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Abstract Background Stress hyperglycemia can persist during an intensive care unit (ICU) stay and result in prolonged requirement for insulin (PRI). The impact of PRI on ICU patient outcomes is not known. We evaluated the relationship between PRI and Day 90 mortality in ICU patients without previous diabetic treatments. Methods This is a post hoc analysis of the CONTROLING trial, involving 12 French ICUs. Patients in the personalized glucose control arm with an ICU length of stay ≥ 5 days and who had never previously received diabetic treatments (oral drugs or insulin) were included. Personalized blood glucose targets were estimated on their preadmission usual glycemia as estimated by their glycated A1c hemoglobin (HbA1C). PRI was defined by insulin requirement. The relationship between PRI on Day 5 and 90-day mortality was assessed by Cox survival models with inverse probability of treatment weighting (IPTW). Glycemic control was defined as at least one blood glucose value below the blood glucose target value on Day 5. Results A total of 476 patients were included, of whom 62.4% were male, with a median age of 66 (54–76) years. Median values for SAPS II and HbA1C were 50 (37.5–64) and 5.7 (5.4–6.1)%, respectively. PRI was observed in 364/476 (72.5%) patients on Day 5. 90-day mortality was 23.1% in the whole cohort, 25.3% in the PRI group and 16.1% in the non-PRI group (p

Abstract Background Acute respiratory distress syndrome (ARDS) is a severe complication of COVID-19 pneumonia, with a mortality rate amounting to 34–50% in moderate and severe ARDS, and is associated with prolonged duration of invasive mechanical ventilation. Such as in non-COVID ARDS, harmful mechanical ventilation settings might be associated with worse outcomes. Reducing the tidal volume down to 4 mL kg−1 of predicted body weight (PBW) to provide ultra-low tidal volume ventilation (ULTV) is an appealing technique to minimize ventilator-inducted lung injury. Furthermore, in the context of a worldwide pandemic, it does not require any additional material and consumables and may be applied in low- to middle-income countries. We hypothesized that ULTV without extracorporeal circulation is a credible option to reduce COVID-19-related ARDS mortality and duration of mechanical ventilation. Methods The VT4COVID study is a randomized, multi-centric prospective open-labeled, controlled superiority trial. Adult patients admitted in the intensive care unit with COVID-19-related mild to severe ARDS defined by a PaO2/FiO2 ratio ≤ 150 mmHg under invasive mechanical ventilation for less than 48 h, and consent to participate to the study will be eligible. Patients will be randomized into two balanced parallels groups, at a 1:1 ratio. The control group will be ventilated with protective ventilation settings (tidal volume 6 mL kg−1 PBW), and the intervention group will be ventilated with ULTV (tidal volume 4 mL kg−1 PBW). The primary outcome is a composite score based on 90-day all-cause mortality as a prioritized criterion and the number of ventilator-free days at day 60 after inclusion. The randomization list will be stratified by site of recruitment and generated using random blocks of sizes 4 and 6. Data will be analyzed using intention-to-treat principles. Discussion The purpose of this manuscript is to provide primary publication of study protocol to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. Enrollment of patients in the study is ongoing. Trial registration ClinicalTrials.gov NCT04349618 . Registered on April 16, 2020

Abstract Background Acute respiratory failure is the leading reason for intensive care unit (ICU) admission in immunocompromised patients, and the need for invasive mechanical ventilation has become a major clinical endpoint in randomized controlled trials (RCTs). However, data are lacking on whether intubation is an objective criteria that is used unbiasedly across centers. This study explores how this outcome varies across ICUs. Methods Hierarchical models and permutation procedures for testing multiple random effects were applied on both data from an observational cohort (the TRIAL-OH study: 703 patients, 17 ICUs) and a randomized controlled trial (the HIGH trial: 776 patients, 31 ICUs) to characterize ICU variation in intubation risk across centers. Results The crude intubation rate varied across ICUs from 29 to 80% in the observational cohort and from 0 to 86% in the RCT. This center effect on the mean ICU intubation rate was statistically significant, even after adjustment on individual patient characteristics (observational cohort: p value = 0.013, median OR 1.48 [1.30–1.72]; RCT: p value 0.004, median OR 1.51 [1.36–1.68]). Two ICU-level characteristics were associated with intubation risk (the annual rate of intubation procedure per center and the time from respiratory symptoms to ICU admission) and could partly explain this center effect. In the RCT that controlled for the use of high-flow oxygen therapy, we did not find significant variation in the effect of oxygenation strategy on intubation risk across centers, despite a significant variation in the need for invasive mechanical ventilation. Conclusion Intubation rates varied considerably among ICUs, even after adjustment on individual characteristics.

Abstract Background Acute respiratory failure (ARF) is the leading reason for intensive care unit (ICU) admission in immunocompromised patients. High-flow nasal oxygen (HFNO) therapy is an alternative to standard oxygen. By providing warmed and humidified gas, HFNO allows the delivery of higher flow rates via nasal cannula devices, with FiO2 values of nearly 100%. Benefits include alleviation of dyspnea and discomfort, decreased respiratory distress and decreased mortality in unselected patients with acute hypoxemic respiratory failure. However, in preliminary reports, HFNO benefits are controversial in immunocompromised patients in whom it has never been properly evaluated. Methods/design This is a multicenter, open-label, randomized controlled superiority trial in 30 intensive care units, part of the Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique (GRRR-OH). Inclusion criteria will be: (1) adults, (2) known immunosuppression, (3) ARF, (4) oxygen therapy ≥ 6 L/min, (5) written informed consent from patient or proxy. Exclusion criteria will be: (1) imminent death (moribund patient), (2) no informed consent, (3) hypercapnia (PaCO2 ≥ 50 mmHg), (4) isolated cardiogenic pulmonary edema, (5) pregnancy or breastfeeding, (6) anatomical factors precluding insertion of a nasal cannula, (7) no coverage by the French statutory healthcare insurance system, and (8) post-surgical setting from day 1 to day 6 (patients with ARF occurring after day 6 of surgery can be included). The primary outcome measure is day-28 mortality. Secondary outcomes are intubation rate, comfort, dyspnea, respiratory rate, oxygenation, ICU length of stay, and ICU-acquired infections. Based on an expected 30% mortality rate in the standard oxygen group, and 20% in the HFNO group, error rate set at 5%, and a statistical power at 90%, 389 patients are required in each treatment group (778 patients overall). Recruitment period is estimated at 30 months, with 28 days of additional follow-up for the last included patient. Discussion The HIGH study will be the largest multicenter, randomized controlled trial seeking to demonstrate that survival benefits from HFNO reported in unselected patients also apply to a large immunocompromised population. Trial registration ClinicalTrials.gov, ID: NCT02739451. Registered on 15 April 2016.