β-Blocker therapy may control heart rate and attenuate the deleterious effects of
β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not
traditionally used for this condition and may worsen cardiovascular decompensation related through
negative inotropic and hypotensive effects.
To investigate the effect of the short-acting β-blocker esmolol in patients with severe
Design, Setting, and Patients
Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit
(ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of
95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg
We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain
heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment.
Main Outcomes and Measures
Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to
maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary
outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and
96 hours; and adverse events and mortality occurring within 28 days after randomization.
Targeted heart rates were achieved in all patients in the esmolol group compared with those in
the control group. The median AUC for heart rate during the first 96 hours was −28/min (IQR,
−37 to −21) for the esmolol group vs −6/min (95% CI, −14 to 0) for the
control group with a mean reduction of 18/min (P < .001). For stroke
volume index, the median AUC for esmolol was 4 mL/m2 (IQR, −1 to 10) vs 1
mL/m2 for the control group (IQR, −3 to 5; P = .02),
whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1
mL/m2 for the control group (IQR, −2 to 5; P = .03).
For arterial lactatemia, median AUC for esmolol was −0.1 mmol/L (IQR, −0.6 to 0.2) vs
0.1 mmol/L for the control group (IQR, −0.3 for 0.6; P = .007);
for norepinephrine, −0.11 μg/kg/min (IQR, −0.46 to 0.02) for the esmolol group vs
−0.01 μg/kg/min (IQR, −0.2 to 0.44) for the control group
(P = .003). Fluid requirements were reduced in the esmolol group:
median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for
the control group (P < .001). We found no clinically relevant
differences between groups in other cardiopulmonary variables nor in rescue therapy requirements.
Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted
hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P < .001).
Conclusions and Relevance
For patients in septic shock, open-label use of esmolol vs standard care was associated with
reductions in heart rates to achieve target levels, without increased adverse events. The observed
improvement in mortality and other secondary clinical outcomes warrants further investigation.
clinicaltrials.gov Identifier: NCT01231698