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.

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.

Eligibility Criteria:
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.