Dose-dependent effects of esmolol-epinephrine combination therapy in myocardial ischemia

Epinephrine has been included in resuscitation guidelines worldwide since the 1960s. It is believed that epinephrine increases the chance of restoring a person’s heartbeat and improves long-term neurological outcome through increasing coronary and cerebral perfusion pressure. However, recent studies have raised doubts about the benefit of epinephrine regarding neurological outcomes in cardiac arrest. Moreover, epinephrine use in the stabilization of a cardiogenic shock in post-myocardial infarction patients has been found to increase the incidence of refractory shock. In fact, beta-adrenergic receptor stimulation has been suggested to have deleterious effects as stimulation of this pathway increases oxygen consumption and reduces sub-endocardial perfusion. In contrast, esmolol, a cardio-selective β1-blocker, has been shown to provide cardioprotection after myocardial ischemia in animal and human studies. Therefore, esmolol co-administration with epinephrine may help to reduce epinephrine-reperfusion injury but maintain esmolol-cardioprotection and epinephrine mediated increases in chronotropy and inotropy. Indeed, recent studies in animals have uncovered beneficial effects of epinephrine and esmolol co-administration in a cardiac arrest model. Based on these findings, Dr. Tobias Eckle and his team at the University of Colorado School of Medicine, University of Colorado have investigated esmolol-epinephrine combination therapy in a mouse model of myocardial ischemia and reperfusion injury.

Comparing different esmolol doses in combination with epinephrine in a mouse model of myocardial infarction, Eckle’s team demonstrated that at a specific esmolol-epinephrine ratio (15:1), esmolol-cardioprotection and epinephrine β1 mediated hemodynamic activity can both simultaneously exist during myocardial ischemia and reperfusion injury. “These findings might have implications for current clinical practice in the treatment of patients with cardiogenic shock or cardiac arrest”, says Eckle. “In fact, a cardiogenic shock after myocardial ischemia disallows the use of esmolol due to hemodynamic instability.” Interestingly, a definite recommendation for a specific catecholamine regimen in cardiogenic shock is lacking.

Combination therapy of epinephrine with esmolol seems less intuitive in cardiogenic shock after myocardial ischemia according to the research; higher esmolol doses could compromise epinephrine mediated increases of cardiac output via β1 adrenergic receptor inotropic and chronotropic effects, or higher epinephrine doses could compromise esmolol mediated cardioprotection via β1 adrenergic receptor blockade. Surprisingly, by increasing the esmolol dose, the study team was able to restore esmolol-cardioprotection while heart rate and some blood pressures in the early reperfusion phase were significantly increased compared to an esmolol treatment alone. “This finding is novel and highlights that esmolol cardioprotection is not fully understood,” says Eckle. Having increased heart rates, which is β1 mediated, and at the same time seeing cardioprotection via esmolol β1 blockade, indicates that only a part or short-term blockade of β1 receptors is necessary for the salutary effects of esmolol in myocardial ischemia and reperfusion injury.

While some clinicians occasionally use esmolol in patients on epinephrine infusion due to cardiogenic shock going off cardiac bypass to treat epinephrine-induced arrhythmias, no study to date has evaluated potential cardioprotective effects of esmolol-epinephrine co-administration during cardiac bypass surgery or a cardiogenic shock. As this is the first animal study on epinephrine-esmolol co-administration during myocardial ischemia and reperfusion injury, further studies in larger animals using multiple dosing protocols are suggested.

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The complete paper is published in Current Pharmaceutical Design. Please visit the following link to access the paper: http://www.eurekaselect.com/node/172732/article/dose-dependent-effects-of-esmolol-epinephrine-combination-therapy-in-myocardial-ischemia-and-reperfusion-injury

This work was supported by the NIH-NHLBI grant 5R01HL122472.