Protocol and statistical analysis plan for the Antibiotic Choice On ReNal outcomes (ACORN) randomised clinical trial.

INTRODUCTION: Antibiotics are time-critical in the management of sepsis. When infectious organisms are unknown, patients are treated with empiric antibiotics to include coverage for gram-negative organisms, such as antipseudomonal cephalosporins and penicillins. However, in observational studies, some antipseudomonal cephalosporins (eg, cefepime) are associated with neurologic dysfunction while the most common antipseudomonal penicillin (piperacillin-tazobactam) is associated with acute kidney injury (AKI). No randomised control trials have compared these regimens. This manuscript describes the protocol and analysis plan for a trial designed to compare the effects of antipseudomonal cephalosporins and antipseudomonal penicillins among acutely ill patients receiving empiric antibiotics. METHODS AND ANALYSIS: The Antibiotic Choice On ReNal outcomes trial is a prospective, single-centre, non-blinded randomised trial being conducted at Vanderbilt University Medical Center. The trial will enrol 2500 acutely ill adults receiving gram-negative coverage for treatment of infection. Eligible patients are randomised 1:1 to receive cefepime or piperacillin-tazobactam on first order entry of a broad-spectrum antibiotic covering gram-negative organisms. The primary outcome is the highest stage of AKI and death occurring between enrolment and 14 days after enrolment. This will be compared between patients randomised to cefepime and randomised to piperacillin-tazobactam using an unadjusted proportional odds regression model. The secondary outcomes are major adverse kidney events through day 14 and number of days alive and free of delirium and coma in 14 days after enrolment. Enrolment began on 10 November 2021 and is expected to be completed in December 2022. ETHICS AND DISSEMINATION: The trial was approved by the Vanderbilt University Medical Center institutional review board (IRB#210591) with a waiver of informed consent. Results will be submitted to a peer-reviewed journal and presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT05094154.

Assessment of Awake Prone Positioning in Hospitalized Adults With COVID-19: A Nonrandomized Controlled Trial.

Importance: Awake prone positioning may improve hypoxemia among patients with COVID-19, but whether it is associated with improved clinical outcomes remains unknown. Objective: To determine whether the recommendation of awake prone positioning is associated with improved outcomes among patients with COVID-19-related hypoxemia who have not received mechanical ventilation. Design, Setting, and Participants: This pragmatic nonrandomized controlled trial was conducted at 2 academic medical centers (Vanderbilt University Medical Center and NorthShore University HealthSystem) during the COVID-19 pandemic. A total of 501 adult patients with COVID-19-associated hypoxemia who had not received mechanical ventilation were enrolled from May 13 to December 11, 2020. Interventions: Patients were assigned 1:1 to receive either the practitioner-recommended awake prone positioning intervention (intervention group) or usual care (usual care group). Main Outcomes and Measures: Primary outcome analyses were performed using a bayesian proportional odds model with covariate adjustment for clinical severity ranking based on the World Health Organization ordinal outcome scale, which was modified to highlight the worst level of hypoxemia on study day 5. Results: A total of 501 patients (mean [SD] age, 61.0 [15.3] years; 284 [56.7%] were male; and most [417 (83.2%)] were self-reported non-Hispanic or non-Latinx) were included. Baseline severity was comparable between the intervention vs usual care groups, with 170 patients (65.9%) vs 162 patients (66.7%) receiving oxygen via standard low-flow nasal cannula, 71 patients (27.5%) vs 62 patients (25.5%) receiving oxygen via high-flow nasal cannula, and 16 patients (6.2%) vs 19 patients (7.8%) receiving noninvasive positive-pressure ventilation. Nursing observations estimated that patients in the intervention group spent a median of 4.2 hours (IQR, 1.8-6.7 hours) in the prone position per day compared with 0 hours (IQR, 0-0.7 hours) per day in the usual care group. On study day 5, the bayesian posterior probability of the intervention group having worse outcomes than the usual care group on the modified World Health Organization ordinal outcome scale was 0.998 (posterior median adjusted odds ratio [aOR], 1.63; 95% credibility interval [CrI], 1.16-2.31). However, on study days 14 and 28, the posterior probabilities of harm were 0.874 (aOR, 1.29; 95% CrI, 0.84-1.99) and 0.673 (aOR, 1.12; 95% CrI, 0.67-1.86), respectively. Exploratory outcomes (progression to mechanical ventilation, length of stay, and 28-day mortality) did not differ between groups. Conclusions and Relevance: In this nonrandomized controlled trial, prone positioning offered no observed clinical benefit among patients with COVID-19-associated hypoxemia who had not received mechanical ventilation. Moreover, there was substantial evidence of worsened clinical outcomes at study day 5 among patients recommended to receive the awake prone positioning intervention, suggesting potential harm. Trial Registration: ClinicalTrials.gov Identifier: NCT04359797.