Glucagon's Cardiovascular Effects With and Without Beta-blocker-induced Cardioinhibition (GLUCAGON)

October 16, 2019 updated by: Kasper Meidahl Petersen, University Hospital Bispebjerg and Frederiksberg

A Randomized, Participant-blinded Five-arm Crossover Study With Blinded Outcome Assessment Investigating Glucagon's Cardiovascular Effects With and Without Beta-blocker-induced Cardioinhibition.

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

10

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Copenhagen, Denmark
        • University Hospital Bispebjerg

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 40 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • Healthy male determined by investigator, based upon physical examination, medical history, ECG, vital signs and laboratory results
  • Body mass index (BMI) ≥ 18.5 and ≤ 29.9 kg/m2 and body weight between 50 and 100 kg, inclusive, at screening visit.

Exclusion Criteria:

  • Abnormal blood levels of sodium, potassium, creatinine, alanine transaminase (ALT), alkaline phosphatase, albumin, bilirubin, hemoglobin, HbA1c, cholesterol fractions.
  • Bradycardia (<45 beats per minute)
  • Hypotension (systolic blood pressure < 100 mmHg)
  • Second or third degree atrioventricular conduction delay
  • Sick sinus syndrome
  • Any heart disease or hypertension
  • Pheochromocytoma
  • Allergy to any active or inactive ingredient contained in investigatory medicines or tools.
  • Raynaud's syndrome
  • Prinzmetal's angina
  • Diabetes
  • Pulmonary disease
  • Pheochromocytoma
  • Any contraindication against investigatory medicines or tools.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Esmolol-placebo+glucagon 1 placebo (A)

Physiologic saline - esmolol dummy (10 mg esmolol/ml) is administered as a loading dose at baseline (time= -15 minutes) (corresponding to 0.125 ml/kg/min of saline). Continuous infusion (0.05-0.075 ml/kg/min) of saline is then administered until T=30 minutes.

+ Physiologic saline - glucagon dummy bolus 50 ml at time=0.
Drug: Physiologic saline - glucagon dummy
Isotonic 0.9 % sodium chloride solution is administered as matching placebo to glucagon, and injected in identical rates on corresponding days.
Other Names:
  • normal saline
Drug: Physiologic saline - esmolol dummy
Isotonic 0.9 % sodium chloride solution is administered as matching placebo to esmolol, and injected in identical rates on corresponding days.
Other Names:
  • normal saline
Experimental: Esmolol+glucagon 1 placebo (B)

Esmolol intravenous solution (10 mg/ml esmolol hydrochloride) is administered as a loading dose (1.25 mg/kg/min esmolol) at baseline (time= -15 minutes). Continuous infusion (500-750 micrograms/kg/min) of esmolol/placebo is then administered until T=30 minutes.

+ Physiologic saline - glucagon dummy bolus (50 ml) at time=0.
Drug: Physiologic saline - glucagon dummy
Isotonic 0.9 % sodium chloride solution is administered as matching placebo to glucagon, and injected in identical rates on corresponding days.
Other Names:
  • normal saline
Drug: Esmolol
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.
Other Names:
  • Brevibloc
  • ATC C07AB09
Experimental: Esmolol+glucagon 1 (C)

Esmolol intravenous solution (10 mg/ml esmolol hydrochloride) is administered as a loading dose (1.25 mg/kg/min esmolol) at baseline (time= -15 minutes). Continuous infusion (500-750 micrograms/kg/min) of esmolol/placebo is then administered until T=30 minutes.

+Glukagon 1 (50 μg/kg bolus - over 1-3 min from time=0 min in 50 ml isotonic fluid)
Drug: Esmolol
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.
Other Names:
  • Brevibloc
  • ATC C07AB09
Drug: Glucagon
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.
Other Names:
  • GlucaGen
  • ATC H04AA01
Experimental: Esmolol-placebo+glucagon 2 (D)

Physiologic saline - esmolol dummy (10 mg esmolol/ml) is administered as a loading dose at baseline (time= -15 minutes) (corresponding to 0.125 ml/kg/min of saline). Continuous infusion (0.05-0.075 ml/kg/min) of saline is then administered until T=30 minutes.

+Glukagon 2 (50 μg/kg bolus - over 30 min in 50 ml isotonic fluid from time=0 min)
Drug: Physiologic saline - esmolol dummy
Isotonic 0.9 % sodium chloride solution is administered as matching placebo to esmolol, and injected in identical rates on corresponding days.
Other Names:
  • normal saline
Drug: Glucagon
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.
Other Names:
  • GlucaGen
  • ATC H04AA01
Experimental: Esmolol-placebo+glucagon 1 (E)

Physiologic saline - esmolol dummy (10 mg esmolol/ml) is administered as a loading dose at baseline (time= -15 minutes) (corresponding to 0.125 ml/kg/min of saline). Continuous infusion (0.05-0.075 ml/kg/min) of saline is then administered until T=30 minutes.

+ Glukagon 1 (50 μg/kg bolus - over 1-3 min from time=0 min in 50 ml isotonic fluid)
Drug: Physiologic saline - esmolol dummy
Isotonic 0.9 % sodium chloride solution is administered as matching placebo to esmolol, and injected in identical rates on corresponding days.
Other Names:
  • normal saline
Drug: Glucagon
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.
Other Names:
  • GlucaGen
  • ATC H04AA01

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Heart rates on the esmolol+glucagon-day compared to the esmolol+placebo-day (2 minute average)
Time Frame: Glucagon bolus + 5±1 minute
Arterial catheter connected to a pressure transducer records heart rate (beats per minute).
Glucagon bolus + 5±1 minute

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in heart rate from baseline compared between study days.
Time Frame: -20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
Arterial catheter connected to a pressure transducer records heart rate (beats per minute).
-20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
Change in stroke volume (ml) from baseline compared between study days.
Time Frame: -20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
Stroke volume (ml) derived from arterial pulse contour analysis.
-20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
Change in systolic, diastolic and mean arterial pressure (mmHg) from baseline compared between study days.
Time Frame: -20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
Arterial catheter connected to a pressure transducer records blood pressure in mm Hg.
-20, -10, 0, glucagon+3, +5, +10, +15, +20, +30, +40, +50, +60 minutes
Glucagon pharmacokinetics
Time Frame: Baseline and glucagon +2, +4, +6, +10, +15, +20, +30, +40, +50, +60 minutes
Blood samples drawn for measurements of plasma glucagon
Baseline and glucagon +2, +4, +6, +10, +15, +20, +30, +40, +50, +60 minutes
Effects of glucagon on blood glucose compared to placebo
Time Frame: Baseline and glucagon +2, +4, +6, +10, +15, +20, +30, +40, +50, +60 minutes
Full blood glucose measured with a blood glucose meter
Baseline and glucagon +2, +4, +6, +10, +15, +20, +30, +40, +50, +60 minutes
Adverse effects of glucagon
Time Frame: Baseline and glucagon +6,+10, +30, +60 minutes
Nausea rated by a 4-point, verbal description scale (VDS) (no nausea=0, mild=1, moderate=2, severe=3).
Baseline and glucagon +6,+10, +30, +60 minutes

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Effects of glucagon compared to placebo on gastric emptying time
Time Frame: Baseline and glucagon +10, +20, +30, +40, +50, +60 minutes
Blood samples drawn for measurements of plasma paracetamol. Paracetamol is used as a tool for measuring gastric emptying time
Baseline and glucagon +10, +20, +30, +40, +50, +60 minutes
Effects of glucagon compared to placebo on norepinephrine levels
Time Frame: T-20, T0, glucagon+5, +30, +60 minutes
Blood samples drawn for measurements of norepinephrine.
T-20, T0, glucagon+5, +30, +60 minutes
Cardiac conductivity compared between days with glucagon1 and corresponding placebo days.
Time Frame: Baseline and glucagon +5, +10, +20, +30, +40, +50, +60 minutes
5-lead ECG
Baseline and glucagon +5, +10, +20, +30, +40, +50, +60 minutes

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital Bispebjerg and Frederiksberg

Investigators

  • Principal Investigator: Kasper M Petersen, MD, University Hospital Bispebjerg and Frederiksberg

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 1, 2018

Primary Completion (Actual)

October 1, 2019

Study Completion (Actual)

October 1, 2019

Study Registration Dates

First Submitted

March 9, 2018

First Submitted That Met QC Criteria

May 9, 2018

First Posted (Actual)

May 23, 2018

Study Record Updates

Last Update Posted (Actual)

October 17, 2019

Last Update Submitted That Met QC Criteria

October 16, 2019

Last Verified

October 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Glucagon+Beta-blocker

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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