ropivacaine,
  Mepivacaine
• Bupropion and lamotrigine
• Beta blockers
• Haloperidol and other antipsychotics
• Calcium channel blockers
• Tricyclic antidepressants

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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

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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

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EAPCCT Investigation of the Poisoned
Patient-Case Studies
Bordeaux, May 2010
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

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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

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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
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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)

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Summary

• Understand the physiology
• Understand the toxicology
• Define the physiology
• Labs
• ECG
• Clinical status
• Tailor the antidotes to the physiology and
  toxicology

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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