All Pharmacy Pearls

Introduction

  • 1. Myocardial depression, bradycardia, and hypotension result from both CCB and BB toxicity
  • 2. Management of hemodynamic instability resulting from toxicity of CCBs and/or BBs follows similar principles
  • 3. GI decontamination may be warranted for patients who have ingested significant amounts of BB or CCB
  • 4. Initial management options include glucagon, high-dose insulin, calcium, and catecholamines with beta-

    • adrenergic activity

  • 5. Symptoms should occur within 6 hours post-ingestion, with the exception of sotalol and extended release

    • formulations

Pharmacology

Initial management of hemodynamic instability from CCB and/or BB toxicity follows similar principles. Core antidotal options include glucagon, high-dose insulin euglycemia therapy, calcium salts, and catecholamines with beta-adrenergic activity.

AgentDoseOnset of ActionAdverse EffectsMechanism of ActionComments
GlucagonPeds: Initial 50 mcg/kg IV
Adult: Initial 3 to 5 mg IV over 1–2 min
May start a glucagon infusion based on response dose/hr		5–20 min
Tachyphylaxis after 12–24h		Emesis, hyperglycemia, hypercalcemiaBypasses inhibited beta receptors, ↑ cAMP leading to ↑ chronotropy and inotropyIf full 10 mg dose fails, start drip at 10 mg/hr because glucagon will have synergistic effects with subsequent antidotes. Patients may develop tachyphylaxis.
High Dose Insulin Euglycemia (HIET)LD: 1 u/kg regular insulin IV
MD: 1–10 u/kg/hr IV, max 10 units/kg/hr
PLUS Dextrose 10–50% @ 0.5 gm/kg/hr IV to maintain euglycemia (BG goal 150–250)		Delayed, 15–60 minHypokalemia, hypoglycemiaInhibits Na+/Ca2+ antiporter, ↑ myocardial Ca2+, ↑ carbohydrate delivery to myocardium, mild vasodilation ↑ perfusionMust administer with dextrose source. Monitor glucose every 15 min initially. Consider addition of potassium 20–40 mEq/L of dextrose infusion to prevent hypokalemia.
Calcium SaltsAdult: 1–3 gm IV
Peds: 60 mg/kg IV up to 3 gm
May repeat every 10–20 minutes up to 9 gm in adults and 180 mg/kg in peds		Mins, titrate to effectVasoconstriction, renal failure↑ Ca2+ concentration gradient, ↓ the negative inotropy, impaired conduction, and hypotension. No effect on heart rate.Calcium chloride : gluconate concentration ratio 1:3. Calcium chloride has a higher risk of extravasation.
Catecholamines (epinephrine, isoproterenol, dopamine)Usual doses; titrated to clinical effect with hemodynamic monitoringMins, titrate to effectTachyarrhythmia, hypertension, ischemiaProviding ↑ adrenergic activity at α + β receptorsTo be used after or in addition to other agents. Attempt to wean off vasopressors first.

Additional therapies

  • Pharmacologic: methylene blue, vasopressin, milrinone, IV lipid emulsion (Intralipid)
  • Non-pharmacologic: pacing, ECMO, MARS

Evidence

Evidence for CCB and BB toxicity management is increasing but remains limited to case reports and case series.

Author, YearDesign / Sample SizeIntervention & ComparisonOutcome
Doepker, 2014Case series
Patient 1: PEA post-amlodipine, verapamil, and metoprolol ingestion
Patient 2: cardiogenic shock post-amlodipine, simvastatin, lisinopril, and metformin ingestion		Both treated with: calcium, glucagon, vasopressors, high-dose insulin, and IV lipid emulsionBoth initially treated with glucagon, calcium, and vasopressors. Both had subsequent hemodynamic improvement, resolution of shock, and full neurologic recovery.
Holger, 2011Case series
BB overdose, n=5
CCB overdose, n=2
BB + CCB overdose, n=2
Poly-drug, n=2		High-dose insulin + dextroseAEs: hypoglycemia in half of patients, hypokalemia. High-dose insulin therapy based on a 1–10 U/kg/h dosing guideline appears to be effective in these cardiotoxic overdoses.
Page, 2009Case report
Massive metoprolol overdose (5 g)		1–2 u/kg regular insulin IV ×4, then insulin drip @ 10 u/kg
Additional therapies: atropine, isoprenaline, metaraminol, 0.9% saline bolus		Improvement in heart rate and blood pressure seen with addition of insulin + glucose. Patient hemodynamically stable at hour 7.
Stellpflug, 2010Case report
Cardiac arrest secondary to intentional BB overdose		IV lipid emulsion and high-dose insulinCare with intravenous lipid emulsions and insulin therapy up to 21.8 u/kg/hr were utilized for treatment. Patient survived to discharge with baseline neurologic function.
Love, 1998Case report
Patients with symptomatic bradycardia who failed atropine after beta blocker toxicity
N=9		Glucagon post atropineGlucagon was effective in correcting symptomatic bradycardia and hypotension in 8/9 patients.
Levine, 2013Retrospective chart review
48 patients with diltiazem and verapamil overdoses		33 patients treated with vasopressors
8 patients treated with glucagon and/or calcium		29/33 patients treated with vasopressors survived without complication (3 patients had cardiac arrest; 1 patient expired). 8/8 calcium/glucagon patients survived without complication.
Meany, 2013Case report
Amlodipine overdose in combination with unknown amount of ethanol		Intravenous lipid emulsion after failure of activated charcoal, IV fluids, and calcium bolusesHemodynamically unstable on 3 different vasopressors when intralipid infusion was initiated over 4.5 hours. At end of infusion patient was tapered off 2 vasopressors with stable MAP.
Lashari, 2018Case report
Unknown ingestion with medication history of lisinopril, clonidine, chlorthalidone, labetalol, and nifedipine		Intravenous lipid emulsion and high-dose insulin therapy after failure of atropine, calcium boluses, and multiple vasopressorsPatient improvement seen on day 3 when 4/5 vasopressors were tapered off. Patient was off all vasopressors on day 4 and extubated on day 5.

Conclusions

●

Evidence for CCB and BB toxicity is increasing but still limited to case reports and case series

●

In the setting of toxic CCB and/or BB ingestions, there are a variety of therapeutic modalities available

●

Treatment may require combined use of the agents described above

●

Contact your regional poison center: 1-800-222-1222

References

1.
Kerns II W, et al. Insulin improves survival in a canine model of acute beta-blocker
toxicity. Ann Emerg Med . 1997;29:748-757.
2.
Holger JS, et al. Insulin versus vasopressin and epinephrine to treat beta-blocker
toxicity. Clin Toxicol 2007;45:396-401.
3.
Holger JS, et al. High-dose insulin: a consecutive case series in toxin-induced
cardiogenic shock. Clin Toxicol. 2011;49:653-658.
4.
Page C, et al. The use of high-dose insulin-glucose euglycemia in beta-blocker
overdose: a case report. J Med Toxicol . 2009;5:139-143.
5.
Stellpflug SJ, et al. Intentional overdose with cardiac arrest treated with intravenous
fat emulsion and high-dose insulin. Clin Toxicol. 2010;48:227-229.
6.
Engebretsen KM, et al. High-dose insulin therapy in beta-blocker and calcium
channel-blocker poisoning. Clin Toxicol . 2011;49:277-283.
7.
Love JN, et al. A potential role for glucagon in the treatment of drug-induced
symptomatic bradycardia. Chest. 1998;114:323-326.
8.
Kerns II, W., 2007. Management of β-adrenergic blocker and calcium channel
antagonist toxicity. Emergency medicine clinics of North America, 25(2), pp.309-
331.
9.
Doepker B, Healy W, Cortez E, Adkins EJ. High-dose insulin and intravenous lipid
emulsion therapy for cardiogenic shock induced by intentional calcium-channel
blocker and beta-blocker overdose: a case series. The Journal of emergency
medicine. 2014 Apr 1;46(4):486-90.
10.
Meany CJ, Sare H, Hayes BD, Gonzales JP. Intravenous lipid emulsion in the
management of amlodipine overdose. Hosp Pharm. 2013:48(10):848-54.
11.
Lashari BH, Minalyan A, Khan W, Naglak M, Ward W. The use of high-dose insulin
infusion and lipid emulsion therapy in concurrent beta-blocker and calcium
channel blocker overdose. Cureus 10(11):e3534. DOI 10.7759/cureus.3534
Tags: glucagon high-dose insulin calcium catecholamines

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