Septic shock is associated with the excessive sympathetic stress associated with a number of adverse physiological effects, ranging from myocardial depression to immunosuppression. Morelli and colleagues from the Sapienza University of Rome conducted a study to determine whether administration of a short-acting beta-adrenoreceptor blocker, esmolol, could reduce heart rate to a target range of 80 to 94 beats per minute (bpm) in patients with septic shock. The physiologic consequences of heart rate reduction were also examined, as well as secondary clinical outcomes.
In this single-center, open-label (non-blinded), randomized two-group trial, patients with septic shock requiring norepinephrine to maintain a mean arterial pressure above 65 mm Hg, and a heart rate greater than 95 bpm were monitored with a pulmonary artery catheter using continuous thermodilution. Esmolol was titrated, starting at a dose of 25 mg/h, to achieve the primary outcome: reduction of heart rate to between 80 and 94 bpm. Secondary outcomes included the effect of esmolol on norepinephrine requirements, cardiorespiratory and oxygenation indices, safety endpoints, and 28-day overall survival. The intention-to-treat principle was used in all analyses. Nonparametric and parametric statistics were used together with a multivariable Cox regression model to adjust for multiple covariates such as age, presence of multidrug-resistant infections, and severity of illness (Simplified Acute Physiology Score version II).
After 336 patients were screened, 77 were included in the experimental arm and 77 in the control arm. Baseline data were similar in the groups. Patients treated with esmolol had significantly lower heart rates throughout the study period. Mean arterial pressure was maintained despite a reduction in norepinephrine requirements in the esmolol group. Stroke volume, stroke volume ratio, and left ventricular stroke work index were increased in the esmolol group. Patients in the esmolol group had higher glomerular filtration rates, a trend maintained when patients requiring dialysis were excluded. Both unadjusted and adjusted mortality at 28 days was significantly lower in the esmolol group compared to the control group (49.4% vs. 80.5%; hazard ratio, 0.392; 95% confidence interval, 0.261 to 0.59; P<0.001).
These results represent a single-center experience, and several additional factors may have played a role in the observed physiological changes, such as a high incidence of multidrug-resistant causative organisms, use of hydrocortisone in all patients, and use of the calcium channel sensitizer levosimendan in some patients. As pointed out in the accompanying editorial by Pinsky, beta-blockers may exert beneficial effects. Additional multicenter randomized trials are warranted to replicate the results of Morelli et al and to further elucidate mechanisms responsible for physiological and clinical outcomes in septic shock patients receiving esmolol.
Samuel M. Galvagno Jr., DO, PhD, is editor of Concise Critical Care Appraisal. An assistant professor at the University of Maryland, R Adams Cowley Shock Trauma Center, he is board certified in anesthesiology, critical care medicine, and public health.