Ziortza Fernández de Pinedo Artaraz

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.

PURPOSE: The landiolol and organ failure in patients with septic shock (STRESS-L study) included a pre-planned sub-study to assess the effect of landiolol treatment on inflammatory and metabolomic markers. METHODS: Samples collected from 91 patients randomised to STRESS-L were profiled for immune and metabolomic markers. A panel of pro- and anti-inflammatory cytokines were measured through commercially acquired multiplex Luminex assays and statistically analysed by individual and cluster-level analysis (patient). Metabolite fingerprinting was carried out by flow infusion electrospray ionisation high-resolution mass spectrometry and metabolomic data were analysed using the R-based platform MetaboAnalyst. The metabolites were identified using DIMEdb (dimedb.ibers.aber.ac.uk) from their mass/charge ratios. These metabolomic data were also re-analysed using individual and cluster-level analysis. The individual-level models were adjusted for confounders, such as age, sex, noradrenaline dosage and patient (random effect). RESULTS: Analysis was undertaken at cluster- and individual-level. There were no significant differences in cytokine concentration level between trial arms nor survivors and non-survivors over the duration of the observations from day 1 to day 4. Metabolomic analysis showed some separation in the levels of ceramides and cardiolipins between those who survived and those who died. Following adjusted analysis for confounders, plasma metabolite concentrations remained statistically different between landiolol and standard care arms for succinic acid, L-tryptophan, L-alanine, 2,2,2-trichloroethanol, lactic acid and D-glucose. CONCLUSIONS: In a study of ICU patients with established septic shock and a tachycardia, landiolol treatment used to reduce the heart rate from above 95 to a range between 80 and 94 beats per minute did not induce significant cytokine changes. D-Glucose, lactic acid, succinic acid, L-alanine, L-tryptophan and trichloroethanol were pathways that may merit further investigation. TRIAL REGISTRATION: EU Clinical Trials Register Eudra CT: 2017-001785-14 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001785-14/GB ); ISRCTN registry Identifier: ISRCTN12600919 ( https://www.isrctn.com/ISRCTN12600919 ).

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a clinically defined, biologically heterogeneous condition with no proven disease-modifying therapies. Retrospective analyses have identified two biologically distinct subphenotypes (hyperinflammatory and hypoinflammatory) of ARDS, with differing outcomes and responses to therapy. Rapid identification of these subphenotypes in an actionable timeframe has previously not been possible. The PHIND study aimed to prospectively identify these subphenotypes and to demonstrate differing 60-day mortality. METHODS: The PHIND study was a prospective, multicentre, observational cohort study conducted in intensive care units (ICUs) within the National Health Service in the UK and the Health Service Executive in Ireland. Adult patients aged 18 years and older with ARDS or acute hypoxaemic respiratory failure (AHRF) were enrolled within 72 h of onset of the syndrome. Eligible patients were required to be receiving invasive mechanical ventilation, non-invasive ventilation, or high-flow nasal oxygen. Plasma interleukin (IL-6) and soluble TNF receptor-1 (TNFR1) were quantified at enrolment using a near-patient benchtop immunoanalyser (Randox multiSTAT) with a run time of approximately 1 h. Together with plasma bicarbonate measured from an arterial blood sample, these values were used to prospectively determine subphenotypes on an individual patient basis using a validated parsimonious logistic regression model. The primary outcome was 60-day mortality. The study was registered on ClinicalTrials.gov, NCT04009330. FINDINGS: Between Nov 22, 2019, and Sept 28, 2023, 1853 patients from 30 centres were screened for eligibility. Of these, 1328 were excluded and 525 were recruited into the study, with 512 individuals included. 308 (60%) patients were male, 204 (40%) were female, and mean age was 57·0 years (SD 15·1). 443 (87%) patients were white, 18 (4%) were Black, and 16 (3%) were Asian. 490 were subphenotyped using the near-patient assay: 89 (18%) were classified as hyperinflammatory and 401 (82%) as hypoinflammatory. The primary outcome of 60-day mortality was measured in 486 patients after four patients withdrew consent for confirmation of vital status. 60-day mortality was significantly higher in the hyperinflammatory group (45 [51%] of 88) than in the hypoinflammatory group (111 [28%] of 398; risk ratio 1·8 [95% CI 1·4-2·4], p<0·0001). After adjustment, hyperinflammatory patients had increased odds of 60-day mortality (adjusted odds ratio 2·7 [95% CI 1·6-4·4], p=0·0002). INTERPRETATION: Rapid identification of ARDS inflammatory subphenotypes using a near-patient assay was feasible and associated with many clinical characteristics and outcomes consistent with those described in earlier retrospective studies, including mortality, prevalence of sepsis, and incidence of metabolic acidosis. These findings support the implementation of precision medicine approaches in ARDS and the urgent need for prospective, subphenotype-stratified interventional trials. FUNDING: Innovate UK, Randox Laboratories, and Belfast Health & Social Care Trust.