Esmolol in Septic Shock
ABSTRACT & COMMENTARY
By Andrew J. Boyle, MBBS, PhD
Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco
Dr. Boyle reports no financial relationships relevant to this field of study.
This article originally appeared in the December 2013 issue of Clinical Cardiology Alert. It was edited by Michael H. Crawford, MD, Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco, and peer reviewed by Ethan Weiss, MD, Assistant Professor of Medicine, Division of Cardiology and CVRI, University of California, San Francisco. Dr. Crawford reports no financial relationships relevant to this field of study, and Dr. Weiss is a scientific advisory board member for Bionovo.
Source: Morelli A, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: A randomized clinical trial. JAMA 2013;310:1683-1691.
Cardiac patients are prone to develop sepsis in the intensive care unit (ICU) setting. The physiological changes associated with septic shock, such as tachycardia and hypotension, may be particularly deleterious to cardiac patients. Therefore, knowledge of ways to ameliorate these physiological changes may benefit cardiologists. Morelli and colleagues addressed the issue of whether beta-adrenoceptor blockade would be beneficial by reducing tachycardia or deleterious by reducing inotropy in patients with septic shock. They performed a single-center, randomized, open-label study of patients in ICU with septic shock, a heart rate > 95/min, and requiring high-dose norepinephrine to maintain mean arterial blood pressure (MAP) > 65 mmHg. They excluded minors, those on beta-blocker therapy prior to randomization, patients with significant cardiac impairment (cardiac index < 2.2 L/min/m2 and pulmonary capillary wedge pressure > 18 mmHg) or valve disease, and pregnant women. All patients had a pulmonary artery catheter and arterial line, and received fluid resuscitation to achieve a right atrial pressure ≥ 8 mmHg. Patients were randomized to a continuous infusion of esmolol, titrated to heart rate 80-94/min for the duration of ICU stay, vs usual care. The primary endpoint was attaining heart rate 80-94/min. Secondary endpoints included hemodynamic parameters and 28-day survival.
A total of 154 patients were randomized to receive esmolol infusion (n = 77) vs usual care (n = 77). Baseline demographics were similar between groups; the mean age was 68 years and 54% were male. Pneumonia was the most common source of sepsis. There was a wide spectrum of bacteria isolated as the causative organisms, with Klebsiella being the most common and Staphylococcus aureus being isolated in 8%. The target heart rate was achieved in 100% of patients receiving esmolol with a mean reduction of 18 beats/min (P < 0.001 vs usual care). Patients receiving esmolol showed improved hemodynamic parameters compared to usual care, including significant improvements in stroke volume, systemic vascular resistance, and left ventricular stroke work index. Fluid requirements were lower in the esmolol group (3.98 L/d vs 4.43 L/d; P < 0.001) and norepinephrine requirements, which were equivalent at baseline, were also reduced. Renal function improved in the esmolol group, but not in the usual care group. Unadjusted mortality at 28 days was lower in the esmolol group (49.4% vs 80.5%; P < 0.001). Multivariate analysis showed that the Simplified Acute Physiology (SAPS) II score and esmolol were the only independent predictors of survival. The authors conclude that for patients in septic shock, open-label use of esmolol compared to usual care was associated with reductions in heart rates to target levels, without increased adverse events, and that the observed improvements in mortality and other secondary endpoints warrant further investigation.
Heart rate control in septic shock is controversial. Studying patients in the ICU is inherently difficult because of the heterogeneous nature of the diseases that caused them to be there, and also because of the myriad comorbidities that may confound their clinical course and treatment. Thus, randomizing patients to a particular treatment regimen is mandatory in such studies to exclude biases. In addition, the high acuity of such patients makes blinding of treatment difficult, and titrating to a heart rate goal makes a placebo problematic to deliver. The randomized, open-label design of this trial is therefore appropriate and the authors should be commended on completing such a study. However, the open-label design does allow for some confounding of the results.
Several aspects of this study should be highlighted. First, they excluded patients with significant cardiac impairment (cardiac index < 2.2 + wedge pressure > 18 mmHg) and patients on beta-blockers prior to randomization. Therefore, the results may not be generalizable to all cardiac patients. Second, the doses of esmolol used were modest, with the mean being 100 mg/hr, and the dose used did not predict mortality at 28 days. Third, the heart rate goal was arbitrarily chosen, and the optimal heart rate in patients with septic shock remains unknown.
How should one incorporate these data into clinical practice? It is reasonable in patients with septic shock, in whom tachycardia may be producing deleterious cardiac effects, to try low-dose esmolol to reduce the heart rate. There were no safety concerns raised by this study, and this may allow reduction in vasopressor doses. However, routine use of esmolol to reduce mortality based on the secondary endpoints of this study would be premature.