Hemodynamic Effects Of Glucagon Research Articles

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

BackgroundIntravenous 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 ResultsIn 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.ConclusionsHigh‐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 InformationURL: https://www.clinicaltrials.gov; Unique identifier: NCT03533179.

Hemodynamic Effects of Glucagon: A Literature Review.

Glucagon's effects on hemodynamic parameters, most notably heart rate and cardiac contractility, are often overlooked. The glucagon receptor is a central target in novel and anticipated type 2 diabetes therapies, and hemodynamic consequences of glucagon signaling have therefore become increasingly important. In this review, we summarize and evaluate published studies on glucagon pharmacology with a focus on clinical hemodynamic effects in humans. PubMed, Embase, and the Cochrane Library were searched for clinical studies concerning hemodynamic effects of glucagon (no year restriction). Papers reporting effects of a defined glucagon dose on any hemodynamic parameter were included. Reference searches were conducted in retrieved articles. Hemodynamic effects of glucagon have been investigated mainly in cohort studies of patients suffering from heart failure receiving large glucagon bolus injections. The identified studies had shortcomings related to restricted patient groups, lack of a control group, randomization, or blinding. We identified no properly conducted randomized clinical trials. The majority of human studies report stimulating effects of pharmacological glucagon doses on heart rate, cardiac contractility, and blood pressure. The effects were characterized by short duration, interindividual variation, and rapid desensitization. Some studies reported no measurable effects of glucagon. The level of evidence regarding hemodynamic effects of glucagon is low, and observations in published studies are inconsistent. Actual effects, interindividual variation, dose-response relationships, and possible long-term effects of supraphysiological glucagon levels warrant further investigation.

Hemodynamic effects of glucagon after acute mesenteric ischemia in rats

We have previously shown that iv glucagon improved survival in rats from 33 to 83% when given after, but not during, superior mesenteric artery (SMA) occlusion. This study investigated potential hemodynamic mechanisms of this effect. In Part 1, cardiac output (CO) was measured in 12 male Sprague-Dawley rats with an electromagnetic flow-probe that had been placed around the ascending aorta 5 days previously. Under pentobarbital anesthesia, the SMA was occluded for 85 min. All rats received normal saline (NS, 15 ml/kg/hr) for 1 hr before and after SMA declamping. Control rats ( n = 6) received only NS. Treated rats ( n = 6) received NS plus glucagon (1.6 μg/kg/min iv) for 1 hr postocclusion. CO decreased 50% during the first hour after SMA declamping in control rats, but only 11% in glucagon-treated rats ( P < 0.02). Systemic vascular resistance (SVR) increased by 90% in control rats by 1 hr after declamp, but only 9% in glucagon rats ( P < 0.04). Systemic blood pressure and heart rate were not different in the two groups. In Part 2, relative distribution of visceral blood flow was measured with radiolabeled microspheres injected in the aortic root before clamping, before declamping, and 1 hr postdeclamping in 10 rats (5 glucagon, 5 control) using the above protocol. After SMA clamping, the proportion of visceral blood flow distributed to the intestine fell from 45 to 20% ( P < 0.05). During reperfusion, the proportion of intestinal flow exceeded baseline ( P < 0.05), but was not different in control (64%) and glucagon-treated rats (56%). Since decreased CO was prevented by glucagon, however, these results imply that normal mesenteric blood flow was restored sooner after reperfusion. We conclude that the survival benefit conferred by glucagon after SMA occlusion in rats is related to cardiac inotropic support. Whether this is a primary effect, or relates to prevention of myocardial depression by further mesenteric ischemia, remains to be determined.

Hemodynamic effects of glucagon in portal hypertension

It has been suggested that glucagon contributes to the pathogenesis of portal hypertension by increasing portal blood flow. This study examined this issue by assessing the hemodynamic effects of a pharmacological dose of glucagon (1 mg, intravenously) in patients with cirrhosis and portal hypertension (n = 10) and in subjects without significant liver disease (controls = n = 5). Patients with cirrhosis had much higher glucagon levels than control subjects (875 +/- 167 vs. 186 +/- 25 pg/ml, p less than 0.01) and showed blunted hemodynamic responses after glucagon administration. This occurred despite greater circulating glucagon levels, probably because of a significant prolongation of the plasma half-life of exogenously administered glucagon (4.9 +/- 0.4 vs. 2.7 +/- 0.1 min, p less than 0.1). Control subjects had marked increases in heart rate (+ 19% +/- 4%, p less than 0.01), cardiac index (+ 16% +/- 4%, p = 0.01) and arterial pressure (+ 10% +/- 3%, p less than 0.05), but corresponding changes in patients with cirrhosis (+ 7% +/- 1%, + 6% +/- 1%, and + 6% +/- 2%, respectively) were significantly less pronounced (p = 0.05), and there was a negative correlation between basal glucagon levels and the response of heart rate to glucagon injection (r = -0.804, p less than 0.001). Resistance to the systemic effects of glucagon in cirrhosis may thus be caused by a down-regulation of vascular glucagon receptors. In addition, glucagon administration caused a significant increase in portal pressure (from 18.1 +/- 1.1 to 19.0 +/- 1.2 mm Hg, p less than 0.01), as well as in azygos blood flow (from 0.54 +/- 0.03 to 0.64 +/- 0.04 L/min, + 19% +/- 4%, p less than 0.02), reflecting increased portocollateral blood flow. These findings are consistent with the hypothesis that glucagon is one of the factors contributing to the splanchnic vasodilatation and increased portal pressure of cirrhosis.

Postcountershock pulseless rhythms: Hemodynamic effects of glucagon in a canine model: Niemann JT, Haynes KS, Garner D, et al Crit Care Med 15:554–558 Jun 1987

Postcountershock pulseless rhythms: Hemodynamic effects of glucagon in a canine model: Niemann JT, Haynes KS, Garner D, et al Crit Care Med 15:554–558 Jun 1987

Hemodynamic effects of glucagon in patients following open-heart surgery

Hemodynamic effects of glucagon in patients following open-heart surgery

Effects of simultaneous infusions of glucagon and cyclic AMP on glomerular filtration rate in the dog

In this study, we tested the hypothesis that the renal vasodilator properties of glucagon are mediated by the intracellular release of cyclic AMP. In eight normal dogs, we tested the effect on glomerular filtration rate (GFR) of intravenous glucagon (5 μg/min), after having administered cyclic AMP (1.6 mg/min) into the left renal artery. GFR for both the right and left kidneys increased by 38% (p &lt; 0.05), compared with an increment of 29% when glucagon alone had previously been administered. Similar studies were carried out in five dogs with steady-state hemorrhagic hypotension (arterial blood pressure = 75 mmHg). In this group as well, the prior infusion of cyclic AMP did not blunt or abolish the tendency of glucagon to promote renal perfusion or increase GFR. When cyclic AMP was administered alone, GFR and the clearance of p-aminohippurate usually declined by about 20% (p &lt; 0.05). In six dogs, glucagon was administered intravenously at 5 μg/min prior to the infusion of cyclic AMP (1.6 mg/min) into the left renal artery. For this kidney, the anticipated decline in renal perfusion occurred. The prior administration of theophylline into the left renal artery did not prevent an intravenous infusion of glucagon from elevating GFR. These experiments indicate that the prior flooding of the microvasculature with either cyclic AMP or glucagon does not prevent the pharmacological effects of each of these substances. The renal hemodynamic effects of glucagon in normal and hypotensive dogs does not appear to depend on the release of cyclic AMP.

The effect of glucagon on glomerular filtration rate in dogs during reduction of renal blood flow.

Glucagon in small intravenous (i.v.) doses markedly increases glomerular filtration rate (GFR) in normal anesthetized dogs. In this study, the effects of glucagon 5 mug/min (i.v.) on renal hemodynamics was tested in four canine models of acute pre-renal failure (hemorrhage, barbiturate overdose; renal arterial clamping and renal arterial infusions of noradrenaline) and in a model of unilateral acute tubular necrosis at 4 h and 6-7 days following completion of the ischemic insult. Following hemorrhage and barbiturate excess, with arterial blood pressure maintained at 65-70 mm Hg, whole-kidney GFR and clearance rate of p-aminohippurate decreased by 50-70%. During this reduction of perfusion pressure, the subsequent infusion of glucagon increased GFR by 90-130%. In models where arterial pressure was normal during the period of ischemia (clamping and noradrenaline infusion), not only did glucagon significantly increase renal perfusion, but the ischemic kidney proved to be far more sensitive to the hemodynamic effects of glucagon (delta GFR - 120-160%) than the contralateral control (deltaGFR = 30-40%). In three dogs completely anuric following renal arterial clamping, glucagon was able to improve blood flow and restart urine formation. Glucagon, but not dopamine, was able to simulate the beneficial effects of hypertonic mannitol on renal function in dogs with hemorrhagic hypotension. Glucagon was without effect in established acute tubular necrosis. This study, therefore, indicates that, during renal ischemia, glucagon may be quite effective in preserving urine output and perfusion of the kidneys.

Modification in dogs of the systemic and coronary hemodynamic effects of glucagon by sotalol

T he systemic hemodynamic effects of glucagon in man, 1-3 the intact anima1,4-6 and the isolated animal organ preparation4*5t1*8 have been previously described. The mechanism by which glucagon exerts its effect is not clear. Several investigators have reported that most or all of the hemodynamic effects of glucagon are unaffected by prior beta-blockade with propranolol.4-6 Sotalol (dl 4-[2-isopropylamino-l-hydroxyethyl] methane Sulfonanilide-HCI, MJ 1999) has been reported to be a beta adrenergic receptor blocking agent free of any intrinsic adrenergic activity.g Its coronary and systemic hemodynamic effects have been extensively studied and reported.‘O-I5 We are not aware, however, of any report of the combined hemodynamic effects of glucagon and sotalol. In this communication we report our findings of the hemodynamic effects of the interaction of beta adrenergic receptor blockade with sotalol and the intravenous administration of glucagon in the anesthetized dog.

Hemodynamic effects of glucagon following hemorrhagic and endotoxic shock in the dog.

The circulatory effects of glucagon were studied in hemorrhagic and endotoxic shock. Glucagon administration had several significant effects—increase in cardiac output, decrease in arterial pressure, decrease in peripheral resistance, increase in heart rate, increase in stroke volume following hemorrhage but not after endotoxin administration, and a tendency to increase central venous pressure. From this study, it appears that glucagon is a beneficial agent in improving the cardiovascular status of experimental animals subjected to hemorrhagic and endotoxic shock.

Hemodynamic effects of glucagon and intraaortic balloon counterpulsation in canine myocardial infarction

The hemodynamic effects of glucagon (50 μg/kg) and intraaortic balloon counterpulsation were investigated in open chest anesthetized dogs after production of myocardial infarction and cardiogenic shock. Glucagon produced striking increases in arterial pressure, cardiac output and maximal left ventricular dp/dt together with a reduction in left ventricular end-diastolic pressure and systemic vascular resistance. The condition of most animals was stabilized at a viable level with 1 or more doses of glucagon. The effects of counterpulsation during severe cardiogenic shock were slight, although good counterpulsation was always achieved during control studies with normal pressure. When counterpulsation was instituted in combination with glucagon therapy there was an increase in mean arterial pressure together with a reduction in maximal left ventricular dp/dt and peak systolic pressure. Thus, counterpulsation tended to reduce the increased oxygen cost of the inotropic effects of glucagon. We suggest that an appropriate combination of counterpulsation and inotropic support (as with glucagon) may be better than either method alone.

Hemodynamic effects of glucagon in patients with fixed-rate pacemakers

Hemodynamic effects of glucagon in patients with fixed-rate pacemakers

Cardiocirculatory effects of glucagon in patients with congestive heart failure and cardiogenic shock

Cardiocirculatory Effects of Glucagon in Patients with Congestive Heart Failure and Cardiogenic Shock EZRA A. AMSTERDAM, MD/ROBERT ZELIS, MD/JAMES F. SPANN, Jr., MD, FACC EDWARD J. HURLEY, MD, FACC and DEAN T. MASON, MD, FACC Davis, California Although the powerful inotropic property of glucagon is well established in isolated heart muscle and experimentd animals, the efficacy of the agent in patients with severe cardiac malfunction has not been determined. The purpose of this study was to define the cardiocirculatory effects of glucagon in patients with congestive heart failure or cardiogenie shock. Accordingly, the hemodynamic actions of intravenously administered glucagon (50 k there was a small but significant (P < 0.05) rise in heart rate (93 to 99). In the 5 patients of both groups whose cardiac output rose, the maximal increase was 14%. In the 3 patients with cardiogenic shock whose blood pressure increased, the increases were 5, 11 and 30%, respectively. These data suggest that glucagon, as administered in these studies, produces inconsistent hemodynamic improvement in patients with congestive heart failure and cardiogenic shock ahd that when favorable changes occur, they are usually of small magnitude. Signs and Symptoms of the Different Causes of Endocarditis Dr. FELIX ANSCHOTZ Dafmstadt, West Germany Knowledge of the causative inflammable process of the heart valves is important to understanding of the origin, progress, prognosis and treatment of the valvular disease. It is impossible to describe valvular heart disease with the aid of hemodynamic studies alone. The origin of the endocarditis is the central problem because of the consequences in therapy and prophylaxis. The differential diagnosis of endocarditis is described by our own studies in which the signs and symptoms are related in each case to the autopsy findings (137 cases of rheumatic heaxt disease, 85 cases of subacute bacterial endocarditis, 44 cases of acute bacterial endocarditis and 40 cases of rafe causes of endocarditis) . It is easier to recognize carditis in acute rheumatic fever than in cases of chronic valvular disease in which the inflammation doubtless influences the progress of the valvular damage. In these cases other possible explanations of inflammation must be considered. Subacute bacterial endocarditis, too, will be easy to recognize, particularly if the bacterial culture is positive. Often abacterial endocarditis may be hard to diagnose because of its indistinct symptoms. The central problem is to find the strains, which is difficult because many patients have already been given antibiotics. In some cases it is impossible to diagnose the cause of the endocarditis definitely even with the help of the most modern clinical studies. Hemodynamic Effects of Glucagon in Patients with Fixed-Rate Pacemakers WILLIAM W. ASHLEY, MD/DAVID M KAMINSKY, MD/JANET I. LIPSKI, MD ARTHUR C. WEISENSEEL, Jr., MD/EPHRAIM DONOSO, MD, FACC and CHARLES K. FRIEDBERG, MD, FACC New York, New York The effects of glucagon (50 clg/kg) on cardiac output (dye dilution) and brachial arterial pressure were studied in 7 patients, aged 57 to 73, with fixed-rate pacemakers. Mean cardiac index at rest increased 0.8 + 0.07 liters/ min per m2 (9% confidence interval) without significant change in braehial arterial pressures. Exercise performed by 5 patients, without glucagon, increased the cardiac index. During the same amount of exercise with glucagon, there was no aignifioant further increase in cardiac index (0.5 + 0.06 liters/min per m*). One additional patient with congestive heart failure did not show an increased cardiac index with glucagon at rest or during exercise. Isoproterenol administered to 2 patients increased cardiac index by 1.91 and 1.90 liters/min per ma compared to 1.02 and 0.75, respectively, with glucagon. Six of 8 patients experienced nausea and lightheadedness, and in 2 patients ventricular premature systoles developed after administration of glucagon. Mean serum potassium in 9 patients decreased from 82 The Amodem JoounMl of CARDlOLOaY

Hemodynamic effects of glucagon in patients following prosthetic valve replacement.

The intravenous administration of 5.0 mg of glucagon to 16 digitalized patients on the first postoperative day after prosthetic valve replacement resulted in significant cardiac inotropic effects. Since glucagon is effective in the presence of catecholamine depletion or beta-adrenergic blockade and appears to have little arrhythmogenic potential, it would appear to be a useful agent for the treatment of myocardial depression occurring in association with open cardiac surgery.

Hemodynamic effects of glucagon in patients with heart disease.

The intravenous administration of 3 or 5 mg of glucagon to 13 patients with heart disease resulted in a statistically significant increase in heart rate, cardiac index, stroke power index, mean rate of left ventricular ejection, and maximum rate of rise of left ventricular pressure, whereas systemic vascular resistance declined. A moderate increase in mean stroke volume index and stroke work index and a slight fall in left ventricular end-diastolic pressure also occurred, although these changes were not statistically significant. The increase in cardiac index averaged 19%, with nine of the patients demonstrating an increase exceeding 10% of their respective control value. These effects of glucagon generally reached a maximum within 15 min after drug administration and also were of short duration. Positive inotropic and chronotropic effects of glucagon were observed in most but not all of these patients. In addition, the magnitude of these effects varied considerably among patients; the variation, however, did not appear to be related to the severity or duration of the heart disease. In eight patients, the infusion of isoproterenol produced greater increases in cardiac index and decreases in left ventricular end-diastolic pressure than glucagon did. Although the effect of glucagon was short, the frequent improvement in hemodynamics which occurred in the absence of significant side effects, notably arrhythmias, indicates that the inotropic actions of this agent may be useful under certain clinical conditions.