Abstract Background Excessive sympathetic activation in sepsis and septic shock contributes to myocardial injury, metabolic derangements, and immune dysregulation. Beta-blockers have been proposed as adjunctive therapy to mitigate these effects, yet trial results remain conflicting. We conducted a systematic review and network meta-analysis (NMA) to evaluate the comparative effects of beta-blockers on mortality in adult patients with sepsis or septic shock. Methods We systematically searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials through November 1, 2025, for randomized controlled trials (RCTs) comparing intravenous esmolol, landiolol, or metoprolol with standard care or placebo in adults with sepsis or septic shock. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Cochrane RoB 2 tool. The primary outcome was 28-day all-cause mortality. A Bayesian random-effects NMA (weakly informative priors; convergence verified by R-hat 1.05) was performed using Python (NumPy/SciPy). Statistical heterogeneity was quantified using I² and τ², and network inconsistency was assessed by node-splitting. The primary analysis included only studies rated at low or moderate overall risk of bias; a sensitivity analysis incorporated all identified trials. Treatments were ranked using surface-under-the-cumulative-ranking-curve (SUCRA) probabilities. Results Eight RCTs enrolling 825 patients met inclusion criteria. Six trials (n = 629) were classified as low or moderate risk of bias and included in the primary analysis. Beta-blocker therapy as a class did not significantly reduce 28-day mortality (Risk Ratio RR 0.86; 95% Credible Interval CrI 0.64-1.16; I² = 48%). Esmolol demonstrated a trend toward benefit (RR 0.67; 95% CrI 0.48-0.92), while landiolol showed no mortality effect (RR 1.06; 95% CrI 0.73-1.56). Including two high-risk, single-center trials (Morelli 2013 and Fayed 2024) produced an apparent mortality reduction (RR 0.77; 95% CrI 0.61-0.97) but increased heterogeneity (I² = 57%). SUCRA rankings suggested esmolol was most likely to be effective, followed by control, and then landiolol. Conclusions When analysis is restricted to higher-quality trials, beta-blocker therapy does not confer a significant mortality benefit in septic shock. The apparent survival advantage observed in earlier analyses is driven by small, high-risk studies with questionable validity. Current evidence does not support routine beta-blocker use in sepsis; however, these agents may merit investigation in specific hemodynamically stable subgroups. Large, blinded, multi-center RCTs are required to definitively determine whether β-blockade offers clinical benefit in septic shock. This abstract is funded by: None
Elhassan et al. (Fri,) studied this question.