Glucagon as an Antidote

Reviewed and revised 21 November 2016

OVERVIEW

Glucagon is traditionally considered a first line antidote for beta-blocker overdose

glucagon has also been used in the setting of calcium channel blocker toxicity

In Australia, the toxicology community rarely advises the use of glucagon as an antidote, for these reasons:

no proof of effectiveness
hard to source the doses required
commonly induces vomiting, with concomitant aspiration risk in the unprotected airway
risk of distraction from the delivery of other therapies (e.g. high-dose insulin as an antidote or supportive measures)

This page discusses glucagon as an an antidote, see Glucagon Therapy for an overview of glucagon pharmacology and other possible therapeutic uses

RATIONALE FOR GLUCAGON USE AS AN ANTIDOTE

From O’Connor et al (2003) in response to BestBET review by Boyd and Ghosh (2003):

…

[In toxicology an] evidence basis is often lacking and one therefore needs to rely on a combination of practical experience, case reports and assessment of biological plausibility. There is a sound theoretical basis for the use of glucagon in the cardiovascularly compromised patient who has taken a b blocker overdose. Glucagon activates adenyl cyclase and exerts an inotropic and chronotropic effect by a pathway that bypasses the b receptors.

Each of us has personal experience of the dramatic improvement in cardiovascular parameters that can occur following the administration of glucagon in this clinical situation.

Patients seldom take an overdose solely of a b blocker and the purist evidence base sought by Boyd is unlikely to be achievable. There is a wealth of clinical experience in support of administration of glucagon. Nobody would suggest that naloxone should not be used for opiate overdose yet the evidence base for its use is as flimsy as that of glucagon in b blocker overdose. We suggest that to attempt to undertake a randomised clinical trial of the use of glucagon in the compromised b blocker overdosed patient would be unethical.

…

PHARMACOLOGY

see Glucagon Therapy

EVIDENCE

Cell and organ models (see Bailey, 2003)

catecholamine-like effects on animal organs first noted by Farah and Tuttle in 1960. These effects were not blocked by propanolol
Glick et al and Luchessi both suggested glucagon as a beta blocker antidote in 1968

Animal models

BB overdose: glucagon increased heart rate, no change in MAP (Kern et al, 1997)
CCB overdose: appeared to increase heart rate, cardiac output and reverse AV blocks in animal models (at least transiently), no change in mean arterial blood pressure (MAP)
no survival benefit in animal models
all small studies, unblinded with variable doses of glucagon

Human studies

no human studies evaluating the efficacy of glucagon in BB or CCB overdose
multiple case reports/ anecdotes reporting clinical improvement following glucagon administration (causation not established)
First case report for propanolol in NEJM 1971, first for verapamil in Lancet 1982

An interesting aside from ‘The Short Coat’ (also mentioned in Kerns, 2007):

“Nearly all studies examining glucagon in CCB toxicity were conducted prior to the availability of recombinant glucagon and used Eli Lilly’s standard glucagon preparations instead… The standard preparation of glucagon, made from mammalian pancreatic extract, contained insulin (also from pancreatic cells) until recombinant glucagon was available in 1998. Some vials of glucagon, when analyzed by this study group at Carolinas Medical Center, contained 100 units of insulin. This was demonstrated in the study on HIE therapy in verapamil poisoning by Kline et al (1995).”
Thus, there is a possibility that any benefit seen from using these glucagon preparations may have been due to the insulin that was also present.

PRACTICAL ISSUES

Practical issues with glucagon as an antidote

no proof of effectiveness (see evidence above)
relatively expensive
- ~AUS$1,500 to treat a 70kg man for 4 hours
use in overdose will rapidly deplete hospital stores
- very few Australian hospitals have sufficient stocks to treat a 70kg man for 4 hours (2% in Queensland according to Nissen et al, 2010)
induces vomiting (dose dependent, more likely with bolus doses)
High-dose euglycemic therapy is now used by most toxicologists base on case series and growing clinical experience – I am aware of only one low quality animal study comparing insulin (6/6 survived) vs glucagon (4/6 survived) in propanolol toxicity (Kerns et al, 1997)
risk of distraction from the delivery of other therapies (e.g. high-dose insulin as an antidote or supportive measures)

References and Links

Lifeinthefastlane.com

CCC — Glucagon therapy

Journal articles

Bailey B. Glucagon in beta-blocker and calcium channel blocker overdoses: a systematic review. J Toxicol Clin Toxicol. 2003;41(5):595-602. Review. PubMed PMID: 14514004.
Boyd R, Ghosh A. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Glucagon for the treatment of symptomatic beta blocker overdose. Emerg Med J. 2003 May;20(3):266-7. Review. PubMed PMID: 12748150; PubMed Central PMCID: PMC1726108.
Crump BJ, Holt DW, Vale JA. Lack of response to intravenous calcium in severe verapamil poisoning. Lancet. 1982 Oct 23;2(8304):939-40. PubMed PMID: 6126785.
Kerns W 2nd, Schroeder D, Williams C, Tomaszewski C, Raymond R. Insulin improves survival in a canine model of acute beta-blocker toxicity. Ann Emerg Med. 1997 Jun;29(6):748-57. PubMed PMID: 9174520.
Kerns W 2nd. Management of beta-adrenergic blocker and calcium channel antagonist toxicity. Emerg Med Clin North Am. 2007 May;25(2):309-31; abstract viii. Review. PubMed PMID: 17482022.
Kline JA, Leonova E, Raymond RM. Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine. Crit Care Med. 1995 Jul;23(7):1251-63. PubMed PMID: 7600835.
Kosinski EJ, Stein N, Malindzak GS Jr, Boone E. Glucagon and propranolol (Inderal) toxicity. N Engl J Med. 1971 Dec 2;285(23):1325. PubMed PMID: 5113739.
Mahr NC, Valdes A, Lamas G. Use of glucagon for acute intravenous diltiazem toxicity. Am J Cardiol. 1997 Jun 1;79(11):1570-1. PubMed PMID: 9185662.
Nissen LM, Wong KH, Jones A, Roberts DM. Availability of antidotes for the treatment of acute poisoning in Queensland public hospitals. The Australian journal of rural health. 18(2):78-84. 2010. [pubmed]
O’Connor N, Greene S, Dargan P, Jones A. Glucagon use in beta blocker overdose. Emerg Med J. 2005 May;22(5):391. PubMed PMID: 15843722; PubMed Central PMCID: PMC1726782.