Mortality patients with sepsis treated with esmolol or landiolol. a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis

Background: The latest meta-analysis indicated potential survival benefits from ultra-short-acting β-blockers in patients with sepsis with persistent tachycardia. However, subsequent multicenter randomized controlled trials (RCTs) have reported conflicting findings, prompting the need for an updated meta-analysis to incorporate these newly published RCTs. Research Question: Does the use of ultra-short-acting β-blockers (esmolol or landiolol) in patients with sepsis with persistent tachycardia improve mortality? Study Design and Methods: We conducted an updated systematic search through April 2, 2024, exploring the MEDLINE, Cochrane Central Register of Controlled Trials, and Embase databases for RCTs reporting mortality in adult patients with sepsis treated with esmolol or landiolol as compared with those treated with neither of these or receiving placebo and published in English. Meta-analyses were conducted with the random effects model. The primary outcome was mortality at the longest follow-up, with subgroup analysis separating single-center RCTS from large multicenter RCTs. Results: Eight RCTs (885 patients) were included in the primary analysis. Ultra-short-acting β-blockers did not improve mortality significantly at the longest follow-up (risk ratio, 0.84; 95% CI, 0.68-1.02; P =.08; I2 = 51%; very low certainty of the evidence) and 28-day mortality (risk ratio, 0.77; 95% CI, 0.59-1.00; P =.05; I2 = 62%). Subgroup analyses of mortality outcomes pointed toward different results between single-center and multicenter RCTs. Trial sequence analyses showed that both mortality outcomes were not robust. The sensitivity analyses suggested a significant reduction in mortality by adding RCTs published in non-English languages. Interpretation: In this updated meta-analysis, the use of esmolol or landiolol did not reduce mortality in patients with sepsis with persistent tachycardia. However, results were not robust and outcomes differed between single-center and multicenter RCTs. Moreover, sensitivity analyses showed the fragility of the primary outcome. Further studies regarding ultra-short-acting β-blockers with advanced cardiac monitoring or serial echocardiography are warranted. Trial Registry: International Prospective Register of Systematic Reviews; No.: CRD42024503570; URL: https://www.crd.york.ac.uk/prospero/