Comment on “Cardiovascular and Adverse Effects of Glucagon for the Management of Suspected Beta Blocker Toxicity: a Case Series”

Dear Editors,

We thank the authors for contributing their case series, which evaluated glucagon efficacy in beta-adrenergic antagonist (BAA) toxicity [1]. Mean heart rate (HR) and median systolic blood pressure (SBP) increased by statistically significant but questionably clinically relevant degrees. In accordance with toxicology reporting guidance [2–4], we caution that “confirmed overdose” should not describe “reported” or “suspected” exposures absent definitive laboratory confirmation. Given a mean HR of 53 and median SBP of 102 mmHg, it is unclear to what extent this population was substantially BAA poisoned (as opposed to merely reportedly exposed). Use of only two vital signs is a suboptimal surrogate for the endpoint of interest, adequate tissue perfusion. Other clinical, laboratory, analytical, or echocardiographic evidence of cardiac output, perfusion, or compromise would be welcome indicators. The 20-minute interval assessment after glucagon bolus administration is problematic. While the referenced package insert [5] reports that maximal glucose concentrations occur 5–20 minutes following IV bolus administration, controlled studies spanning decades have demonstrated that glucagon’s rapid cardiovascular response is followed by near-complete dissipation within 20 minutes [6–10]. The reported glucagon dose appears inadequate. Animal and human studies support a recommended bolus of (at least) 50 mcg/kg (and use of an infusion); adult doses of up to 10 mg are employed pragmatically [6–11]. The average glucagon bolus was 2.66 mg in this population, less than a recommended dose of at least 4.1 mg based on the mean weight of 82 kg. Misdosing highlights a common obstacle faced by toxicologists when recommending therapies provided at alternative doses for non-toxicological indications. Glucagon may actually decrease systemic vascular resistance or produce hypotension with inadequate and therapeutic administration [5–7, 9]. Finally, in order to determine antidotal efficacy for poisoning management, it is important to distinguish the effects of both the toxin and the therapy. A substantial percentage of patients reported polysubstance exposures. However, details on specific co-ingestants, which could impact both the clinical presentation and the response to glucagon, are absent and uncontrolled for. Similarly, while additional BAA therapies – which differ in their onset and duration (e.g., fluids, calcium, and vasopressors) – are presented, their timing with respect to glucagon is obscure. We appreciate the sensitivity analysis excluding (presumably sicker) patients receiving vasopressors, but each intervention must be controlled for to appropriately interpret the results. In order to optimally evaluate the attributable efficacy of glucagon in the treatment of BAA toxicity, we look forward to prospective studies which control for degree of poisoning, co-ingestants, and concomitant interventions, which utilize adequately dosed glucagon, and which apply comprehensive assessments at pharmacologically appropriate intervals.

Author Contributions

All authors contributed to the writing of this letter. All authors read and approved the final manuscript.

Sources of Funding

None.

Declarations

Conflicts of Interest

None.