Landiolol and Organ Failure in Patients With Septic Shock

Abstract

ImportancePatients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. β-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality.ObjectivesTo assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (>24 hours) vasopressor support.Design, Setting, and ParticipantsAn open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 μg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm.InterventionSixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion.Main Outcomes and MeasuresThe primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group.ResultsThe trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, −0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, −4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, −1.7% to 31.6%]; P = .08). There were no differences in the number of patients having at least one adverse event.Conclusion and RelevanceAmong patients with septic shock with tachycardia and treated with norepinephrine for more than 24 hours, an infusion of landiolol did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock.Trial RegistrationEU Clinical Trials Register Eudra CT: 2017-001785-14; isrctn.org Identifier: ISRCTN12600919

Use of Landiolol for Patients With Septic Shock and Organ Failure

“…To the Editor The use of β-blockers during septic shock aims to counter adrenergic stress and may be justified by the early reduction in deleterious effects resulting from sympathetic overactivation. Contrary to a previous study, the authors of the Study Into the Reversal of Septic Shock With Landiolol (STRESS-L) conclude that an infusion of landiolol did not reduce organ failure, and thus, the results of the study do not support its use among patients treated with norepinephrine for established septic shock.…”

Impact of premorbid use of beta‑blockers on survival outcomes of patients with sepsis: A systematic review and meta‑analysis

“…A previous study found that short-acting beta-blockers such as esmolol and landiolol are able to efficiently control tachycardia in patients with sepsis without any relative decrease in the mean arterial pressure, and improve patient survival ( 40 ). However, recently published STRESS-L RCT ( 41 ) has revealed that in patients with septic shock and tachycardia that were managed by norepinephrine for >24 h, the use of beta-blocker landiolol did not affect SOFA scores or mortality rates. The trial had to be stopped prematurely due to the possible adverse effects of beta-blockers.…”

Ivabradine in Septic Shock: A Narrative Review

“…Although β-blockers are effective in reducing HR, they also have a negative inotropic effect and thus may be potentially harmful in MODS patients with myocardial dysfunction [3,5]. These concerns are even supported by the premature interruption of the recent STRESS-L randomized trial using landiolol, a highly β1-selective blocker, for an increase in mortality and severity of organ dysfunction at 28 days associated with the use of this drug [47]. Similar issues emerge from the multi-center randomized J-Land 3S trial [48], where adverse events occurred in 64% of patients in the landiolol group, with serious adverse events, including events leading to death, in 12% of patients.…”