Glucagon's Cardiovascular Effects With and Without Beta-blocker-induced Cardioinhibition
Condition: Drug Overdose; Overdose of Beta-adrenergic Blocking Drug
MeSH terms: Drug Overdose
Study type: Interventional
Phase: Phase 4

Summary: 
      This trial investigates effects of a glucagon bolus injection on heart rate, blood pressure
      and cardiac output during beta-blocker-induced cardiodepression. Furthermore, the effects of
      two different doses of intravenous glucagon on hemodynamic parameters are explored.
    

Detailed description: 
      This trial investigates effects of a glucagon bolus injection on heart rate, blood pressure
      and cardiac output during beta-blocker-induced cardiodepression. Furthermore, the effects of
      two different doses of intravenous glucagon on hemodynamic parameters are explored.

      Glucagon, administered as a 50 micrograms/kg bolus injection which can be repeated or
      followed by continuous infusion (50 -150 micrograms / kg / hour) is a well-accepted and
      recommended treatment of beta-blocker poisoned patients [1-4]. The evidence for the
      recommended glucagon dose is based on animal trials and human case studies suggesting
      beneficial effects. Theoretically, high-dose glucagon mimics effect of beta-receptor agonists
      (increasing heart rate and cardiac output) [5] via activation of cardiac glucagon receptors,
      which cannot be blocked by beta blockers [1,6]. Glucagon receptors in the heart muscle are
      seemingly activated only at high glucagon levels [7] (but could also theoretically be an
      off-target effect); therefore the recommended glucagon dose for beta-blocker poisonings is
      higher than that recommended for reversal of hypoglycemia. Despite some animal and human case
      data suggesting beneficial effects of glucagon, other data suggest that glucagon may actually
      be inferior to other therapies of cardiovascular collapse due to cardioinhibitory drug
      poisonings [2]. It is important to keep in mind that the knowledge about glucagon's effects
      in poisoning situations is derived from uncontrolled cohort studies and case reports as well
      as animal studies [3,8]. Thus, the recommended dose has never been studied in a controlled
      clinical trial in humans. Therefore, the overall level of evidence pertaining to glucagon in
      the management of beta-blocker overdoses is low. There is a need for clinical human data
      investigating the glucagon doses recommended for treatment of beta-blocker overdose. The
      purpose of this participant- and outcome assessor blinded, randomized placebo-controlled
      crossover clinical trial is to investigate the effects of intravenous glucagon on the
      circulation alone or during beta-blocker-induced heart (rate) suppression. The trial includes
      a total of six visits; a screening visit and five trial days as described under Arms and
      Interventions. At the screening visit, anthropometric data (weight, height, blood pressure
      and pulse) is measured. Additionally, blood samples are collected in accordance with
      in/exclusion criteria. A spot urine sample measuring the albumin/creatinine ratio is
      collected and an electrocardiogram (ECG) is recorded to verify normality of heart rhythm and
      electrical impulses. In addition, an investigator carries out a clinical examination. Based
      on the clinical examination, urine and blood tests and ECG measurement, an investigator
      assesses whether the trial participant meet all inclusion criteria and no exclusion criteria.
      After screening and inclusion, participants will be invited to five trial days at the trial
      site (days A-E). The participant is blinded to interventions. On each day, participants are
      required to be fasting for 8±2 hours. A peripheral venous line is inserted into each
      antecubital vein. An arterial catheter connected to a pressure transducer is inserted into
      the radial artery in the wrist. In randomized order, one of the five interventions are
      performed (see below). A 5 lead ECG connected to a computer is placed on the participant. At
      T=-15 minutes, esmolol intravenous solution (10 mg esmolol/ml esmolol hydrochloride) or
      matching placebo is administered as a loading dose at baseline (time= -15 min) (corresponding
      to 1,25 mg/kg/min esmolol) [9]. Continuous infusion (500-750 micrograms/kg/min) of
      esmolol/placebo is then administered until T=30 minutes. Infusion is halted if heart rate
      decreases below 30 bpm or >25% from baseline, the systolic blood pressure drops below 80 mm
      Hg, or the participant experiences subjective side effects. Esmolol/placebo infusion stops at
      T=30 minutes. Glucagon (GlucaGen injectable solution) or saline solution is administered at
      time=0 minutes as an intravenous bolus (50 micrograms /kg over 1-2 minutes) on days C & E or
      as a continuous infusion (50 micrograms/kg over 30 min on day D). One point five grams of
      acetaminophen administered as a disintegrating tablet dissolved in 100 ml of water with guar
      gum is given orally shortly before study start on each day [10]. Repeated ECG's are recorded
      and blood is drawn for measurements of secondary biochemical endpoints. A drop of blood is
      used to test glucose levels using a blood glucose meter. Cardiovascular parameters (heart
      rate, blood pressure and pulse contour curve/arterial pressure wave) are recorded via the
      arterial catheter and pressure transducer connected to a computer. The participant is closely
      monitored on site until T=60 minutes.
    

Intervention name(s): Glucagon; Esmolol; Physiologic saline - glucagon dummy; Physiologic saline - esmolol dummy
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Glucagon 1 mg/ml solution is dissolved in 50 ml isotonic fluid and injected as bolus corresponding to 50 micrograms/kg over 1-3 minutes from time=0 on day C+E. on day D ("glucagon 2"), 50 micrograms/kg of glucagon is infused over 30 minutes from time=0 to time =30.; Esmolol hydrochloride 10 mg/ml is infused from time -15 min to time + 30 minutes as an initial bolus followed by an infusion. infusion rate is tapered if heart rate declines below 30 beats per minute (bpm) or >25 % from baseline, systolic blood pressure decreases below 80 mmHg or the participant experiences side effects.; Isotonic 0.9 % sodium chloride solution is administered as matching placebo to glucagon, and injected in identical rates on corresponding days.; Isotonic 0.9 % sodium chloride solution is administered as matching placebo to esmolol, and injected in identical rates on corresponding days.
Other intervention name(s): GlucaGen; ATC H04AA01; Brevibloc; ATC C07AB09; normal saline; normal saline
Intervention MeSH terms: Glucagon; Glucagon-Like Peptide 1; Esmolol
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: 5-arm, participant and outcome-assessor blinded, randomized, placebo-controlled study.
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Glucagon; Beta-adrenergic antagonist; poisoning