Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock: A Randomized Clinical Trial

Study Questions:

What is the effect of the short-acting beta-blocker esmolol in the treatment of severe septic shock?

Methods:

This was a single-center (university intensive care unit), randomized, phase 2, open-label trial of patients with septic shock and a heart rate of 95 bpm or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. Beta-blocker therapy prior to randomization was an exclusion criterion. A total of 77 patients were randomly assigned to receive a continuous infusion of esmolol titrated to maintain a heart rate between 80 bpm and 94 bpm during a 96-hour period; 77 patients were randomized to standard treatment. The primary outcome was reduction in heart rate below the predefined threshold of 95 bpm. Secondary endpoints included hemodynamic measurements of myocardial performance, biochemical measurements of metabolic demand, norepinephrine requirements, safety (including markers of organ function and need for rescue therapy), and 28-day overall survival.

Results:

Esmolol led to successful lowering of heart rate in the esmolol group without increases in hypotension. There was a reduction in norepinephrine requirements in the esmolol group with a median area under the curve (AUC) of -0.11 mcg/kg/min (interquartile range, -0.46 to 0) versus -0.01 mg/kg/min (-0.2 to 0.44) in the control group (p = 0.003). Stroke volume, systemic vascular resistance, and left ventricular stroke work indices were increased in the esmolol group. The esmolol group also had less fluid requirements and lower arterial lactate levels. Between groups, there were no significant differences in the use of rescue therapies. Twenty-eight day mortality was lower in the esmolol group compared to the control group (49.4% vs. 80.5%, p < 0.001).

Conclusions:

Esmolol, when compared to standard care in patients with septic shock with a heart rate >95 bpm, was associated with greater reductions in heart rate, decreased norepinephrine and fluid requirements, and indices of improved myocardial performance and less metabolic demand. There were no adverse effects on organ function.

Perspective:

The limitations of this single-center trial aside, the current analysis generates important questions about the controversial issue of treating tachycardia in septic shock. The observations lend themselves to a large, multicenter, clinical trial that may be able to confirm the findings reported here. As acknowledged by the authors, the mechanism by which esmolol might have improved outcomes (including a dramatic difference in mortality) is unclear. The effects of beta-blockade are multifaceted and, going forward, it will be important to attempt to understand through what mechanism(s) beta-blockers may lead to favorable outcomes.

Clinical Topics: Diabetes and Cardiometabolic Disease

Keywords: Shock, Septic, Hypotension, Heart Rate, Hemodynamics


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