Abstract
BackgroundHigh adrenergic tone appears to be associated with mortality in septic shock, while adrenergic antagonism may improve survival. In preparation for a randomized trial, we conducted a prospective, single-arm pilot study of esmolol infusion for patients with septic shock and tachycardia that persists after adequate volume expansion.MethodsFrom April 2016 to March 2017, we enrolled patients admitted to an intensive care unit with sepsis who were receiving vasopressor infusion and were tachycardic despite adequate volume expansion. All patients received a continuous intravenous infusion of esmolol, targeted to heart rate 80–90/min, while receiving vasopressors. The feasibility outcomes were proportion of eligible patients consented, compliance with pre-infusion safety check, and compliance with the titration protocol. The primary clinical outcome was organ-failure-free days (OFFD) at 28 days.ResultsWe enrolled 7 of 10 eligible patients. Mean age was 46 (± 19) years, and mean admission APACHE II was 28 (± 8). Median norepinephrine infusion rate at the initiation of esmolol infusion was 0.20 (0.14–0.23) μg/kg/min. Compliance with the safety check was 100%; compliance with components of the titration protocol was 98–100%. OFFD were 26 (24.5–26); all patients survived to day 90. Median peak esmolol infusion was 50 (25–50) μg/kg/min. Median peak norepinephrine infusion rate during esmolol infusion was 0.46 (0.13–0.50) μg/kg/min. Four patients achieved target heart rate. Protocol-defined stop events, suggesting possible intolerance to a given infusion rate, occurred in three patients, all of whom were receiving at least 50 μg/kg/min of esmolol.ConclusionsIn a pilot, single-arm study, we report the first published experience with esmolol infusion in tachycardic patients with septic shock in the United States. These findings support a phase 2 trial of esmolol infusion for septic shock. Lower infusion rates of esmolol infusion may be better tolerated and more feasible than higher infusion rates for such a trial.Trial registrationThis study was retrospectively registered at ClinicalTrials.gov (NCT02841241) on 19 July 2016.
Highlights
High adrenergic tone appears to be associated with mortality in septic shock, while adrenergic antagonism may improve survival
Sympathetic overstimulation can drive a positive feedback loop of cardiovascular and other organ dysfunction, called the multiple organ dysfunction syndrome (MODS), which is the signature of septic shock [8, 9]
While several small trials have administered β-blockers to just over 250 patients with septic shock, [22, 23, 49,50,51,52,53,54] we report here, to our knowledge, the first published experience with esmolol infusion in tachycardic patients with septic shock in the United States (US)
Summary
High adrenergic tone appears to be associated with mortality in septic shock, while adrenergic antagonism may improve survival. The hemodynamic changes of septic shock result from interactions among cardiovascular homeostasis, the host immune response, and therapeutic interventions [6]. These aspects of sepsis are likely interdependent [10]. Administration of exogenous catecholamines to maintain arterial blood pressure has been a cornerstone of management of septic shock for decades. Given this ongoing reliance on catecholamine infusions, recent possible improvements (admitting that some dispute these improvements [1]) in sepsis mortality may be difficult to interpret [3, 11]
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