Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Treatments for intracranial hypertension in acute brain-injured patients: grading, timing, and association with outcome. Data from the SYNAPSE-ICU study

Purpose: Uncertainties remain about the safety and efficacy of therapies for managing intracranial hypertension in acute brain injured (ABI) patients. This study aims to describe the therapeutical approaches used in ABI, with/without intracranial pressure (ICP) monitoring, among different pathologies and across different countries, and their association with six months mortality and neurological outcome. Methods: A preplanned subanalysis of the SYNAPSE-ICU study, a multicentre, prospective, international, observational cohort study, describing the ICP treatment, graded according to Therapy Intensity Level (TIL) scale, in patients with ABI during the first week of intensive care unit (ICU) admission. Results: 2320 patients were included in the analysis. The median age was 55 (I-III quartiles = 39-69) years, and 800 (34.5%) were female. During the first week from ICU admission, no-basic TIL was used in 382 (16.5%) patients, mild-moderate in 1643 (70.8%), and extreme in 295 cases (eTIL, 12.7%). Patients who received eTIL were younger (median age 49 (I-III quartiles = 35-62) vs 56 (40-69) years, p < 0.001), with less cardiovascular pre-injury comorbidities (859 (44%) vs 90 (31.4%), p < 0.001), with more episodes of neuroworsening (160 (56.1%) vs 653 (33.3%), p < 0.001), and were more frequently monitored with an ICP device (221 (74.9%) vs 1037 (51.2%), p < 0.001). Considerable variability in the frequency of use and type of eTIL adopted was observed between centres and countries. At six months, patients who received no-basic TIL had an increased risk of mortality (Hazard ratio, HR = 1.612, 95% Confidence Interval, CI = 1.243-2.091, p < 0.001) compared to patients who received eTIL. No difference was observed when comparing mild-moderate TIL with eTIL (HR = 1.017, 95% CI = 0.823-1.257, p = 0.873). No significant association between the use of TIL and neurological outcome was observed. Conclusions: During the first week of ICU admission, therapies to control high ICP are frequently used, especially mild-moderate TIL. In selected patients, the use of aggressive strategies can have a beneficial effect on six months mortality but not on neurological outcome