Esmolol to Treat the Hemodynamic Effects of Septic Shock: A Randomized Controlled Trial

Abstract

Introduction: Septic shock is often characterized by tachycardia and a hyperdynamic hemodynamic profile. Use of the beta antagonist esmolol has been proposed as a therapy to lower heart rate, thereby improving diastolic filling time and improving cardiac output, resulting in a reduction in vasopressor support.

Methods: We conducted a two-center, open-label, randomized, Phase II trial comparing esmolol to placebo in septic shock patients with tachycardia. The primary endpoint was improvement in hemodynamics as measured by the difference in norepinephrine equivalent dose (NED) between groups at 6 hours after initiation of study drug. Secondary outcomes included assessing differences in inflammatory biomarkers and oxygen consumption (VO2).

Results: A total of 1,122 patients were assessed for eligibility and met inclusion criteria; 42 underwent randomization, and 40 received study interventions (18 in the esmolol arm and 22 in the usual care arm). The mean NED at 6 h was 0.30 ± 0.17 mcg/kg/min in the esmolol arm compared to 0.21 ± 0.19 in the standard care arm (P = 0.15). There was no difference in number of shock free days between the esmolol (2, IQR 0, 5) and control groups (2.5, IQR 0, 6) (P = 0.32). There were lower levels of C-reactive protein at 12 and 24 h in the esmolol arm, as well as a statistically significant difference in trend over time between groups. There were no differences in terms of IL-4, IL-6, IL-10, and TNFα. Among a subset who underwent VO2 monitoring, there was decreased oxygen consumption in the esmolol patients; the mean difference between groups at 24 h was -2.07 mL/kg/min (95% CI -3.82, -0.31) (P = 0.02), with a significant difference for the trend over time (P < 0.01).

Conclusion: Among patients with septic shock, infusion of esmolol did not improve vasopressor requirements or time to shock reversal. Esmolol was associated with decreased levels of C-reactive protein over 24 h.

Trial registration: www.clinicaltrials.gov. Registered February 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02369900.

FIG. 1.

CONSORT diagram.

FIG. 2.

Hourly esmolol dose during the duration of the study. H0 indicates the first hour after initial drug infusion, that is, hour 0 to 1. Ticks on X axis indicate every 4th hour after drug infusion. The number of patients who contributed to the calculation of the median dose at each time point are indicated with the “n=“ annotations. The shaded purple area represents the inter-quartile range, with the lower and upper edges of the shaded area representing the 1^st and 3^rd quartiles of the esmolol dose, respectively. The central point within the shaded area represents the median esmolol dose.

FIG. 3.

Plot of mean VO₂/kg over time at hourly intervals after study drug administration. On the X axis, 1 indicates the 1st hour after drug administration(all data between hour 0 [time of drug administration] and hour 1), 2 indicates the 2^nd hour (data between hour 1 and hour 2), and soon. The number of patients contributing to means at certain select timepoints is specified in the annotations (annotating text is colored red for the placebo group and blue for the esmolol group). Over all timepoints, a total of 15 patients (6 patients from esmolol group and 9 from control group) contributed VO₂ data.

FIG. 4.

Inflammatory markers by treatment group.