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Effect of Heart Rate Control with Esmolol on Hemodynamic and Clinical Outcomes in Patients with Septic Shock: a Randomized Clinical Trial
Study Question: Can intravenous (IV) b-blockade control heart rate to enhance myocardial function and improve outcomes in patients with septic shock?
Study Description: This randomized, single-center, open-label phase 2 trial evaluated septic shock patients requiring norepinephrine to maintain a mean arterial pressure (MAP) ≥ 65 mm Hg, with a heart rate (HR) ≥ 95 bpm despite appropriate volume resuscitation (CVP ≥ 8 mm Hg). Patients were enrolled after 24 hours of optimized hemodynamics, and randomized to the control group or esmolol starting at 25 mg/hr, titrated by 50 mg/hr (maximum 2000 mg/hr), to achieve target HR between 80 – 95/min within 12 hours of initiation. The primary outcome evaluated if esmolol could reduce HR < 95 bpm to the target HR. Treatment was continued until ICU discharge or death.
Results: Of 336 screened patients, a total of 154 patients met study inclusion criteria (n = 77 for each group). The median Simplified Acute Physiology Score II was 52 [IQR 47 – 60] in the esmolol group and 57 [49 – 62] in the control group. Norepinephrine median doses were 0.38 mcg/kg/min [IQR 0.21 – 0.87] and 0.40 mcg/kg/min [0.18 – 0.71] for the esmolol and control groups, respectively. Median esmolol dose was 100 mg/hr (IQR 50 – 300). The esmolol group achieved the primary endpoint with a HR reduction in the area under the curve (AUC) -28 bpm [IQR -37 to -21) vs. -6 [IQR -14 to 0] (p < 0.001). The esmolol group had a reduction in norepinephrine dose requirements compared to the control (median AUC -0.11 mcg/kg/min [IQR -0.46 to 0] vs. -0.01mcg/kg/min [-0.2 to 0.44]), while maintaining MAP > 65 mm Hg. Esmolol was associated with lower 28-day mortality vs. control (49.4% vs. 80.5%, p < 0.001).
Conclusion(s): Open-label esmolol allowed patients with septic shock to achieve a lower targeted HR versus standard therapy.
Perspective: This study demonstrates that esmolol appears to be safe in reducing HR in patients with septic shock. The study was not adequately powered to detect differences in requirements of secondary outcomes including norepinephrine dosing or mortality. Potential confounding variables including concomitant treatment, past medical history, and high severity of illness may affect the associated mortality benefit with the treatment group. This study is hypothesis generating and larger randomized clinical trials are needed to evaluate the effect of esmolol on clinical outcomes with septic shock patients.