Septic shock remains a leading cause of intensive care unit admissions and mortality worldwide, with approximately 50% of affected patients dying. Excess beta-adrenergic activity, triggered by the body's stress response, drives much of this mortality by causing persistent tachycardia, increased myocardial oxygen consumption, reduced coronary perfusion, impaired cardiac output, endothelial dysfunction, and cellular metabolic derangements.
Beta-adrenergic blockers offer a physiologically plausible approach to counteract these harmful effects. A meta-analysis of 12 randomized controlled trials enrolling 1170 patients suggests beta-blockers may reduce 28-day mortality (risk ratio 0.76, 95% confidence interval 0.62-0.93). However, substantial heterogeneity exists across trials, with results ranging from a 44% mortality reduction to an 11% increase. One multicenter trial was stopped early for potential harm. This heterogeneity may be explained by inadvertent enrollment of patients at high risk of harm from beta-blockade: those with inadequate fluid resuscitation who depend on tachycardia to maintain cardiac output, and those with left or right ventricular dysfunction who cannot tolerate the negative inotropic effects of beta-blockers.
This pilot trial implements a predictive enrichment strategy using point-of-care ultrasound to exclude high-risk phenotypes before randomization. Eligible patients undergo POCUS assessment of fluid responsiveness using left ventricular outflow tract velocity time integral or carotid corrected flow time with passive leg raise. Patients demonstrating fluid responsiveness (greater than 15% change) are excluded as inadequately resuscitated. Cardiac function assessment excludes patients with moderate to severe left ventricular systolic dysfunction (ejection fraction less than 35%) or right ventricular dysfunction (tricuspid annular plane systolic excursion less than 17mm, severe RV dilation, septal shift, or RV S prime less than 9.5 cm/second).
Patients meeting eligibility criteria after POCUS screening are randomized 1:1 to esmolol or standard care. The intervention arm receives intravenous esmolol initiated at 50 mcg/kg/minute and titrated by 50 mcg/kg/minute every 15 minutes to achieve a target heart rate of 75-95 beats per minute, with a maximum dose of 300 mcg/kg/minute. Treatment continues for up to 5 days or until ICU discharge, death, or discontinuation of vasopressors for at least 6 hours. Both arms receive standard septic shock management per Surviving Sepsis Campaign guidelines.
Primary outcomes focus on feasibility: recruitment rate (target 4 patients per month), consent rate (target 80% or greater), POCUS screening completion rate (target 80% or greater), and protocol adherence (target 80% or greater). Secondary outcomes include 28-day and 90-day mortality, days alive and free of organ support therapies, and ICU and hospital length of stay.
