Emmanuel Charbonney

OBJECTIVES: Research examining informed consent in critical care studies is limited. The objective of this study was to describe the patterns and predictors of consent. DESIGN: Research coordinators prospectively documented each consent encounter including consent model (a priori or deferred, also known as consent to continue), who requested consent (research coordinator, site investigator, and ICU physician), who provided or declined consent (patient, substitute decision-maker [SDM], and other), the method to obtain consent (in-person or via telephone), and reasons for consent decline, if applicable. Research coordinators retrospectively reported center characteristics. Using multilevel logistic regression, we evaluated the association of consent provision with characteristics of the consent encounter and participating center. SETTING: International randomized trial of stress ulcer prophylaxis for invasively ventilated patients. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Among 5024 patients or SDMs approached for consent, the consent rate was 85.0% (ranging from 27.3% to 100%). In 2638 patients (52.5%), an a priori approach was used, and of these, 696 patients (26.4%) declined. The remaining 2386 participants (47.5%) were enrolled by deferred consent, of whom 58 participants (2.4%) ultimately declined. Among first consent encounters, 80.2% were with SDMs, 19.6% with patients, and 0.2% with others. Higher consent rates were independently associated with the deferred consent model (odds ratio [OR], 16.56; 95% CI, 11.50–23.84), consent encounters involving patients (OR, 2.67; 95% CI, 1.63–4.37), and consent encounters during the COVID-19 pandemic (OR, 2.01; 95% CI, 1.30–3.11) or postpandemic period (OR, 2.26; 95% CI, 1.34–3.80) compared with prepandemic. Consent rates were not associated with center characteristics including ICU size, ICU research experience, or research coordinator experience. CONCLUSIONS: Deferred consent was used as often as a priori consent in this trial. The informed consent rate was associated with the deferred model, consent from patients, and consent encounters during or after the pandemic.

In critically ill patients, acceleration of liberation from mechanical ventilation is important in order to reduce the risk of complications and to improve long-term outcomes. Whether the use of proportional-assist ventilation with load-adjustable gain factors (PAV+) results in a shorter time to successful liberation from mechanical ventilation than pressure-support ventilation (PSV) is unclear. In this international clinical trial, we randomly assigned adult patients who had been receiving mechanical ventilation for at least 24 hours and were able to undergo partial ventilatory support with PSV but were not yet ready for liberation from ventilation to undergo PAV+ (which targeted normal work of breathing) or PSV (which targeted a normal respiratory rate and tidal volume). The primary outcome was the time from randomization to successful liberation from mechanical ventilation. Across 23 centers in seven countries, 722 patients were enrolled, and 573 underwent randomization and were included in the analysis. The median time to successful liberation from mechanical ventilation was 7.3 days (95% confidence interval [CI], 6.2 to 9.7) in the PAV+ group and 6.8 days (95% CI, 5.4 to 8.8) in the PSV group (P = 0.58). The median number of ventilator-free days, the incidence of reintubation and tracheostomy, and the incidence of death by day 90 (29.6% in the PAV+ group and 26.6% in the PSV group), all of which were secondary outcomes, were similar in the two groups. With respect to sedative drugs, the mean (±SD) difference in the midazolam-equivalent dose at day 28 relative to the baseline dose was -1.51±3.28 mg per kilogram of body weight in the PAV+ group and 0.04±0.97 mg per kilogram in the PSV group. Serious adverse events occurred in 31 patients (10.8%) in the PAV+ group and in 28 patients (9.8%) in the PSV group (P = 0.79). The time to liberation from mechanical ventilation did not differ significantly between the group that underwent PAV+ and the group that underwent PSV. (Funded by the Canadian Institutes of Health Research and others; PROMIZING ClinicalTrials.gov number, NCT02447692.).

The effect of a liberal transfusion strategy as compared with a restrictive strategy on outcomes in critically ill patients with traumatic brain injury is unclear. We randomly assigned adults with moderate or severe traumatic brain injury and anemia to receive transfusion of red cells according to a liberal strategy (transfusions initiated at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (transfusions initiated at ≤7 g per deciliter). The primary outcome was an unfavorable outcome as assessed by the score on the Glasgow Outcome Scale-Extended at 6 months, which we categorized with the use of a sliding dichotomy that was based on the prognosis of each patient at baseline. Secondary outcomes included mortality, functional independence, quality of life, and depression at 6 months. A total of 742 patients underwent randomization, with 371 assigned to each group. The analysis of the primary outcome included 722 patients. The median hemoglobin level in the intensive care unit was 10.8 g per deciliter in the group assigned to the liberal strategy and 8.8 g per deciliter in the group assigned to the restrictive strategy. An unfavorable outcome occurred in 249 of 364 patients (68.4%) in the liberal-strategy group and in 263 of 358 (73.5%) in the restrictive-strategy group (adjusted absolute difference, restrictive strategy vs. liberal strategy, 5.4 percentage points; 95% confidence interval, -2.9 to 13.7). Among survivors, a liberal strategy was associated with higher scores on some but not all the scales assessing functional independence and quality of life. No association was observed between the transfusion strategy and mortality or depression. Venous thromboembolic events occurred in 8.4% of the patients in each group, and acute respiratory distress syndrome occurred in 3.3% and 0.8% of patients in the liberal-strategy and restrictive-strategy groups, respectively. In critically ill patients with traumatic brain injury and anemia, a liberal transfusion strategy did not reduce the risk of an unfavorable neurologic outcome at 6 months. (Funded by the Canadian Institutes of Health Research and others; HEMOTION ClinicalTrials.gov number, NCT03260478.).

Whether proton-pump inhibitors are beneficial or harmful for stress ulcer prophylaxis in critically ill patients undergoing invasive ventilation is unclear. In this international, randomized trial, we assigned critically ill adults who were undergoing invasive ventilation to receive intravenous pantoprazole (at a dose of 40 mg daily) or matching placebo. The primary efficacy outcome was clinically important upper gastrointestinal bleeding in the intensive care unit (ICU) at 90 days, and the primary safety outcome was death from any cause at 90 days. Multiplicity-adjusted key secondary outcomes were ventilator-associated pneumonia, Clostridioides difficile infection, and patient-important bleeding. A total of 4821 patients underwent randomization in 68 ICUs. Clinically important upper gastrointestinal bleeding occurred in 25 of 2385 patients (1.0%) receiving pantoprazole and in 84 of 2377 patients (3.5%) receiving placebo (hazard ratio, 0.30; 95% confidence interval [CI], 0.19 to 0.47; P<0.001). At 90 days, death was reported in 696 of 2390 patients (29.1%) in the pantoprazole group and in 734 of 2379 patients (30.9%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.85 to 1.04; P = 0.25). Patient-important bleeding was reduced with pantoprazole; all other key secondary outcomes were similar in the two groups. Among patients undergoing invasive ventilation, pantoprazole resulted in a significantly lower risk of clinically important upper gastrointestinal bleeding than placebo, with no significant effect on mortality. (Funded by the Canadian Institutes of Health Research and others; REVISE ClinicalTrials.gov number, NCT03374800.).

OBJECTIVES: The objective of this review was to depict the physiological and clinical rationale for the use of vasopressin in hemodynamic support of organ donors. After summarizing the physiological, pharmacological concepts and preclinical findings, regarding vasopressin’s pathophysiological impacts, we will present the available clinical data. DATA SOURCES: Detailed search strategies in PubMed, OVID Medline, and EMBASE were undertaken using Medical Subject Headings and Key Words. STUDY SELECTION: Physiological articles regarding brain death, and preclinical animal and human studies about the use of vasopressin or analogs, as an intervention in organ support for donation, were considered. DATA EXTRACTION: Two authors independently screened titles, abstracts, and full text of articles to determine eligibility. Data encompassing models, population, methodology, outcomes, and relevant concepts were extracted. DATA SYNTHESIS: Following brain death, profound reduction in sympathetic outflow is associated with reduced cardiac output, vascular tone, and hemodynamic instability in donors. In addition to reducing catecholamine needs and reversing diabetes insipidus, vasopressin has been shown to limit pulmonary injury and decrease systemic inflammatory response in animals. Several observational studies show the benefit of vasopressin on hemodynamic parameters and catecholamine sparing in donors. Small trials suggest that vasopressin increase organ procurement and have some survival benefit for recipients. However, the risk of bias is overall concerning, and therefore the quality of the evidence is deemed low. CONCLUSIONS: Despite potential impact on graft outcome and a protective effect through catecholamine support sparing, the benefit of vasopressin use in organ donors is based on low evidence. Well-designed observational and randomized controlled trials are warranted.

Background: Proportional assist ventilation with load-adjustable gain factors (PAV+) is a mechanical ventilation mode that delivers assistance to breathe in proportion to the patient’s effort. The proportional assistance, called the gain, can be adjusted by the clinician to maintain the patient’s respiratory effort or workload within a normal range. Short-term and physiological benefits of this mode compared to pressure support ventilation (PSV) include better patient-ventilator synchrony and a more physiological response to changes in ventilatory demand. Methods: The objective of this multi-centre randomized controlled trial (RCT) is to determine if, for patients with acute respiratory failure, ventilation with PAV+ will result in a shorter time to successful extubation than with PSV. This multi-centre open-label clinical trial plans to involve approximately 20 sites in several continents. Once eligibility is determined, patients must tolerate a short-term PSV trial and either (1) not meet general weaning criteria or (2) fail a 2-min Zero Continuous Positive Airway Pressure (CPAP) Trial using the rapid shallow breathing index, or (3) fail a spontaneous breathing trial (SBT), in this sequence. Then, participants in this study will be randomized to either PSV or PAV+ in a 1:1 ratio. PAV+ will be set according to a target of muscular pressure. The weaning process will be identical in the two arms. Time to liberation will be the primary outcome; ventilator-free days and other outcomes will be measured. Discussion: Meta-analyses comparing PAV+ to PSV suggest PAV+ may benefit patients and decrease healthcare costs but no powered study to date has targeted the difficult to wean patient population most likely to benefit from the intervention, or used consistent timing for the implementation of PAV+. Our enrolment strategy, primary outcome measure, and liberation approaches may be useful for studying mechanical ventilation and weaning and can offer important results for patients. Trial registration: ClinicalTrials.gov NCT02447692. Prospectively registered on May 19, 2015.

Background: The importance of investigating sex- and gender-dependent differences has been recently emphasized by major funding agencies. Notably, the influence of biological sex on clinical outcomes in sepsis is unclear, and observational studies suffer from the effect of confounding factors. The controlled experimental environment afforded by preclinical studies allows for clarification and mechanistic evaluation of sex-dependent differences. We propose a systematic review to assess the impact of biological sex on baseline responses to disease induction as well as treatment responses in animal models of sepsis. Given the lack of guidance surrounding sex-based analyses in preclinical systematic reviews, careful consideration of various factors is needed to understand how best to conduct analyses and communicate findings. Methods: MEDLINE and Embase will be searched (2011-present) to identify preclinical studies of sepsis in which any intervention was administered and sex-stratified data reported. The primary outcome will be mortality. Secondary outcomes will include organ dysfunction, bacterial load, and IL-6 levels. Study selection will be conducted independently and in duplicate by two reviewers. Data extraction will be conducted by one reviewer and audited by a second independent reviewer. Data extracted from included studies will be pooled, and meta-analysis will be conducted using random effects modeling. Primary analyses will be stratified by animal age and will assess the impact of sex at the following time points: pre-intervention, in response to treatment, and post-intervention. Risk of bias will be assessed using the SYRCLE’s risk-of-bias tool. Illustrative examples of potential methods to analyze sex-based differences are provided in this protocol. Discussion: Our systematic review will summarize the current state of knowledge on sex-dependent differences in sepsis. This will identify current knowledge gaps that future studies can address. Finally, this review will provide a framework for sex-based analysis in future preclinical systematic reviews. Systematic review registration: PROSPERO CRD42022367726.

Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction.

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