Esmolol stabilizes heart rate in septic shock



The short-acting, intravenous beta-blocker esmolol has been shown to reduce and stabilize heart rates without adverse effects in patients with severe septic shock, a new phase II study has found.

In an open-label study that randomized 154 patients with septic shock and a heart rate of 95 or higher to standard care or titrated esmolol, the beta-blocker was associated with successful reductions in heart rate to between 80 and 94 beats per minute over a 96-hour period: a median of –28 BPM for the esmolol group compared with –6 for controls (P less than .001).

For their research, Dr. Andrea Morelli of the University of Rome La Sapienza and colleagues recruited from the hospital’s intensive care unit patients with septic shock and a heart rate of 95 BPM or above (JAMA 2013;310:1683-91).

Patients with lower heart rates or with previous beta-blocker use were excluded. Subjects in both groups required norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. The primary outcome measure was heart rate stabilization at between 80 and 94 BPM.

The esmolol group, which received a median continuous infusion of 100 mg/hr during the treatment period, also saw improved stroke work index and left ventricular stroke work, which investigators suspected was a result of improved diastolic filling. Esmolol treatment was associated with maintenance of mean arterial pressure and reduced need for norepinephrine. It was not associated with higher hepatic, renal, or myocardial injury compared with controls. Importantly, mortality at 28 days was considerably and significantly lower in the esmolol group than in controls: 49.4% vs. 80.5%. Each group comprised 77 patients.

In an editorial, Dr. Michael R. Pinsky of the department of critical care at the University of Pittsburgh called the findings "consistent with selective blockage of beta-adrenergic hyperactivity causing improved myocardial performance and decreased metabolic demand without compromising peripheral vascular function." Nonetheless, he cautioned clinicians against applying these results to all patients in septic shock (JAMA 2013;310:1677-8). "The reasons for this caution involve the limitations of this study and limitations in the current understanding of how beta-blocker therapy can cause such effects."

Dr. Morelli and colleagues acknowledged several limitations of their study. One was its single-center, open-label design. (As Dr. Pinsky noted in his editorial, a blinded study would be almost impossible to carry out because heart rate titration would be difficult to mask). The results should be replicated in a larger, multicenter trial, the researchers wrote. They noted that they had used "an arbitrary predefined heart rate threshold rather than an individualized approach titrated to specific myocardial characteristics or other biomarkers." Finally, the researchers allowed that the unexpectedly large mortality difference seen in the study could have been the result of confounding.

The study was funded by the University of Rome La Sapienza. Dr. Morelli disclosed honoraria from Baxter, the manufacturer of esmolol. A coauthor, Dr. Mervyn Singer, reported ties with Baxter. Dr. Pinsky did not report any disclosures relevant to his editorial.

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