EM@3AM – Beta-Blocker Toxicity

Author: Erica Simon, DO, MHA (@E_M_Simon, EMS Fellow, SAUSHEC, USAF) and Daniel Sessions, MD (EM Associate Program Director, SAUSHEC, USA / Associate Medical Director, South Texas Poison Center) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Attending Physician, SAUSHEC, USAF)

Welcome to EM@3AM, an emdocs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.

A 3-year-old female arrives in the emergency department approximately 15 minutes following the ingestion of an unknown amount of atenolol. Per the patient’s mother, the toddler was left unattended for “seconds” at her grandparent’s home and was subsequently found holding her grandfather’s medication bottle, chewing the atenolol tabs. Based upon the date of the prescription, the grandfather reports 10 tabs as unaccounted for.

Triage vital signs (VS): BP 88/62, HR 77, T 99.1 Oral, RR 12, SpO2 99% on room air.

Pertinent physical examination findings:
Neuro: Alert, interacting with caregiver, behavior appropriate for age.
CV: Regular rate and rhythm.
Abdomen: soft, non-tender, non-distended. No guarding or rebound.

What’s the next step in your evaluation and treatment?

Answer: Beta-Blocker Toxicity^1-4

• Epidemiology: In 2015, U.S. poison centers received > 40,000 calls regarding beta-blocker exposures. Of these calls, 3,000 involved children under the age of 5.²
• Pathophysiology: Beta-blockers competitively inhibit catecholamines at beta-adrenergic receptors:¹
  • β₁ adrenergic receptors: beta-blockers block the catecholamine effects of positive inotropy, dromotropy, and chronotropy.
  • β₂ adrenergic receptors: beta-blockers limit smooth muscle relaxation and vasodilation (vascular beds), glycogenolysis and gluconeogenesis (liver), bronchodilation (lung), and the release of free fatty acids (adipose tissue).
• Beta-adrenergic blockers:¹
  • Cardio-selective (β₁): atenolol, acebutolol, betaxolol, bisoprolol, esmolol, metoprolol, practolol.
  • Non-selective (β₁ and β₂): carvedilol, labetolol (α blockade also), oxprenolol, pindolol, propranolol, nadolol, sotalol (class II and III antidysrhythmic properties), and timolol.
    • Note: acetabolol, betaxolol, propranolol, and nadolol demonstrate a membrane stabilizing effect (fast sodium channel blockade).
•  Pharmacodynamics:¹
  • Metabolism: Beta-blockers undergo first pass hepatic metabolism => reduced bioavailability following ingestion vs. intravenous injection.
  • Volume of distribution: For the majority of beta-blockers, the volume of distribution exceeds 1L/kg => hemodialysis not efficacious for the majority (except as noted: see treatment).
  • Protein binding varies from 0% for sotalol to 93% for propranolol.
  • Propranolol is highly lipophilic => CNS penetration and toxicity secondary to sodium channel blockade = toxic exposures associated with the highest fatality rate amongst beta-blockers.
  • Peak effects vary between drugs. Individuals may experience life-threatening bradycardia or CNS effects within 30 minutes of exposure. Patients ingesting delayed-release preparations are often initially asymptomatic with a period of toxicity lasting up to 24 hours.
•  Clinical Presentation: Bradycardia (most common initial sign), hypotension, altered mental status, respiratory arrest, dysrhythmias (atrioventricular block (AV) (beta-blockers capable of fast sodium channel blockade), or ventricular fibrillation. Hypoglycemia is more common in the pediatric population. Seizures are often witnessed following toxic propranolol exposure.
  • Note: Acebutolol, oxprenolol, and pindolol exhibit intrinsic sympathomimetic activity => may manifest as sinus or ventricular tachycardia.
  • Labetolol: significant exposure likely to result in hypotension and distributive shock (α₁ blockade).
•  Evaluation:
  • Assess ABCs and obtain VS. Initiate cardiac monitoring.
  • Obtain an EKG:
    • Evaluate for bradycardia, AV blocks, and QRS widening (sodium channel blockade), or alternatively sinus or ventricular tachycardias.
  • Determine a blood glucose level.
  • Perform a thorough history (as able). Question specifically regarding the details of exposure, e.g. drug, dose, route, time of exposure, witnessed or un-witnessed exposure, co-ingestions, and intent.
  • Perform a physical examination.
  • Labs: Evaluate for co-ingestions as applicable (i.e. serum ETOH, serum salicylates, serum acetaminophen, etc.)
•  Treatment:^1,3,4
  • Consult toxicology.
  • Activated charcoal, whole-bowel irrigation, and gastric lavage have failed to demonstrate efficacy in clinical trials;³ however, these interventions should be considered in the setting of presumed life-threatening exposure or ingestion of sustained-release preparations, in consultation with a toxicologist.¹
  • Initiate fluid resuscitation.
  • Atropine advised for symptomatic bradycardia:
    • Adult dose: 0.5-1 mg IV bolus. Pediatric dose: 0.02 mg/kg IV bolus (min 0.1 mg, max 3 mg).
  • Refractory hypotension: consider calcium administration (final common pathway for stimulation of beta-andrenergic receptors = increase in intracellular calcium concentration; beta-blockade limits this process).
    • Adult dose: Calcium gluconate 10%, 3 g (30 mL) IV bolus. Calcium chloride 10%, 1 g (10 mL) IV bolus. Pediatric dose: Calcium gluconate 10%, 60 mg/kg (0.6 mL/kg (max: adult dose). Calcium chloride 10%, 20 mg/kg (0.2 mL/kg) (max: adult dose).
  • Glucagon: Displays inotropic and chronotropic effects which function independently of beta-adrenergic stimulation; counteracts beta-blocker induced hypoglycemia => utilized as a bridge to high-dose insulin therapy.
    • Adult dose: 5-10 mg IV bolus. Pediatric dose: 0.05-0.1mg/kg (max: adult dose).
      • Effects are transient: half-life approximately 20 minutes.
    • High-Dose Insulin Euglycemia Therapy (HIET) : Insulin is an inotrope thought to optimize the use of carbohydrates by cardiac myocytes and modulate intracellular calcium.
      • Adult and pediatric dosing: 1 U/kg/hr titrated to 2 U/kg/hr every 10 minutes until a max of 10 U/kg/hr is reached.
        • Recommended: Administer a bolus of dextrose prior to insulin infusion (0.5 g/kg IV) if blood glucose < 200 mg/dL.
      • Initiate a dextrose drip (D25 or D50).
  •  Special Circumstances:
    • Refractory hypotension despite fluid resuscitation, atropine, calcium, glucagon, and high-dose insulin:
      • Consider vasopressors (epinephrine and norepinephrine first line).
      • Consider intravenous lipid emulsion (ILE) in consultation with a toxicologist.
        •  Indications and dosing not universally agreed upon.  Experts recommend: 1.5 ml/kg of 20% lipid emulsion given over 2-3 minutes, immediately followed by an infusion of 0.25 mL/kg/min.¹
      • Refractory bradycardia: consider transcutaneous or transvenous pacing. (Note: Unlikely to improve perfusion if stroke volume is significantly reduced. Recommend bedside echo prior to initiation).
      • Sodium channel blockade with QRS widening:
        • Administer bicarbonate (1-2 mEq/kg IV as a repeated bolus every 3-5 minutes until QRS < 120 msec).
      • If perceived life-threatening ingestion of acebutolol, atenonol, nadolol, sotalol, or timolol: consider hemodialysis or hemoperfusion.
      • If a patient is refractory to all of the above measures => consider extracorporeal membrane oxygenation (ECMO). ECMO is compatible with HIET and ILE.
•  Disposition:¹
  • Symptomatic patients require ICU level care.
  • A patient who remains asymptomatic for 6 hours following an alleged toxic ingestion of a normal-release preparation: refer for psychiatric evaluation vs. home with parental guidance (pediatric).¹ 
  • Asymptomatic patients reporting ingestion of sustained release formulations: admit for 24-hour monitoring.
•  Pearls:
  • In the setting of presumed toxic ingestion, the differential diagnosis of a patient presenting with bradycardia and hypotension should include: beta-blockade, calcium channel blockade, digoxin toxicity, and clonidine toxicity.¹

 References:

1. Cole J. Cardiovascular Drugs. In Rosen’s Emergency Medicine: Concepts and Clinical Practice. 9^th ed. Philadelphia, Elsevier. 2018; 147:1876-1889.e2.
2. Mowry J, Spyker D, Brooks D, et al. 2015 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 33^rd Annual Reports. Clin Tox (Phila). 2015; 1075.
3. Thanacoody R, Caravati E, Troutman B, et al. Position paper update: whole bowel irrigation for gastrointestinal decontamination of overdose patients. Clin Toxicol (Phila). 2015; 53:5-12.
4. Wax P, Erdman A, Chyka P, et al. Beta-blocker ingestion: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2005; 43(3):131-146.

 For Additional Reading:

Core EM: Hyperinsulinemia Euglycemia Therapy (HIET) for BB and CCB Toxicity