High-Dose Glucagon Has Hemodynamic Effects Regardless of Cardiac Beta-Adrenoceptor Blockade: A Randomized Clinical Trial

Abstract

Background Intravenous high-dose glucagon is a recommended antidote against beta-blocker poisonings, but clinical effects are unclear. We therefore investigated hemodynamic effects and safety of high-dose glucagon with and without concomitant beta-blockade. Methods and Results In a randomized crossover study, 10 healthy men received combinations of esmolol (1.25 mg/kg bolus+0.75 mg/kg/min infusion), glucagon (50 µg/kg), and identical volumes of saline placebo on 5 separate days in random order (saline+saline; esmolol+saline; esmolol+glucagon bolus; saline+glucagon infusion; saline+glucagon bolus). On individual days, esmolol/saline was infused from -15 to 30 minutes. Glucagon/saline was administered from 0 minutes as a 2-minute intravenous bolus or as a 30-minute infusion (same total glucagon dose). End points were hemodynamic and adverse effects of glucagon compared with saline. Compared with saline, glucagon bolus increased mean heart rate by 13.0 beats per minute (95% CI, 8.0-18.0; P<0.001), systolic blood pressure by 15.6 mm Hg (95% CI, 8.0-23.2; P=0.002), diastolic blood pressure by 9.4 mm Hg (95% CI, 6.3-12.6; P<0.001), and cardiac output by 18.0 % (95% CI, 9.7-26.9; P=0.003) at the 5-minute time point on days without beta-blockade. Similar effects of glucagon bolus occurred on days with beta-blockade and between 15 and 30 minutes during infusion. Hemodynamic effects of glucagon thus reflected pharmacologic glucagon plasma concentrations. Glucagon-induced nausea occurred in 80% of participants despite ondansetron pretreatment. Conclusions High-dose glucagon boluses had significant hemodynamic effects regardless of beta-blockade. A glucagon infusion had comparable and apparently longer-lasting effects compared with bolus, indicating that infusion may be preferable to bolus injections. Registration Information URL: https://www.clinicaltrials.gov; Unique identifier: NCT03533179.

Keywords: beta blocker; glucagon; hemodynamics; toxicology.

Conflict of interest statement

None.

Figures

Figure 1. Flowchart of the trial and analyses of trial participants.

Nineteen potential participants were assessed, and 12 were allocated to a random sequence of interventions (A‐E). In case of withdrawal or exclusion, an enrolled participant was replaced with another who was assigned to an identical intervention sequence. Ten participants completed 5 trial days and were included in analyses. Data from withdrawn or excluded participants were excluded from analyses.

Figure 2. Intravenous glucagon bolus and infusion results in glucagon concentration–time curves coinciding with hemodynamic effects.

(A) Plasma glucagon concentrations (nmol/L) presented as means ± SEM (red, esmolol + glucagon bolus; black, saline + glucagon bolus; blue, saline + glucagon infusion). Days without glucagon administrations (and glucagon concentrations at basal levels of 8 pmol/L on average) are not shown. Measures before baseline are moved forward to baseline (the 0‐minute time point). (B) Plasma glucagon incremental area under the curve (iAUC) on the day with glucagon infusion (blue) was significantly lower compared with the AUC on the saline + glucagon bolus‐day (black). iAUCs were compared with the paired t‐test.

Figure 3. Glucagon injections has positive chronotropic effects regardless of beta‐blockade.

(A) Scatter plot of 5‐second heart rate (beats per minute) means on trial days without esmolol (blue, glucagon infusion; black, saline; red, glucagon bolus). (B) Two‐minute heart rate means ± SEM on days without esmolol. (C) Scatter plot of 5‐second heart rate means on trial days with esmolol (black, saline; red, glucagon bolus). (D) Two‐minute heart rate means ± SEM on days with esmolol. Horizontal gray lines mark durations of infusions and boluses. *Statistically significant difference between glucagon bolus and corresponding saline. ‡Statistically significant difference between glucagon infusion and saline. Differences were analyzed by a mixed model with Tukey correction of multiple comparisons (baseline subtracted changes to the 5‐minute time point were compared using the paired t‐test).

Figure 4. Glucagon injections increase systolic blood pressure (BP) regardless of beta‐blockade.

(A) Scatter plot of 5‐second systolic BP (mm Hg) means on trial days without esmolol (blue, glucagon infusion; black, saline; red, glucagon bolus). (B) Two‐minute systolic BP means ± SEM on days without esmolol. (C) Scatter plot of 5‐second systolic BP means on trial days with esmolol (black, saline; red, glucagon bolus). (D) Two‐minute systolic BP means ± SEM on days with esmolol. Horizontal gray lines mark durations of infusions and boluses. *Statistically significant difference between glucagon bolus and corresponding saline. ‡Statistically significant difference between glucagon infusion and saline. Differences were analyzed by a mixed model with Tukey correction of multiple comparisons (baseline subtracted changes to the 5‐minute time point were compared using the paired t‐test).

Figure 5. Glucagon injections increase diastolic blood pressure (BP) regardless of beta‐blockade.

(A) Scatter plot of 5‐second diastolic BP (mm Hg) means on trial days without esmolol (blue, glucagon infusion; black, saline; red, glucagon bolus). (B) Two‐minute diastolic BP means ± SEM on days without esmolol. (C) Scatter plot of 5‐second diastolic BP means on trial days with esmolol (black, saline; red, glucagon bolus). (D) Two‐minute diastolic BP means ± SEM on days with esmolol. Horizontal gray lines mark durations of infusions and boluses. *Statistically significant difference between glucagon bolus and corresponding saline. ‡Statistically significant difference between glucagon infusion and saline. Differences were analyzed by a mixed model with Tukey correction of multiple comparisons (baseline subtracted changes to the 5‐minute time point were compared using the paired t‐test).

Figure 6. Glucagon injections increase stroke volume and cardiac output.

(A) Two‐minute stroke volume means ± SEM (depicted as percentage change from baseline) on days without esmolol (blue, glucagon infusion; black, saline, red: glucagon bolus) (B) Two‐minute means ± SEM of stroke volume percentage change from baseline on days with esmolol (red, glucagon bolus; black, saline). (C) Two‐minute means ± SEM of cardiac output percentage change from baseline on days without esmolol (blue, glucagon infusion; black, saline; red, glucagon bolus) (D) Two‐minute means ± SEM of cardiac output percentage change from baseline on days with esmolol (red, glucagon bolus; black, saline). Horizontal gray lines mark durations of infusions and bolus. *Statistically significant difference between glucagon bolus and corresponding saline. ‡Statistically significant difference between glucagon infusion and saline. Differences were analyzed by a mixed model with Tukey correction of multiple comparisons.

Figure 7. Glucagon injections reduce relative systemic vascular resistance.

(A) Relative systemic vascular resistance (percentage change from baseline) over time depicted as 2‐minute means ± SEM on trial days without esmolol (blue, glucagon infusion; black, saline; red, glucagon bolus). (B) Two‐minute means ± SEM of systemic vascular resistance percentage change from baseline on days with esmolol (red, glucagon bolus; black, saline). Horizontal gray lines mark durations of infusions and boluses. *Statistically significant difference between glucagon and corresponding saline. Differences were analyzed by a mixed model with Tukey correction of multiple comparisons.