Esmolol-induced heart rate reduction may aid in septic shock

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1. Patients in septic shock who received esmolol achieved reductions in heart rate to target levels without an associated increase in adverse events.

2. The 28-day mortality rate was 49.4% among patients receiving esmolol compared to 80.5% among patients receiving standard care (p<.001). 

Evidence Rating Level: 1 (Excellent)

Study Rundown: Septic shock, a low resistance, high-cardiac output state, is associated with excessive sympathetic outflow. Adrenergic stress has numerous well-documented adverse effects on critically ill patients, including increased cardiac workload and myocardial oxygen demand as well as direct cardiomyocyte toxicity from circulating catecholamines. Despite this, treating tachycardia in septic shock is controversial and norepinephrine remains the standard of care for sepsis-related hypotension. This trial aimed to test the hypothesis that intravenous beta blockade titrated to achieve heart rate control in septic shock represents an effective approach to enhance myocardial function and improve outcome without increased complications.

The study concluded that patients in septic shock who receive esmolol, a short-acting beta blocker, achieve target level heart rates without an increase in adverse events.  It is unclear how much of the mortality improvement seen in the esmolol group is due to heart rate reduction alone vs other noncardiac effects of beta blockade. Further research is necessary to determine whether outcomes are further improved with an individualized approach titrated to specific myocardial characteristics rather than a somewhat arbitrary predefined heart rate threshold. Future, larger trials are also necessary to determine the generalizability of results and the magnitude of effect in a population beyond this small sample size of septic patients preselected for their tachycardia and significant norepinephrine requirement.

Click to read the study in JAMA

Click to read an accompanying editorial in JAMA

Relevant Reading: Mechanisms of sepsis-induced cardiac dysfunction

In-Depth [randomized, phase 2 study]: This study aimed to investigate the effect of a short-acting beta blocker in patients with severe septic shock.  Study participants included 154 patients in a university hospital intensive care unit (ICU) between 2010 and 2012 who had septic shock with a heart rate of at least 95 beats per minute and required high-dose norepinephrine to maintain mean arterial pressure of at least 65 mmHg. Seventy-seven patients were randomly assigned to receive continuous infusion of esmolol titrated to maintain a heart rate between 80 and 94 beats per minutes, whereas the remaining 77 received standard treatment. The primary outcome evaluated was heart rate control between 80 and 94 beats per minute. Secondary outcomes included the effect of esmolol on hemodynamic and organ function measures; norephinephrine requirements over a 96 hour period; and adverse events within 28 days of randomization.

All patients in the esmolol group achieved target heart rates, with a mean reduction of 18 beats per minute. As compared to patients receiving standard treatment, the esmolol group had increased stroke volume, systemic vascular resistance, and left ventricular stroke work indices. MAP was maintained in the esmolol group despite a significant reduction in norepinephrine (p=.003) and fluid (p<.001) requirements. Kidney function as measured by estimated glomerular filtration rate was better maintained (p<.001) and markers of myocardial injury were lower (p=.002) in this group as well.  Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (95% CI, 0.26 to 0.59; P < .001).

By Elizabeth Kersten and Andrew Bishara

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