ToxCard: Propranolol

Authors: Marie Wofford, MD, MPH (Emergency Medicine Resident, Atrium Health’s Carolinas Medical Center), Christine Murphy, MD (Emergency Medicine Attending, Medical Toxicologist, Atrium Health’s Carolinas Medical Center) // Reviewed by: James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Alex Koyfman, MD (@EMHighAK); and Brit Long, MD (@long_brit)

Case:

A 19-year-old female with no significant past medical history presented to the emergency department (ED) following ingestion of 50 tabs of 20 mg propranolol, four tabs of 20 mg hydrocodone, two tabs of fluoxetine 20 mg, and a half bottle of wine. She was pale but awake and alert.

Initial vital signs were temperature 97.7°F, heart rate (HR) 56, blood pressure (BP) 117/89, O₂ sat 93% on room air, respiratory rate 26. Her glucose was 148 mg/dL. Another set of vitals were obtained 30 min after arrival. Her HR was in the 40s and BP 100/60.

Questions:

1. How does propranolol toxicity occur?
2. What are the signs and symptoms of propranolol toxicity?
3. Are there EKG changes associated with beta blocker toxicity?
4. What is the management of propranolol toxicity?

Background:

• Propranolol, one of the first beta blockers produced in the United States, is used primarily to treat hypertension, thyrotoxicosis, essential tremors, hemangiomas, dysrhythmias, and angina, among other disorders.¹
• Beta blockers are classified as selective or nonselective according to their receptor specificity.¹
  • Propranolol is a nonselective beta blocker.
• Known to be highly lipophilic, propranolol can easily cross the blood-brain barrier.^1,2
  • High lipophilicity can lead to central nervous system (CNS) effects like seizures and CNS depression even without hypotension.¹
• Propranolol is also known to have the highest membrane-stabilizing activity of beta blockers which leads to sodium channel antagonism and QRS interval prolongation.¹
• Cardiovascular toxicity from beta blockers occurs due to decreased sinoatrial node conduction, atrioventricular (AV) node conduction, and contractility.¹ This results in negative chronotropic and inotropic effects.
• Most patients will exhibit signs of toxicity within two to six hours following an overdose of immediate release beta blockers.¹
  • Sotalol, however, is known to have a delayed onset of action.
  • Immediate release propranolol reaches its peak plasma level in 1-4 hours.²
  • Sustained release propranolol products reach their peak plasma level in 6-14 hours depending on the product used.²
• Propranolol is metabolized by the liver and excreted by the kidneys.

Clinical Presentation:

• Mild to severe symptoms can include nausea, vomiting, fatigue, dizziness, seizures, respiratory depression, and CNS depression.^1,3-65
• Seizures are more commonly associated with propranolol than other beta blockers in overdose given its highly lipophilic nature.¹
• Laboratory findings can include hypoglycemia.¹

Diagnosis:

• Propranolol toxicity is a clinical diagnosis – emphasis should be placed on history, physical exam, and overall clinical picture
• Propranolol concentrations are performed at send out labs and will not aid in the management of patients with toxicity
• Obtaining an EKG is important when considering propranolol toxicity
  • QRS prolongation was frequently reported in propranolol overdoses in one study, and 2^nd degree or higher heart block was noted frequently in another study^3,5
  • First degree heart block and QRS have been reported following beta blocker overdoses⁶
• Consider obtaining acetaminophen concentrations, salicylate concentrations, or ethanol concentrations if there is a high suspicion or uncertainty of co-ingestion

Management:^1,6,7

• The initial treatment is supportive care:
  • Start with your airway, breathing, and circulation(ABCs) and consider consulting your toxicologist early.
• Consider activated charcoal if patients present shortly after their overdose (1-2 hours) and without risks for aspiration.
• For seizures, benzodiazepines are first-line therapy followed by barbiturates.
• For QRS prolongation > 100 msec, consider starting with 1-2 mEq/kg of sodium bicarbonate IV push and reassess for QRS improvement.
• Atropine is usually ineffective for beta blocker-induced bradycardia.
• Hypotension:
  • Start with an IVF bolus, but be conscious of fluid overload and pulmonary edema.
  • Consider treatment with glucagon and calcium.
    • Glucagon dose: 3-5 mg IV over 2-5 minutes (50 mcg/kg for pediatric patients). Be mindful of associated vomiting and risk of aspiration if the patient has CNS depression or altered mental status.
      • Consider starting an infusion at this dose (e.g., 3-5 mg/hour) if this is successful.
    • Calcium dose: calcium gluconate 2-3 g IV bolus via peripheral line or calcium chloride 1 g via central line for adults (60 mg/kg calcium gluconate IV via peripheral line or 20 mg/kg calcium chloride via central line for pediatric patients).
      • Consider starting an infusion at this dose (e.g., 2 g/hour) if this is successful.
    • Vasopressors such as norepinephrine or epinephrine may be needed.
      • Avoid dopamine as it is an indirect vasopressor.
      • Remember that there is no such thing as “max dose” for a vasopressor in a beta blocker overdose setting.
      • Titrate your vasopressors up quickly.
    • Simultaneously evaluate the need for high-dose insulin (HDI) therapy.
      • 1 unit/kg IV bolus followed by 1 unit/kg/hr infusion of regular insulin (can be titrated up to 10 units/kg/hr or higher).
      • Remember to concentrate your insulin to help prevent volume overload. Some hospitals concentrate from 5-16 units/mL but the ability to do this may vary depending on your pharmacy. Your local poison center may be able to help provide evidence for your pharmacist or speak with them about the reasons for concentrating insulin.
      • Consider utilizing bedside ultrasound to evaluate the ejection fraction and its response to HDI therapy.
    • Refractory hypotension despite adequate doses of vasopressors and HDI:
      • Consider lipid emulsion
        • Studies have shown mixed results after intralipid administration in cases of propranolol poisoning.^6,8
        • Dose:
          • Bolus 1.5 mL/kg of 20% lipid emulsion solution
          • Start drip at 0.25 mL/kg/minute and repeat bolus 1-2 times as indicated
        • Consider ECMO if persistently decreased cardiac output.
        • Ventricular pacing is not recommended.¹
        • For additional guidance on treatments, see ToxCard: BB & CCB Treatments.

Case Follow-up:

The patient was given activated charcoal shortly after arrival. She became drowsy and had an episode of vomiting. She was started on IV fluids, and she remained hypotensive. She was intubated due to risk for aspiration and started on HDI, as well as norepinephrine and epinephrine. Due to refractory shock, a bolus of lipid emulsion was administered, and an infusion of lipid emulsion was started. The patient was continued on HDI and vasopressors with hemodynamic improvement. After two days, she was transferred out of the ICU and ultimately made a full recovery.

Clinical Pearls:

• Propranolol is highly lipophilic, and overdoses can have high morbidity and mortality
• Seizures are more likely to occur with propranolol than other beta blockers. First line therapy is benzodiazepines
• Consider activated charcoal early following overdose
• Treatment primarily involves supportive care
• Consider IV fluids, vasopressors, calcium, glucagon, and high-dose insulin for initial treatment

References:

1. Brubacher JR. β-Adrenergic Antagonists. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank’s Toxicologic Emergencies, 11e. McGraw Hill; 2019.
2. Medscape Propranolol (Rx). https://reference.medscape.com/drug/inderal-inderal-la-propranolol-342364#10. Accessed 12/24/22.
3. Lauterbach M. Clinical toxicology of beta-blocker overdose in adults. Basic Clin Pharmacol Toxicol. 2019 Aug;125(2):178-186. doi: 10.1111/bcpt.13231. Epub 2019 Apr 15. PMID: 30916882.
4. Truitt CA, Brooks DE, Dommer P, LoVecchio F. Outcomes of unintentional beta-blocker or calcium channel blocker overdoses: a retrospective review of poison center data. J Med Toxicol. 2012 Jun;8(2):135-9. doi: 10.1007/s13181-011-0209-8. PMID: 22311669.
5. Love JN, Enlow B, Howell JM, Klein-Schwartz W, Litovitz TL. Electrocardiographic changes associated with beta-blocker toxicity. Ann Emerg Med. 2002 Dec;40(6):603-10. doi: 10.1067/mem.2002.129829. PMID: 12447337.
6. Graudins A, Lee HM, Druda D. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies. Br J Clin Pharmacol. 2016 Mar;81(3):453-61. doi: 10.1111/bcp.12763. Epub 2015 Oct 30. PMID: 26344579.
7. Smith S and Howland MA. Calcium. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank’s Toxicologic Emergencies, 11e. McGraw Hill; 2019.
8. Cole JB, et al. Asystole immediately following intravenous fat emulsion for overdose. J Med Toxicol. 2014;10:307–310. PMID: 24519703.