Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial.

BACKGROUND: Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock. METHODS: APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 µg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209). FINDINGS: Of 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction). INTERPRETATION: In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.

Prone Positioning During Extracorporeal Membrane Oxygenation in Patients With Severe ARDS: The PRONECMO Randomized Clinical Trial.

Importance: Prone positioning may improve outcomes in patients with severe acute respiratory distress syndrome (ARDS), but it is unknown whether prone positioning improves clinical outcomes among patients with ARDS who are undergoing venovenous extracorporeal membrane oxygenation (VV-ECMO) compared with supine positioning. Objective: To test whether prone positioning vs supine positioning decreases the time to successful ECMO weaning in patients with severe ARDS supported by VV-ECMO. Design, Setting, and Participants: Randomized clinical trial of patients with severe ARDS undergoing VV-ECMO for less than 48 hours at 14 intensive care units (ICUs) in France between March 3, 2021, and December 7, 2021. Interventions: Patients were randomized 1:1 to prone positioning (at least 4 sessions of 16 hours) (n = 86) or to supine positioning (n = 84). Main Outcomes and Measures: The primary outcome was time to successful ECMO weaning within 60 days following randomization. Secondary outcomes included ECMO and mechanical ventilation-free days, ICU and hospital length of stay, skin pressure injury, serious adverse events, and all-cause mortality at 90-day follow-up. Results: Among 170 randomized patients (median age, 51 [IQR, 43-59] years; n = 60 women [35%]), median respiratory system compliance was 15.0 (IQR, 10.7-20.6) mL/cm H2O; 159 patients (94%) had COVID-19-related ARDS; and 164 (96%) were in prone position before ECMO initiation. Within 60 days of enrollment, 38 of 86 patients (44%) had successful ECMO weaning in the prone ECMO group compared with 37 of 84 (44%) in the supine ECMO group (risk difference, 0.1% [95% CI, -14.9% to 15.2%]; subdistribution hazard ratio, 1.11 [95% CI, 0.71-1.75]; P = .64). Within 90 days, no significant difference was observed in ECMO duration (28 vs 32 days; difference, -4.9 [95% CI, -11.2 to 1.5] days; P = .13), ICU length of stay, or 90-day mortality (51% vs 48%; risk difference, 2.4% [95% CI, -13.9% to 18.6%]; P = .62). No serious adverse events were reported during the prone position procedure. Conclusions and Relevance: Among patients with severe ARDS supported by VV-ECMO, prone positioning compared with supine positioning did not significantly reduce time to successful weaning of ECMO. Trial Registration: ClinicalTrials.gov Identifier: NCT04607551.

Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia.

BACKGROUND: Whether preventive inhaled antibiotics may reduce the incidence of ventilator-associated pneumonia is unclear. METHODS: In this investigator-initiated, multicenter, double-blind, randomized, controlled, superiority trial, we assigned critically ill adults who had been undergoing invasive mechanical ventilation for at least 72 hours to receive inhaled amikacin at a dose of 20 mg per kilogram of ideal body weight once daily or to receive placebo for 3 days. The primary outcome was a first episode of ventilator-associated pneumonia during 28 days of follow-up. Safety was assessed. RESULTS: A total of 850 patients underwent randomization, and 847 were included in the analyses (417 assigned to the amikacin group and 430 to the placebo group). All three daily nebulizations were received by 337 patients (81%) in the amikacin group and 355 patients (83%) in the placebo group. At 28 days, ventilator-associated pneumonia had developed in 62 patients (15%) in the amikacin group and in 95 patients (22%) in the placebo group (difference in restricted mean survival time to ventilator-associated pneumonia, 1.5 days; 95% confidence interval [CI], 0.6 to 2.5; P = 0.004). An infection-related ventilator-associated complication occurred in 74 patients (18%) in the amikacin group and in 111 patients (26%) in the placebo group (hazard ratio, 0.66; 95% CI, 0.50 to 0.89). Trial-related serious adverse effects were seen in 7 patients (1.7%) in the amikacin group and in 4 patients (0.9%) in the placebo group. CONCLUSIONS: Among patients who had undergone mechanical ventilation for at least 3 days, a subsequent 3-day course of inhaled amikacin reduced the burden of ventilator-associated pneumonia during 28 days of follow-up. (Funded by the French Ministry of Health; AMIKINHAL ClinicalTrials.gov number, NCT03149640; EUDRA Clinical Trials number, 2016-001054-17.).

Prospective evaluation of the efficacy, safety, and optimal biomarker enrichment strategy for nangibotide, a TREM-1 inhibitor, in patients with septic shock (ASTONISH): a double-blind, randomised, controlled, phase 2b trial.

BACKGROUND: Activation of the triggering receptor expressed on myeloid cells-1 (TREM-1) pathway is associated with septic shock outcomes. Data suggest that modulation of this pathway in patients with activated TREM-1 might improve survival. Soluble TREM-1 (sTREM-1), a potential mechanism-based biomarker, might facilitate enrichment of patient selection in clinical trials of nangibotide, a TREM-1 modulator. In this phase 2b trial, we aimed to confirm the hypothesis that TREM1 inhibition might improve outcomes in patients with septic shock. METHODS: This double-blind, randomised, placebo-controlled, phase 2b trial assessed the efficacy and safety of two different doses of nangibotide compared with placebo, and aimed to identify the optimum treatment population, in patients across 42 hospitals with medical, surgical, or mixed intensive care units (ICUs) in seven countries. Non-COVID-19 patients (18-85 years) meeting the standard definition of septic shock, with documented or suspected infection (lung, abdominal, or urinary [in patients ≥65 years]), were eligible within 24 h of vasopressor initiation for the treatment of septic shock. Patients were randomly assigned in a 1:1:1 ratio to intravenous nangibotide 0·3 mg/kg per h (low-dose group), nangibotide 1·0 mg/kg per h (high-dose group), or matched placebo, using a computer-generated block randomisation scheme (block size 3). Patients and investigators were masked to treatment allocation. Patients were grouped according to sTREM-1 concentrations at baseline (established from sepsis observational studies and from phase 2a change to data) into high sTREM-1 (≥ 400 pg/mL). The primary outcome was the mean difference in total Sequential Organ Failure Assessment (SOFA) score from baseline to day 5 in the low-dose and high-dose groups compared with placebo, measured in the predefined high sTREM-1 (≥ 400 pg/mL) population and in the overall modified intention-to-treat population. Secondary endpoints included all-cause 28-day mortality, safety, pharmacokinetics, and evaluation of the relationship between TREM-1 activation and treatment response. This study is registered with EudraCT, 2018-004827-36, and Clinicaltrials.gov, NCT04055909. FINDINGS: Between Nov 14, 2019, and April 11, 2022, of 402 patients screened, 355 were included in the main analysis (116 in the placebo group, 118 in the low-dose group, and 121 in the high-dose group). In the preliminary high sTREM-1 population (total 253 [71%] of 355; placebo 75 [65%] of 116; low-dose 90 [76%] of 118; high-dose 88 [73%] of 121), the mean difference in SOFA score from baseline to day 5 was 0·21 (95% CI -1·45 to 1·87, p=0·80) in the low-dose group and 1·39 (-0·28 to 3·06, p=0·104) in the high-dose group versus placebo. In the overall population, the difference in SOFA score from baseline to day 5 between the placebo group and low-dose group was 0·20 (-1·09 to 1·50; p=0·76),and between the placebo group and the high-dose group was 1·06 (-0·23 to 2·35, p=0·108). In the predefined high sTREM-1 cutoff population, 23 (31%) patients in the placebo group, 35 (39%) in the low-dose group, and 25 (28%) in the high-dose group had died by day 28. In the overall population, 29 (25%) patients in the placebo, 38 (32%) in the low-dose, and 30 (25%) in the high-dose group had died by day 28. The number of treatment-emergent adverse events (111 [96%] patients in the placebo group, 113 [96%] in the low-dose group, and 115 [95%] in the high-dose group) and serious treatment-emergent adverse events (28 [24%], 26 [22%], and 31 [26%]) was similar between all three groups. High-dose nangibotide led to a clinically relevant improvement in SOFA score (of two points or more) from baseline to day 5 over placebo in those with higher cutoff concentrations (≥532 pg/mL) of sTREM-1 at baseline. Low dose nangibotide displayed a similar pattern with lower magnitude of effect across all cutoff values. INTERPRETATION: This trial did not achieve the primary outcome of improvement in SOFA score at the predefined sTREM-1 value. Future studies are needed to confirm the benefit of nangibotide at higher concentrations of TREM-1 activation. FUNDING: Inotrem.

Evaluation of the efficacy and safety of TREM-1 inhibition with nangibotide in patients with COVID-19 receiving respiratory support: the ESSENTIAL randomised, double-blind trial.

Background: Activation of the TREM-1 pathway is associated with outcome in life threatening COVID-19. Data suggest that modulation of this pathway with nangibotide, a TREM-1 modulator may improve survival in TREM-1 activated patients (identified using the biomarker sTREM-1). Methods: Phase 2 double-blind randomized controlled trial assessing efficacy, safety, and optimum treatment population of nangibotide (1.0 mg/kg/h) compared to placebo. Patients aged 18-75 years were eligible within 7 days of SARS-CoV-2 documentation and within 48 h of the onset of invasive or non-invasive respiratory support because of COVID-19-related ARDS. Patients were included from September 2020 to April 2022, with a pause in recruitment between January and August 2021. Primary outcome was the improvement in clinical status defined by a seven-point ordinal scale in the overall population with a planned sensitivity analysis in the subgroup of patients with a sTREM-1 level above the median value at baseline (high sTREM-1 group). Secondary endpoints included safety and all-cause 28-day and day 60 mortality. The study was registered in EudraCT (2020-001504-42) and ClinicalTrials.gov (NCT04429334). Findings: The study was stopped after 220 patients had been recruited. Of them, 219 were included in the mITT analysis. Nangibotide therapy was associated with an improved clinical status at day 28. Fifty-two (52.0%) of patients had improved in the placebo group compared to 77 (64.7%) of the nangibotide treated population, an odds ratio (95% CI) for improvement of 1.79 (1.02-3.14), p = 0.043. In the high sTREM-1 population, 18 (32.7%) of placebo patients had improved by day 28 compared to 26 (48.1%) of treated patients, an odds ratio (95% CI) of 2.17 (0.96-4.90), p = 0.063 was observed. In the overall population, 28 (28.0%) of placebo treated patients were not alive at the day 28 visit compared to 19 (16.0%) of nangibotide treated patients, an absolute improvement (95% CI) in all-cause mortality at day 28, adjusted for baseline clinical status of 12.1% (1.18-23.05). In the high sTREM-1 population (n = 109), 23 (41.8%) of patients in the placebo group and 12 (22.2%) of patients in the nangibotide group were not alive at day 28, an adjusted absolute reduction in mortality of 19.9% (2.78-36.98). The rate of treatment emergent adverse events was similar in both placebo and nangibotide treated patients. Interpretation: Whilst the study was stopped early due to low recruitment rate, the ESSENTIAL study demonstrated that TREM-1 modulation with nangibotide is safe in COVID-19, and results in a consistent pattern of improved clinical status and mortality compared to placebo. The relationship between sTREM-1 and both risk of death and treatment response merits further evaluation of nangibotide using precision medicine approaches in life threatening viral pneumonitis. Funding: The study was sponsored by Inotrem SA.

Rapid rEcognition of COrticosteRoiD resistant or sensitive Sepsis (RECORDS): study protocol for a multicentre, placebo-controlled, biomarker-guided, adaptive Bayesian design basket trial.

INTRODUCTION: Corticosteroids 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 ANALYSIS: RECORDS, 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 DISSEMINATION: The 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 NUMBER: ClinicalTrials.gov Registry (NCT04280497).

Low versus standard calorie and protein feeding in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3).

BACKGROUND: The optimal calorie and protein intakes at the acute phase of severe critical illness remain unknown. We hypothesised that early calorie and protein restriction improved outcomes in these patients, compared with standard calorie and protein targets. METHODS: The pragmatic, randomised, controlled, multicentre, open-label, parallel-group NUTRIREA-3 trial was performed in 61 French intensive care units (ICUs). Adults (≥18 years) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned to early nutrition (started within 24 h after intubation) with either low or standard calorie and protein targets (6 kcal/kg per day and 0·2-0·4 g/kg per day protein vs 25 kcal/kg per day and 1·0-1·3 g/kg per day protein) during the first 7 ICU days. The two primary endpoints were time to readiness for ICU discharge and day 90 all-cause mortality. Key secondary outcomes included secondary infections, gastrointestinal events, and liver dysfunction. The trial is registered on ClinicalTrials.gov, NCT03573739, and is completed. FINDINGS: Of 3044 patients randomly assigned between July 5, 2018, and 8 Dec 8, 2020, eight withdrew consent to participation. By day 90, 628 (41·3%) of 1521 patients in the low group and 648 (42·8%) of 1515 patients in the standard group had died (absolute difference -1·5%, 95% CI -5·0 to 2·0; p=0·41). Median time to readiness for ICU discharge was 8·0 days (IQR 5·0-14·0) in the low group and 9·0 days (5·0-17·0) in the standard group (hazard ratio [HR] 1·12, 95% CI 1·02 to 1·22; p=0·015). Proportions of patients with secondary infections did not differ between the groups (HR 0·85, 0·71 to 1·01; p=0·06). The low group had lower proportions of patients with vomiting (HR 0·77, 0·67 to 0·89; p<0·001), diarrhoea (0·83, 0·73 to 0·94; p=0·004), bowel ischaemia (0·50, 0·26 to 0·95; p=0·030), and liver dysfunction (0·92, 0·86-0·99; p=0·032). INTERPRETATION: Compared with standard calorie and protein targets, early calorie and protein restriction did not decrease mortality but was associated with faster recovery and fewer complications. FUNDING: French Ministry of Health.

Factors associated with acute mesenteric ischemia among critically ill ventilated patients with shock: a post hoc analysis of the NUTRIREA2 trial.

PURPOSE: Acute mesenteric ischemia (AMI) is a rare, but life-threatening condition occurring among critically ill patients. Several factors have been associated with AMI, but the causal link is debated, most studies being retrospective. Among these factors, enteral nutrition (EN) could be associated with AMI, in particular among patients with shock. We aimed to study the factors independently associated with AMI in a post hoc analysis of the NUTRIREA-2 trial including 2410 critically ill ventilated patients with shock, randomly assigned to receive EN or parenteral nutrition (PN). METHODS: Post hoc analysis of the NUTRIREA-2 trial was conducted. Ventilated adults with shock were randomly assigned to receive EN or PN. AMI was assessed by computed tomography, endoscopy, or laparotomy. Factors associated with AMI were studied by univariate and multivariate analysis. RESULTS: 2410 patients from 44 French intensive care units (ICUs) were included in the study: 1202 patients in the enteral group and 1208 patients in the parenteral group. The median age was 67 [58-76] years, with 67% men, a SAPS II score of 59 [46-74], and a medical cause for ICU admission in 92.7%. AMI was diagnosed among 24 (1%) patients, mainly by computed tomography (79%) or endoscopy (38%). The mechanism of AMI was non-occlusive mesenteric ischemia (n = 12), occlusive (n = 4), and indeterminate (n = 8). The median duration between inclusion in the trial and AMI diagnosis was 4 [1-11] days. Patients with AMI were older, had a higher SAPS II score at ICU admission, had higher plasma lactate, creatinine, and ASAT concentrations and lower hemoglobin concentration, had more frequently EN, dobutamine, and CVVHDF at inclusion, developed more frequently bacteremia during ICU stay, and had higher 28-day and 90-day mortality rates compared with patients without AMI. By multivariate analysis, AMI was independently associated with EN, dobutamine use, SAPS II score ≥ 62 and hemoglobin concentration ≤ 10.9 g/dL. CONCLUSION: Among critically ill ventilated patients with shock, EN, dobutamine use, SAPS II score ≥ 62 and hemoglobin ≤ 10.9 g/dL were independently associated with AMI. Among critically ill ventilated patients requiring vasopressors, EN should be delayed or introduced cautiously in case of low cardiac output requiring dobutamine and/or in case of multiple organ failure with high SAPS II score.

Global Judicial Opinions Regarding Government-Issued COVID-19 Mitigation Measures.

Laws play an important role in emergency response capacity. During the COVID-19 outbreak, experts have noted both a lack of law where it is needed and a problematic use of laws that exist. To address those challenges, policymakers revising public health emergency laws can examine how existing laws were used during the COVID-19 response to address problems that arose during their application. Judicial opinions can provide a source of data for this review. This study used legal epidemiology methods to perform an environmental scan of global judicial opinions, published from March 1 through August 31, 2020, from 23 countries, related to government-issued COVID-19 mitigation measures. The opinions were coded, and findings categorize the measures based on: (1) the World Health Organization's May 2020 publication, Overview of Public Health and Social Measures in the Context of COVID-19, and (2) related legal challenges brought in courts, including disputes about authority; conflicts of law; rationality, proportionality, or necessity; implementation; and enforcement. The findings demonstrate how judicial review of emergency measures has played a role in the COVID-19 response. In some cases, court rulings required mitigation measures to be amended or stopped. In others, court rulings required the government to issue a measure not yet in place. These findings provide examples for understanding issues related to the application of law during an emergency response.

Impact of the duration of normothermic regional perfusion on the results of liver transplant from controlled circulatory death donors: A retrospective, multicentric study.

In France, the program of controlled donation after circulatory death (cDCD) was established with routine use of in situ normothermic regional perfusion (NRP). There is currently no consensus on its optimal duration. The purpose was to assess the impact of NRP duration on liver graft function and biliary outcomes. One-hundred and fifty-six liver recipients from NRP-cDCD donors from six French centers between 2015 and 2019 were included. Primary endpoint was graft function assessed by early allograft dysfunction (EAD, according to Olthoff's criteria) and MEAF (model for early allograft function) score. Overall, three (1.9%) patients had primary non-function, 30 (19.2%) patients experienced EAD, and MEAF score was 7.3 (±1.7). Mean NRP duration was 179 (±43) min. There was no impact of NRP duration on EAD (170±44 min in patients with EAD vs. 181±42 min in patients without, P = .286). There was no significant association between NRP duration and MEAF score (P = .347). NRP duration did neither impact on overall biliary complications nor on non-anastomotic biliary strictures (overall rates of 16.7% and 3.9%, respectively). In conclusion, duration of NRP in cDCD donors does not seem to impact liver graft function and biliary outcomes after liver transplantation. A 1 to 4-h perfusion represents an optimal time window.

Integrons, a predictive biomarker for antibiotic resistance in acute sepsis: the IRIS study.

BACKGROUND: Considering the increase in MDR Gram-negative bacteria (GNB), the choice of empirical antibiotic therapy is challenging. In parallel, use of broad-spectrum antibiotics should be avoided to decrease antibiotic selection pressure. Accordingly, clinicians need rapid diagnostic tools to narrow antibiotic therapy. Class 1-3 integrons, identified by intI1-3 genes, are genetic elements that play a major role in antibiotic resistance in GNB. OBJECTIVES: The objective of the IRIS study was to evaluate the negative and positive predictive values (NPVs and PPVs, respectively) of intI1-3 as markers of antibiotic resistance. METHODS: The IRIS study was an observational cross-sectional multicentre study that enrolled adult subjects with suspected urinary tract or intra-abdominal infections. intI1-3 were detected directly from routinely collected biological samples (blood, urine or intra-abdominal fluid) using real-time PCR. A patient was considered 'MDR positive' if at least one GNB, expressing acquired resistance to at least two antibiotic families among ß-lactams, aminoglycosides, fluoroquinolones and/or co-trimoxazole, was isolated from at least one biological sample. RESULTS: Over a 2 year period, 513 subjects were enrolled and 409 had GNB documentation, mostly Enterobacterales. intI1 and/or intI2 were detected in 31.8% of patients and 24.4% of patients were considered 'MDR positive'. The NPV of intI1 and/or intI2 as a marker of acquired antibiotic resistances was estimated at 92.8% (89.1%-95.5%). The NPVs for first-line antibiotics were all above 92%, notably >96% for resistance to third-generation cephalosporins. CONCLUSIONS: The IRIS study strongly suggests that the absence of intI1 and intI2 in biological samples from patients with GNB-related infections is predictive of the absence of acquired resistances.

Impact of early low-calorie low-protein versus standard-calorie standard-protein feeding on outcomes of ventilated adults with shock: design and conduct of a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3).

INTRODUCTION: International guidelines include early nutritional support (≤48 hour after admission), 20-25 kcal/kg/day, and 1.2-2 g/kg/day protein at the acute phase of critical illness. Recent data challenge the appropriateness of providing standard amounts of calories and protein during acute critical illness. Restricting calorie and protein intakes seemed beneficial, suggesting a role for metabolic pathways such as autophagy, a potential key mechanism in safeguarding cellular integrity, notably in the muscle, during critical illness. However, the optimal calorie and protein supply at the acute phase of severe critical illness remains unknown. NUTRIREA-3 will be the first trial to compare standard calorie and protein feeding complying with guidelines to low-calorie low-protein feeding. We hypothesised that nutritional support with calorie and protein restriction during acute critical illness decreased day 90 mortality and/or dependency on intensive care unit (ICU) management in mechanically ventilated patients receiving vasoactive amine therapy for shock, compared with standard calorie and protein targets. METHODS AND ANALYSIS: NUTRIREA-3 is a randomised, controlled, multicentre, open-label trial comparing two parallel groups of patients receiving invasive mechanical ventilation and vasoactive amine therapy for shock and given early nutritional support according to one of two strategies: early calorie-protein restriction (6 kcal/kg/day-0.2-0.4 g/kg/day) or standard calorie-protein targets (25 kcal/kg/day, 1.0-1.3 g/kg/day) at the acute phase defined as the first 7 days in the ICU. We will include 3044 patients in 61 French ICUs. Two primary end-points will be evaluated: day 90 mortality and time to ICU discharge readiness. The trial will be considered positive if significant between-group differences are found for one or both alternative primary endpoints. Secondary outcomes include hospital-acquired infections and nutritional, clinical and functional outcomes. ETHICS AND DISSEMINATION: The NUTRIREA-3 study has been approved by the appropriate ethics committee. Patients are included after informed consent. Results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03573739.

Admission criteria and management of critical care patients in a pandemic context: position of the Ethics Commission of the French Intensive Care Society, update of April 2021.

Intensive care unit professionals have experience in critical care and its proportionality, collegial decision-making, withholding or withdrawal of treatment deemed futile, and communication with patients' relatives. These elements rely on ethical values from which we must not deviate in a pandemic situation. The recommendations made by the Ethics Commission of the French Intensive Care Society reflect an approach of responsibility and solidarity towards our citizens regarding the potential impact of a pandemic on critical care resources in France, with the fundamental requirement of respect for human dignity and equal access to health care for all.

Efficacy and safety of human soluble thrombomodulin (ART-123) for treatment of patients in France with sepsis-associated coagulopathy: post hoc analysis of SCARLET.

BACKGROUND: The phase 3 multinational SCARLET study evaluated the efficacy and safety of a recombinant human soluble thrombomodulin (ART-123) for treatment of sepsis-associated coagulopathy (SAC), which correlates with increased mortality risk in patients with sepsis. Although no significant reduction in mortality was observed with ART-123 compared with placebo in the full analysis set (FAS), an efficacy signal of ART-123 was observed in subgroups of patients who sustained coagulopathy until the first treatment and those not administered concomitant heparin. Post hoc analysis was performed of patients treated in France, the country with the largest enrollment (19% of the FAS) and consistent patient enrollment throughout the study duration. METHODS: Adult patients with SAC (international normalized ratio > 1.4; platelets > 30 × 109/L to < 150 × 109/L or platelet decrease > 30% within 24 h) and evidence of bacterial infection were included. The primary efficacy outcome was 28-day all-cause mortality. Safety outcomes included adverse, serious adverse, and major bleeding events. This analysis assessed patient characteristics and efficacy and safety outcomes in France compared with the rest of the world (ROW; excluding France). Mortality rates were assessed in patients in France or the ROW with characteristics previously associated with ART-123 efficacy. RESULTS: Baseline characteristics were similar between France and the ROW, but some measurements of disease severity were higher in patients in France. The 28-day all-cause mortality absolute risk reductions (ARRs) with ART-123 were 8.3% in France and 1.1% in the ROW. The greater ARR in France may be related to a higher rate of sustained coagulopathy and lower rate of heparin use. In France and the ROW, 84.6% and 78.0% of patients sustained coagulopathy from the time of initial SAC diagnosis to first treatment with the study drug, and 65.8% and 43.9% did not receive heparin, respectively. The ARRs for these subgroups of patients in France were 13.4% and 16.6%, respectively. Safety of ART-123 was comparable between France and the ROW. CONCLUSIONS: Results from this exploratory analysis suggest that patients with sustained SAC not receiving concomitant heparin may benefit from ART-123, a fact that should be confirmed in future studies with more restrictive inclusion criteria.

Monitoring circulating dipeptidyl peptidase 3 (DPP3) predicts improvement of organ failure and survival in sepsis: a prospective observational multinational study.

BACKGROUND: Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in the degradation of various cardiovascular and endorphin mediators. High levels of circulating DPP3 (cDPP3) indicate a high risk of organ dysfunction and mortality in cardiogenic shock patients. METHODS: The aim was to assess relationships between cDPP3 during the initial intensive care unit (ICU) stay and short-term outcome in the AdrenOSS-1, a prospective observational multinational study in twenty-four ICU centers in five countries. AdrenOSS-1 included 585 patients admitted to the ICU with severe sepsis or septic shock. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by the Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use and need for renal replacement therapy. cDPP3 levels were measured upon admission and 24 h later. RESULTS: Median [IQR] cDPP3 concentration upon admission was 26.5 [16.2-40.4] ng/mL. Initial SOFA score was 7 [5-10], and 28-day mortality was 22%. We found marked associations between cDPP3 upon ICU admission and 28-day mortality (unadjusted standardized HR 1.8 [CI 1.6-2.1]; adjusted HR 1.5 [CI 1.3-1.8]) and between cDPP3 levels and change in renal and liver SOFA score (p = 0.0077 and 0.0009, respectively). The higher the initial cDPP3 was, the greater the need for organ support and vasopressors upon admission; the longer the need for vasopressor(s), mechanical ventilation or RRT and the higher the need for fluid load (all p < 0.005). In patients with cDPP3 > 40.4 ng/mL upon admission, a decrease in cDPP3 below 40.4 ng/mL after 24 h was associated with an improvement of organ function at 48 h and better 28-day outcome. By contrast, persistently elevated cDPP3 at 24 h was associated with worsening organ function and high 28-day mortality. CONCLUSIONS: Admission levels and rapid changes in cDPP3 predict outcome during sepsis. Trial Registration ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015.

Relationship Between Obesity and Ventilator-Associated Pneumonia: A Post Hoc Analysis of the NUTRIREA2 Trial.

BACKGROUND: Patients with obesity are at higher risk for community-acquired and nosocomial infections. However, no study has specifically evaluated the relationship between obesity and ventilator-associated pneumonia (VAP). RESEARCH QUESTION: Is obesity associated with an increased incidence of VAP? STUDY DESIGN AND METHODS: This study was a post hoc analysis of the Impact of Early Enteral vs Parenteral Nutrition on Mortality in Patients Requiring Mechanical Ventilation and Catecholamines (NUTRIREA2) open-label, randomized controlled trial performed in 44 French ICUs. Adults receiving invasive mechanical ventilation and vasopressor support for shock and parenteral nutrition or enteral nutrition were included. Obesity was defined as BMI ≥ 30 kg/m2 at ICU admission. VAP diagnosis was adjudicated by an independent blinded committee, based on all available clinical, radiologic, and microbiologic data. Only first VAP episodes were taken into account. Incidence of VAP was analyzed by using the Fine and Gray model, with extubation and death as competing risks. RESULTS: A total of 699 (30%) of the 2,325 included patients had obesity; 224 first VAP episodes were diagnosed (60 and 164 in obese and nonobese groups, respectively). The incidence of VAP at day 28 was 8.6% vs 10.1% in the two groups (hazard ratio, 0.85; 95% CI 0.63-1.14; P = .26). After adjustment on sex, McCabe score, age, antiulcer treatment, and Sequential Organ Failure Assessment at randomization, the incidence of VAP remained nonsignificant between obese and nonobese patients (hazard ratio, 0.893; 95% CI, 0.66-1.2; P = .46). Although no significant difference was found in duration of mechanical ventilation and ICU length of stay, 90-day mortality was significantly lower in obese than in nonobese patients (272 of 692 [39.3%] patients vs 718 of 1,605 [44.7%]; P = .02). In a subgroup of patients (n = 123) with available pepsin and alpha-amylase measurements, no significant difference was found in rate of abundant microaspiration of gastric contents, or oropharyngeal secretions between obese and nonobese patients. INTERPRETATION: Our results suggest that obesity has no significant impact on the incidence of VAP.

Performances of disseminated intravascular coagulation scoring systems in septic shock patients.

BACKGROUND: There is no gold standard to diagnose septic shock-induced disseminated intravascular coagulation (DIC). The objective of our multicenter prospective study was to assess the performances of the different major scoring systems in terms of mortality prediction and DIC diagnosis. The JAAM-DIC 2016 score, the ISTH overt-DIC 2001 score, the associations of sepsis-induced coagulopathy (SIC) score with JAAM-DIC 2016 or ISTH overt-DIC scores were tested in patients within 12 h of their admission in ICU for septic shock (day 1) and at day 2. RESULTS: 582 patients were enrolled in the study. 182/567 (32.1%) were diagnosed with DIC according to ISTH overt-DIC score, and 193/561 (34.4%) according to JAAM-DIC score; 486/577 patients (84.2%) were diagnosed with a coagulopathy according to SIC score. A moderate concordance was observed between ISTH overt-DIC and JAAM-DIC [κ = 0.67 (0.60, 0.73), p < 0.001]. The delay of positivity of the scores for early DIC patients was not different between JAAM-DIC and ISTH overt-DIC scores. Although it was positive earlier, SIC score had worse diagnosis specificity, as 84.2% of the patients with septic shock were diagnosed with "coagulopathy". The specificity of SIC score alone to predict mortality was very low [0.18 (0.15; 0.22)], compared to the ones of JAAM-DIC score [0.71 (0.67; 0.75)], and of ISTH overt-DIC score [0.76 (0.72; 0.80)], p < 0.001. The sensitivity of SIC score to predict mortality was 0.95 [0.89; 0.98], and the ones of JAAM-DIC score and ISTH overt-DIC score were 0.61 [0.50; 0.70] and 0.68 [0.58; 0.77], respectively. There was no benefit in sensitivity and specificity in combining SIC score to JAAM-DIC score or to ISTH overt-DIC score, compared to JAAM-DIC score or ISTH overt-DIC score alone. CONCLUSIONS: Our data suggest that the added value of SIC score alone or combined with other scores is limited, and that both JAAM-DIC score and ISTH overt-DIC score can be used in septic shock patients. Trial registration clinicaltrial; Trial registration number: NCT02391792; Date of registration: 18/03/2015; URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT02391792?term=meziani&draw=4&rank=1.

Predicting the microbial cause of community-acquired pneumonia: can physicians or a data-driven method differentiate viral from bacterial pneumonia at patient presentation?

BACKGROUND: Community-acquired pneumonia (CAP) requires urgent and specific antimicrobial therapy. However, the causal pathogen is typically unknown at the point when anti-infective therapeutics must be initiated. Physicians synthesize information from diverse data streams to make appropriate decisions. Artificial intelligence (AI) excels at finding complex relationships in large volumes of data. We aimed to evaluate the abilities of experienced physicians and AI to answer this question at patient admission: is it a viral or a bacterial pneumonia? METHODS: We included patients hospitalized for CAP and recorded all data available in the first 3-h period of care (clinical, biological and radiological information). For this proof-of-concept investigation, we decided to study only CAP caused by a singular and identified pathogen. We built a machine learning model prediction using all collected data. Finally, an independent validation set of samples was used to test the pathogen prediction performance of: (i) a panel of three experts and (ii) the AI algorithm. Both were blinded regarding the final microbial diagnosis. Positive likelihood ratio (LR) values > 10 and negative LR values < 0.1 were considered clinically relevant. RESULTS: We included 153 patients with CAP (70.6% men; 62 [51-73] years old; mean SAPSII, 37 [27-47]), 37% had viral pneumonia, 24% had bacterial pneumonia, 20% had a co-infection and 19% had no identified respiratory pathogen. We performed the analysis on 93 patients as co-pathogen and no-pathogen cases were excluded. The discriminant abilities of the AI approach were low to moderate (LR+ = 2.12 for viral and 6.29 for bacterial pneumonia), and the discriminant abilities of the experts were very low to low (LR+ = 3.81 for viral and 1.89 for bacterial pneumonia). CONCLUSION: Neither experts nor an AI algorithm can predict the microbial etiology of CAP within the first hours of hospitalization when there is an urgent need to define the anti-infective therapeutic strategy.

Sedation practice and discomfort during withdrawal of mechanical ventilation in critically ill patients at end-of-life: a post-hoc analysis of a multicenter study.

PURPOSE: Little is known on the incidence of discomfort during the end-of-life of intensive care unit (ICU) patients and the impact of sedation on such discomfort. The aim of this study was to assess the incidence of discomfort events according to levels of sedation. METHODS: Post-hoc analysis of an observational prospective multicenter study comparing immediate extubation vs. terminal weaning for end-of-life in ICU patients. Discomforts including gasps, significant bronchial obstruction or high behavioural pain scale score, were prospectively assessed by nurses from mechanical ventilation withdrawal until death. Level of sedation was assessed using the Richmond Agitation-Sedation Scale (RASS) and deep sedation was considered for a RASS - 5. Psychological disorders in family members were assessed up until 12 months after the death. RESULTS: Among the 450 patients included in the original study, 226 (50%) experienced discomfort after mechanical ventilation withdrawal. Patients with discomfort received lower doses of midazolam and equivalent morphine, and were less likely to have deep sedation than patients without discomfort (59% vs. 79%, p < 0.001). After multivariate logistic regression, extubation (as compared terminal weaning) was the only factor associated with discomfort, whereas deep sedation and administration of vasoactive drugs were two factors independently associated with no discomfort. Long-term evaluation of psychological disorders in family members of dead patients did not differ between those with discomfort and the others. CONCLUSION: Discomfort was frequent during end-of-life of ICU patients and was mainly associated with extubation and less profound sedation.

Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial.

IMPORTANCE: Norepinephrine, the first-line vasopressor for septic shock, is not always effective and has important catecholaminergic adverse effects. Selepressin, a selective vasopressin V1a receptor agonist, is a noncatecholaminergic vasopressor that may mitigate sepsis-induced vasodilatation, vascular leakage, and edema, with fewer adverse effects. OBJECTIVE: To test whether selepressin improves outcome in septic shock. DESIGN, SETTING, AND PARTICIPANTS: An adaptive phase 2b/3 randomized clinical trial comprising 2 parts that included adult patients (n = 868) with septic shock requiring more than 5 µg/min of norepinephrine. Part 1 used a Bayesian algorithm to adjust randomization probabilities to alternative selepressin dosing regimens and to trigger transition to part 2, which would compare the best-performing regimen with placebo. The trial was conducted between July 2015 and August 2017 in 63 hospitals in Belgium, Denmark, France, the Netherlands, and the United States, and follow-up was completed by May 2018. INTERVENTIONS: Random assignment to 1 of 3 dosing regimens of selepressin (starting infusion rates of 1.7, 2.5, and 3.5 ng/kg/min; n = 585) or to placebo (n = 283), all administered as continuous infusions titrated according to hemodynamic parameters. MAIN OUTCOMES AND MEASURES: Primary end point was ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) of commencing study drug. Key secondary end points were 90-day mortality, kidney replacement therapy-free days, and ICU-free days. RESULTS: Among 868 randomized patients, 828 received study drug (mean age, 66.3 years; 341 [41.2%] women) and comprised the primary analysis cohort, of whom 562 received 1 of 3 selepressin regimens, 266 received placebo, and 817 (98.7%) completed the trial. The trial was stopped for futility at the end of part 1. Median study drug duration was 37.8 hours (IQR, 17.8-72.4). There were no significant differences in the primary end point (ventilator- and vasopressor-free days: 15.0 vs 14.5 in the selepressin and placebo groups; difference, 0.6 [95% CI, -1.3 to 2.4]; P = .30) or key secondary end points (90-day mortality, 40.6% vs 39.4%; difference, 1.1% [95% CI, -6.5% to 8.8%]; P = .77; kidney replacement therapy-free days: 18.5 vs 18.2; difference, 0.3 [95% CI, -2.1 to 2.6]; P = .85; ICU-free days: 12.6 vs 12.2; difference, 0.5 [95% CI, -1.2 to 2.2]; P = .41). Adverse event rates included cardiac arrhythmias (27.9% vs 25.2% of patients), cardiac ischemia (6.6% vs 5.6%), mesenteric ischemia (3.2% vs 2.6%), and peripheral ischemia (2.3% vs 2.3%). CONCLUSIONS AND RELEVANCE: Among patients with septic shock receiving norepinephrine, administration of selepressin, compared with placebo, did not result in improvement in vasopressor- and ventilator-free days within 30 days. Further research would be needed to evaluate the potential role of selepressin for other patient-centered outcomes in septic shock. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02508649.