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IntroductionThe optimal method for removing the endotracheal tube (ETT) during extubation in the intensive care unit (ICU) remains uncertain. Two methods are described for removing the ETT in ICU, namely the ‘Traditional technique’ with continuous aspiration during cuff deflation and ETT removal; and the ‘PEEP’ method, which consists in applying positive end-expiratory pressure (PEEP) before and during cuff deflation and ETT removal. Our hypothesis is that applying PEEP during extubation in the ICU would improve clinical outcome.Methods and analysisThis is a prospective, multicentre, randomised, open-label, controlled, superiority trial, analysed by intention-to-treat, comparing ETT removal with concomitant suction vs application of PEEP before and during ETT removal. In total, 424 patients will be recruited and randomly assigned in a 1:1 ratio to one of two groups, according to the strategy of ETT removal. The primary outcome is the number of days free from any mechanical ventilation within 28 days following extubation. Secondary outcomes include the reintubation rate up to 7 days after ETT removal, the cumulative duration of non-invasive ventilation up to 7 days following extubation, the rate of acute respiratory failure, the rate of acquired pneumonia during the first 7 days following ETT removal, the length of stay in ICU and in hospital and all-cause mortality at 28 days following ETT removal.Ethics and disseminationThe study was approved by the Ethics Committee ‘CPP Ile de France II’. Patients will be included after providing written informed consent. The results will be submitted for publication in peer-reviewed journals, and in national and international congresses.Trial registration numberNCT05147636.

Background The Artificial Kidney Initiation in Kidney Injury (AKIKI) trial showed that a delayed renal replacement therapy (RRT) strategy for severe acute kidney injury (AKI) in critically ill patients was safe and associated with major reduction in RRT initiation compared with an early strategy. The five criteria which mandated RRT initiation in the delayed arm were: severe hyperkalemia, severe acidosis, acute pulmonary edema due to fluid overload resulting in severe hypoxemia, serum urea concentration > 40 mmol/l and oliguria/anuria > 72 h. However, duration of anuria/oliguria and level of blood urea are still criteria open to debate. The objective of the study is to compare the delayed strategy used in AKIKI (now termed “standard”) with another in which RRT is further delayed for a longer period (termed “delayed strategy”). Methods/design This is a prospective, multicenter, open-label, two-arm randomized trial. The study is composed of two stages (observational and randomization stages). At any time, the occurrence of a potentially severe condition (severe hyperkalemia, severe metabolic or mixed acidosis, acute pulmonary edema due to fluid overload resulting in severe hypoxemia) suggests immediate RRT initiation. Patients receiving (or who have received) intravenously administered catecholamines and/or invasive mechanical ventilation and presenting with AKI stage 3 of the KDIGO classification and with no potentially severe condition are included in the observational stage. Patients presenting a serum urea concentration > 40 mmol/l and/or an oliguria/anuria for more than 72 h are randomly allocated to a standard (RRT is initiated within 12 h) or a delayed RRT strategy (RRT is initiated only if an above-mentioned potentially severe condition occurs or if the serum urea concentration reaches 50 mmol/l). The primary outcome will be the number of RRT-free days at day 28. One interim analysis is planned. It is expected to include 810 patients in the observational stage and to randomize 270 subjects. Discussion The AKIKI2 study should improve the knowledge of RRT initiation criteria in critically ill patients. The potential reduction in RRT use allowed by a delayed RRT strategy might be associated with less invasive care and decreased costs. Enrollment is ongoing. Inclusions are expected to be completed by November 2019. Trial registration ClinicalTrials.gov, ID: NCT03396757 . Registered on 11 January 2018.

PurposeThe effect of renal replacement therapy (RRT) in comatose patients with acute kidney injury (AKI) remains unclear. We compared two RRT initiation strategies on the probability of awakening in comatose patients with severe AKI.MethodsWe conducted a post hoc analysis of a trial comparing two delayed RRT initiation strategies in patients with severe AKI. Patients were monitored until they had oliguria for more than 72 h and/or blood urea nitrogen higher than 112 mg/dL and then randomized to a delayed strategy (RRT initiated after randomization) or a more-delayed one (RRT initiated if complication occurred or when blood urea nitrogen exceeded 140 mg/dL). We included only comatose patients (Richmond Agitation-Sedation scale [RASS] < − 3), irrespective of sedation, at randomization. A multi-state model was built, defining five mutually exclusive states: death, coma (RASS < − 3), incomplete awakening (RASS [− 3; − 2]), awakening (RASS [− 1; + 1] two consecutive days), and agitation (RASS >  + 1). Primary outcome was the transition from coma to awakening during 28 days after randomization.ResultsA total of 168 comatose patients (90 delayed and 78 more-delayed) underwent randomization. The transition intensity from coma to awakening was lower in the more-delayed group (hazard ratio [HR] = 0.36 [0.17–0.78]; p = 0.010). Time spent awake was 10.11 days [8.11–12.15] and 7.63 days [5.57–9.64] in the delayed and the more-delayed groups, respectively. Two sensitivity analyses were performed based on sedation status and sedation practices across centers, yielding comparable results.ConclusionIn comatose patients with severe AKI, a more-delayed RRT initiation strategy resulted in a lower chance of transitioning from coma to awakening.

IntroductionCorticosteroids affect variably survival in sepsis trials, suggesting heterogeneity in patients’ response to corticosteroids. The RECORDS (Rapid rEcognition of COrticosteRoiD resistant or sensitive Sepsis) trial aimed at defining endotypes associated with adults with sepsis responsiveness to corticosteroids.Methods and analysisRECORDS, a multicentre, placebo-controlled, biomarker-guided, adaptive Bayesian design basket trial, will randomly assign to a biomarker stratum 1800 adults with community-acquired pneumonia, vasopressor-dependent sepsis, septic shock or acute respiratory distress syndrome. In each stratum, patients will be randomly assigned to receive a 7-day course of hydrocortisone and fludrocortisone or their placebos. Patients with COVID-19 will be treated with a 10-day standard course of dexamethasone and randomised to fludrocortisone or its placebo. Primary outcome will be 90-day death or persistent organ dysfunction. Large simulation study will be performed across a range of plausible scenarios to foresee power to detect a 5%–10% absolute difference with corticosteroids. We will assess subset-by-treatment interaction by estimating in a Bayesian framework two quantities: (1) measure of influence, relying on the value of the estimation of corticosteroids’ effect in each subset, and (2) measure of interaction.Ethics and disseminationThe protocol was approved by the Ethics Committee (Comité de Protection des Personnes, Dijon, France), on 6 April 2020. Trial results will be disseminated at scientific conferences and results will be published in peer-reviewed journals.Trial registration numberClinicalTrials.gov Registry (NCT04280497).

BACKGROUND: Delaying renal replacement therapy (RRT) for some time in critically ill patients with severe acute kidney injury and no severe complication is safe and allows optimisation of the use of medical devices. Major uncertainty remains concerning the duration for which RRT can be postponed without risk. Our aim was to test the hypothesis that a more-delayed initiation strategy would result in more RRT-free days, compared with a delayed strategy. METHODS: This was an unmasked, multicentre, prospective, open-label, randomised, controlled trial done in 39 intensive care units in France. We monitored critically ill patients with severe acute kidney injury (defined as Kidney Disease: Improving Global Outcomes stage 3) until they had oliguria for more than 72 h or a blood urea nitrogen concentration higher than 112 mg/dL. Patients were then randomly assigned (1:1) to either a strategy (delayed strategy) in which RRT was started just after randomisation or to a more-delayed strategy. With the more-delayed strategy, RRT initiation was postponed until mandatory indication (noticeable hyperkalaemia or metabolic acidosis or pulmonary oedema) or until blood urea nitrogen concentration reached 140 mg/dL. The primary outcome was the number of days alive and free of RRT between randomisation and day 28 and was done in the intention-to-treat population. The study is registered with ClinicalTrial.gov, NCT03396757 and is completed. FINDINGS: Between May 7, 2018, and Oct 11, 2019, of 5336 patients assessed, 278 patients underwent randomisation; 137 were assigned to the delayed strategy and 141 to the more-delayed strategy. The number of complications potentially related to acute kidney injury or to RRT were similar between groups. The median number of RRT-free days was 12 days (IQR 0-25) in the delayed strategy and 10 days (IQR 0-24) in the more-delayed strategy (p=0·93). In a multivariable analysis, the hazard ratio for death at 60 days was 1·65 (95% CI 1·09-2·50, p=0·018) with the more-delayed versus the delayed strategy. The number of complications potentially related to acute kidney injury or renal replacement therapy did not differ between groups. INTERPRETATION: In severe acute kidney injury patients with oliguria for more than 72 h or blood urea nitrogen concentration higher than 112 mg/dL and no severe complication that would mandate immediate RRT, longer postponing of RRT initiation did not confer additional benefit and was associated with potential harm. FUNDING: Programme Hospitalier de Recherche Clinique.