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. 2023 Nov 7;330(17):1641-1652.
doi: 10.1001/jama.2023.20134.

Landiolol and Organ Failure in Patients With Septic Shock: The STRESS-L Randomized Clinical Trial

Tony Whitehouse  1   2 , Anower Hossain  3 , Gavin D Perkins  1   3 , Anthony C Gordon  4 , Julian Bion  1   5 , Duncan Young  6 , Danny McAuley  7   8 , Mervyn Singer  9 , Janet Lord  2 , Simon Gates  10 , Tonny Veenith  1   2 , Niall S MacCallum  11 , Joyce Yeung  1   3 , Richard Innes  12 , Ingeborg Welters  13 , Nafisa Boota  3 , Emma Skilton  3 , Belinder Ghuman  3 , Maddy Hill  3 , Scott E Regan  3 , Dipesh Mistry  3 , Ranjit Lall  3 ; STRESS-L Collaborators
Collaborators, Affiliations

Landiolol and Organ Failure in Patients With Septic Shock: The STRESS-L Randomized Clinical Trial

Tony Whitehouse et al. JAMA. .

Abstract

Importance: Patients 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.

Objectives: To assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (>24 hours) vasopressor support.

Design, setting, and participants: An 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.

Intervention: Sixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion.

Main outcomes and measures: The 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.

Results: The 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 relevance: Among 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 registration: EU Clinical Trials Register Eudra CT: 2017-001785-14; isrctn.org Identifier: ISRCTN12600919.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Perkins reported receiving grants from the Academic Research Collaboration West Midlands. Dr Gordon reported receiving grant RP-2015-06-18 from the National Institute for Health Research (NIHR); nonfinancial support from the NIHR Imperial Biomedical Research Centre (BRC) and the NIHR Clinical Research Network; and consulting fees paid to his institution from AstraZeneca, Janssen, and Novartis. Dr McAuley reported receiving grants from the NIHR, Wellcome Trust, Innovate UK, MRC, and the Northern Ireland Health and Social Care Research and Development Division; consulting fees from Aptarion, Aviceda, Bayer, Boehringer Ingelheim, Direct Biologics, Eli Lilly, GlaxoSmithKline, and Novartis; personal fees from Vir Biotechnology Inc; being a member of the Disability Management Employer Coalition, having patent US8962032 issued to Queen's University Belfast; and serving as the codirector of research for the Intensive Care Society and director of the NIHR/MRC EME Programme. Dr Singer reported receiving grants from DSTL and personal fees from AOP Health, Aptarian, deePull, Pfizer, Roche, and Safeguard; serving as chair of the NewB DMSC and on the advisory board of Biotest and Deltex Medical. Dr Lord reported receiving grants from NIHR. Dr Yeung reported being the director of the UK Perioperative Clinical Trials Network and a member of the NIHR Health Technology Assessment General Committee and receiving grant funding from the NIHR. Dr Hill reported receiving grants from the University of Warwick. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow of Patients in the STRESS-L Trial
aA Child-Pugh score of 7 or more was excluded because of the risk of inappropriate inclusion in the study. bOne patient was randomized in error because their heart rate was 84/min at the point of randomization. However, the patient remained in the trial on an intention-to-treat basis, and their routine data were collected. cOnly 1 patient was recruited who had COVID-19. dNine patients (7.1%) withdrew from treatment but remained in the follow-up. Of these, 8 were withdrawn by the clinician and 1 by their personal legal representative.
Figure 2.
Figure 2.. The Sequential Organ Failure Assessment Scores
The median number of days from which the mean Sequential Organ Failure Assessment (SOFA) score was calculated from randomization was 11 days (IQR, 5-14) for the standard care group and 7 days (IQR, 3-14) for the landiolol group. The horizontal black lines represent the median; box ends, IQR; the upper and lower whiskers, Q3+1.5 × IQR and Q1+1.5 × IQR, respectively; open circles, the mean of the SOFA score; and the filled circles, outliers.
Figure 3.
Figure 3.. Mean Arterial Pressure and Heart Rate
A statistically significant difference in the mean arterial pressure was noted between the interventions at day 2 (mean difference [MD], −4.53 [95% CI, −7.69 to −1.36]; P = .005). Statistically significant differences in the heart rate between the interventions was noted at day 1 (MD, −8.66 [95% CI, −13.20 to −4.12]; P < .001) and day 4 (MD, −8.68 [95% CI, −14.73 to 2.62]; P = .003). The horizontal black lines represent the median; box, IQR; the upper and lower whiskers, Q3+1.5 × IQR and Q1+1.5 × IQR, respectively; open circles, the mean; and the filled circles, outliers.
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Comment in

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