Resilience after severe critical illness: a prospective, multicentre, observational study (RESIREA).

BACKGROUND: Critical-illness survivors may experience post-traumatic stress disorder (PTSD) and quality-of-life impairments. Resilience may protect against psychological trauma but has not been adequately studied after critical illness. We assessed resilience and its associations with PTSD and quality of life, and also identified factors associated with greater resilience. METHODS: This prospective, multicentre, study in patients recruited at 41 French ICUs was done in parallel with the NUTRIREA-3 trial in patients given mechanical ventilation and vasoactive amines for shock. Three months to one year after intensive-care-unit admission, survivors completed the Connor-Davidson Resilience Scale (CD-RISC-25), Impact of Event-Revised scale for PTSD symptoms (IES-R), SF-36 quality-of-life scale, Multidimensional Scale of Perceived Social Support (MSPSS), and Brief Illness Perception Questionnaire (B-IPQ). RESULTS: Of the 382 included patients, 203 (53.1%) had normal or high resilience (CD-RISC-25 ≥ 68). Of these resilient patients, 26 (12.8%) had moderate to severe PTSD symptoms (IES-R ≥ 24) vs. 45 (25.4%) patients with low resilience (p = 0.002). Resilient patients had higher SF-36 scores. Factors independently associated with higher CD-RISC-25 scores were higher MSPSS score indicating stronger social support (OR, 1.027; 95%CI 1.008-1.047; p = 0.005) and lower B-IPQ scores indicating a more threatening perception of the illness (OR, 0.973; 95%CI 0.950-0.996; p = 0.02). CONCLUSIONS: Resilient patients had a lower prevalence of PTSD symptoms and higher quality of life scores, compared to patients with low resilience. Higher scores for social support and illness perception were independently associated with greater resilience. Thus, our findings suggest that interventions to strengthen social support and improve illness perception may help to improve resilience. Such interventions should be evaluated in trials with PTSD mitigation and quality-of-life improvement as the target outcomes.

Increased Incidence of Ventilator-Acquired Pneumonia in Coronavirus Disease 2019 Patients: A Multicentric Cohort Study.

OBJECTIVES: Little is known about the epidemiology of ventilator-acquired pneumonia among coronavirus disease 2019 patients such as incidence or etiological agents. Some studies suggest a higher risk of ventilator-associated pneumonia in this specific population. DESIGN: Cohort exposed/nonexposed study among the REA-REZO surveillance network. SETTING: Multicentric; ICUs in France. PATIENTS: The coronavirus disease 2019 patients at admission were matched on the age, sex, center of inclusion, presence of antimicrobial therapy at admission, patient provenance, time from ICU admission to mechanical ventilation, and Simplified Acute Physiology Score II at admission to the patients included between 2016 and 2019 within the same surveillance network (1:1). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The overall incidence of ventilator-associated pneumonia, the cumulative incidence, and hazard rate of the first and the second ventilator-associated pneumonia were estimated. In addition, the ventilator-associated pneumonia microbiological ecology and specific resistant pattern in coronavirus disease 2019 exposed and nonexposed patients were compared. Medication data were not collected. A total of 1,879 patients were included in each group. The overall incidence of ventilator-associated pneumonia was higher among coronavirus disease 2019 exposed patients (25.5; 95% CI [23.7-27.45] vs 15.4; 95% CI [13.7-17.3] ventilator-associated pneumonia per 1,000 ventilation days). The cumulative incidence was higher for the first and the second ventilator-associated pneumonia among the coronavirus disease 2019 exposed patients (respective Gray test p < 0.0001 and 0.0167). The microbiological ecology and resistance were comparable between groups with a predominance of Enterobacterales and nonfermenting Gram-negative bacteria. The documented resistance pattern was similar between groups, except for a lower rate of methicillin-resistant Staphylococcus aureus in the coronavirus disease 2019 exposed patient (6% vs 23%; p = 0.013). CONCLUSIONS: There was a higher incidence of ventilator-associated pneumonia occurring among coronavirus disease 2019 patient compared with the general ICU population, with a similar microbiological ecology and resistance pattern.

Effect of an enteral amino acid blend on muscle and gut functionality in critically ill patients: a proof-of-concept randomized controlled trial.

BACKGROUND: A defining feature of prolonged critical illness is muscle wasting, leading to impaired recovery. Supplementation with a tailored blend of amino acids may bolster the innate gut defence, promote intestinal mucosa repair and limit muscle loss. METHODS: This was a monocentric, randomized, double-blind, placebo-controlled study that included patients with sepsis or acute respiratory distress syndrome. Patients received a specific combination of five amino acids or placebo mixed with enteral feeding for 21 days. Markers of renal function, gut barrier structure and functionality were collected at baseline and 1, 2, 3 and 8 weeks after randomization. Muscle structure and function were assessed through MRI measurements of the anterior quadriceps volume and by twitch airway pressure. Data were compared between groups relative to the baseline. RESULTS: Thirty-five critically ill patients were randomized. The amino acid blend did not impair urine output, blood creatinine levels or creatinine clearance. Plasma citrulline levels increased significantly along the treatment period in the amino acid group (difference in means [95% CI] 5.86 [1.72; 10.00] nmol/mL P = 0.007). Alanine aminotransferase and alkaline phosphatase concentrations were lower in the amino acid group than in the placebo group at one week (ratio of means 0.5 [0.29; 0.86] (P = 0.015) and 0.73 [0.57; 0.94] (P = 0.015), respectively). Twitch airway pressure and volume of the anterior quadriceps were greater in the amino acid group than in the placebo group 3 weeks after randomization (difference in means 10.6 [0.99; 20.20] cmH20 (P = 0.035) and 3.12 [0.5; 5.73] cm3/kg (P = 0.022), respectively). CONCLUSIONS: Amino acid supplementation increased plasma citrulline levels, reduced alanine aminotransferase and alkaline phosphatase levels, and improved twitch airway pressure and anterior quadriceps volume. Trial registration ClinicalTrials.gov, NCT02968836. Registered November 21, 2016.

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.

BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock. METHODS: In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group). RESULTS: Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group. CONCLUSIONS: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).

Overexpression of GILZ in macrophages limits systemic inflammation while increasing bacterial clearance in sepsis in mice.

Studies support the beneficial effects of glucocorticoids (GCs) during septic shock, steering research toward the potential role of GC-induced proteins in controlling excessive inflammatory responses. GILZ is a glucocorticoid-induced protein involved in the anti-inflammatory effects of GCs. We investigated whether the overexpression of GILZ specifically limited to monocytes and macrophages (M/M) alone could control inflammation, thus improving the outcome of septic shock in animal models. We also monitored the expression of GILZ in M/M from septic mice and septic-shock patients. M/M from patients and septic mice displayed significantly lower expression of GILZ than those isolated from controls. Furthermore, transgenic mice (Tg-mice) experiencing sepsis, with increased expression of GILZ restricted to M/M, showed lower frequencies of inflammatory monocytes than their littermates and lower plasma levels of inflammatory cytokines. Tg-mice also had lower blood bacterial counts. We further established that the upregulation of GILZ in M/M enhanced their phagocytic capacity in in vivo assays. The increase of GILZ in M/M was also sufficient to improve the survival rates of septic mice. These results provide evidence for a central role of both GILZ and M/M in the pathophysiology of septic shock and a possible clue for the modulation of inflammation in this disease.

Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2).

BACKGROUND: Whether the route of early feeding affects outcomes of patients with severe critical illnesses is controversial. We hypothesised that outcomes were better with early first-line enteral nutrition than with early first-line parenteral nutrition. METHODS: In this randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2 trial) done at 44 French intensive-care units (ICUs), adults (18 years or older) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned (1:1) to either parenteral nutrition or enteral nutrition, both targeting normocaloric goals (20-25 kcal/kg per day), within 24 h after intubation. Randomisation was stratified by centre using permutation blocks of variable sizes. Given that route of nutrition cannot be masked, blinding of the physicians and nurses was not feasible. Patients receiving parenteral nutrition could be switched to enteral nutrition after at least 72 h in the event of shock resolution (no vasopressor support for 24 consecutive hours and arterial lactate <2 mmol/L). The primary endpoint was mortality on day 28 after randomisation in the intention-to-treat-population. This study is registered with ClinicalTrials.gov, number NCT01802099. FINDINGS: After the second interim analysis, the independent Data Safety and Monitoring Board deemed that completing patient enrolment was unlikely to significantly change the results of the trial and recommended stopping patient recruitment. Between March 22, 2013, and June 30, 2015, 2410 patients were enrolled and randomly assigned; 1202 to the enteral group and 1208 to the parenteral group. By day 28, 443 (37%) of 1202 patients in the enteral group and 422 (35%) of 1208 patients in the parenteral group had died (absolute difference estimate 2·0%; [95% CI -1·9 to 5·8]; p=0·33). Cumulative incidence of patients with ICU-acquired infections did not differ between the enteral group (173 [14%]) and the parenteral group (194 [16%]; hazard ratio [HR] 0·89 [95% CI 0·72-1·09]; p=0·25). Compared with the parenteral group, the enteral group had higher cumulative incidences of patients with vomiting (406 [34%] vs 246 [20%]; HR 1·89 [1·62-2·20]; p<0·0001), diarrhoea (432 [36%] vs 393 [33%]; 1·20 [1·05-1·37]; p=0·009), bowel ischaemia (19 [2%] vs five [<1%]; 3·84 [1·43-10·3]; p=0·007), and acute colonic pseudo-obstruction (11 [1%] vs three [<1%]; 3·7 [1·03-13·2; p=0·04). INTERPRETATION: In critically ill adults with shock, early isocaloric enteral nutrition did not reduce mortality or the risk of secondary infections but was associated with a greater risk of digestive complications compared with early isocaloric parenteral nutrition. FUNDING: La Roche-sur-Yon Departmental Hospital and French Ministry of Health.

Effect of an ICU Diary on Posttraumatic Stress Disorder Symptoms Among Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Keeping a diary for patients while they are in the intensive care unit (ICU) might reduce their posttraumatic stress disorder (PTSD) symptoms. Objectives: To assess the effect of an ICU diary on the psychological consequences of an ICU hospitalization. Design, Setting, and Participants: Assessor-blinded, multicenter, randomized clinical trial in 35 French ICUs from October 2015 to January 2017, with follow-up until July 2017. Among 2631 approached patients, 709 adult patients (with 1 family member each) who received mechanical ventilation within 48 hours after ICU admission for at least 2 days were eligible, 657 were randomized, and 339 were assessed 3 months after ICU discharge. Interventions: Patients in the intervention group (n = 355) had an ICU diary filled in by clinicians and family members. Patients in the control group (n = 354) had usual ICU care without an ICU diary. Main Outcomes and Measures: The primary outcome was significant PTSD symptoms, defined as an Impact Event Scale-Revised (IES-R) score greater than 22 (range, 0-88; a higher score indicates more severe symptoms), measured in patients 3 months after ICU discharge. Secondary outcomes, also measured at 3 months and compared between groups, included significant PTSD symptoms in family members; significant anxiety and depression symptoms in patients and family members, based on a Hospital Anxiety and Depression Scale score greater than 8 for each subscale (range, 0-42; higher scores indicate more severe symptoms; minimal clinically important difference, 2.5); and patient memories of the ICU stay, reported with the ICU memory tool. Results: Among 657 patients who were randomized (median [interquartile range] age, 62 [51-70] years; 126 women [37.2%]), 339 (51.6%) completed the trial. At 3 months, significant PTSD symptoms were reported by 49 of 164 patients (29.9%) in the intervention group vs 60 of 175 (34.3%) in the control group (risk difference, -4% [95% CI, -15% to 6%]; P = .39). The median (interquartile range) IES-R score was 12 (5-25) in the intervention group vs 13 (6-27) in the control group (difference, -1.47 [95% CI, -1.93 to 4.87]; P = .38). There were no significant differences in any of the 6 prespecified comparative secondary outcomes. Conclusions and Relevance: Among patients who received mechanical ventilation in the ICU, the use of an ICU diary filled in by clinicians and family members did not significantly reduce the number of patients who reported significant PTSD symptoms at 3 months. These findings do not support the use of ICU diaries for preventing PTSD symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT02519725.

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.

StO2 guided early resuscitation in subjects with severe sepsis or septic shock: a pilot randomised trial.

The scientific community has agreed upon developing accurate monitoring of tissue perfusion and oxygenation to improve the management of subjects with sepsis. This pilot study aimed to investigate the feasibility of targeting tissue oxygen saturation (StO2) in addition to the currently recommended resuscitation goals, central venous pressure, mean arterial pressure and central venous oxygen saturation, in patients with severe sepsis or septic shock. A pilot, single-centre, randomised, non-blinded trial recruited 30 subjects with severe sepsis upon intensive care unit admission at an academic medical centre in France. Subjects were randomly assigned to a 6 h resuscitation strategy following the Surviving Sepsis Campaign guidelines with (experimental) or without (control) StO2. StO2 was measured over several muscles (masseter, deltoid and pectoral or thenar muscles), and a StO2 above 80 % over at least 2 muscles was the therapeutic goal. The primary outcome was evaluated as follows: 7-day mortality or worsening of SOFA score between day 7 and study onset, i.e., DSOFA > 0). Thirty subjects were included in the study over a period of 40 weeks. Fifteen subjects were included in each group. Monitoring of StO2 over three areas was performed in the experimental group. However, measures over the pectoral muscle provided poor results. At study day 7, there were 5/15 (33.3 %) subjects who died or had a DSOFA > 0 in the experimental arm and 4/15 (26.6 %) who died or had a DSOFA > 0 in the control arm (p = 1.00). This pilot study was the first randomised controlled trial using an algorithm derived from the SSC recommendations, which included StO2 as a treatment goal. However, the protocol showed no clear trend for or against targeting StO2.

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.

Masseter tissue oxygen saturation predicts normal central venous oxygen saturation during early goal-directed therapy and predicts mortality in patients with severe sepsis.

OBJECTIVE: This study aimed to investigate, in patients with severe sepsis, the correlation between central venous oxygen saturation and tissue oxygen saturation at different levels. DESIGN: Prospective observational study. SETTING: General intensive care unit at an academic medical center in France. PATIENTS: Thirty-eight patients with underresuscitated severe sepsis and septic shock on intensive care unit admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During early resuscitation according to the 6-hr bundles of the Surviving Sepsis Campaign guidelines, tissue oxygen saturation was recorded every other hour at the level of the thenar, masseter, and deltoid muscles along with central hemodynamics, arterial lactate concentrations, and central venous oxygen saturation. Over the 6-hr resuscitation period, thenar tissue oxygen saturation was consistently higher than masseter tissue oxygen saturation (p = .04) and deltoid tissue oxygen saturation (p = .002), and masseter tissue oxygen saturation was consistently higher than deltoid tissue oxygen saturation (p = .04). Receiver operating characteristic curves analyses showed that masseter tissue oxygen saturation was better predictor of central venous oxygen saturation >70% than thenar tissue oxygen saturation (area under the curve, 0.80; 95% confidence interval 0.71-0.89 vs. 0.67; 95% confidence interval 0.56-0.77; p = .02). The crude 28-day mortality was 36.8%. Receiver operating characteristic curve analysis showed that masseter tissue oxygen saturation (area under the curve 0.87; 0.75-0.98) and deltoid tissue oxygen saturation (area under the curve 0.88; 0.77-0.98) but not thenar tissue oxygen saturation (area under the curve 0.66; 0.46-0.86) or central venous oxygen saturation (area under the curve 0.56; 0.38-0.80) were strong predictors of 28-day mortality. CONCLUSIONS: This study suggested that in the early 6-hr resuscitation period, masseter tissue oxygen saturation accurately identified patients with severe sepsis and central venous oxygen saturation >70%. Both masseter tissue oxygen saturation and deltoid tissue oxygen saturation but not central venous oxygen saturation or thenar tissue oxygen saturation are strong predictors of 28-day mortality.

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.

Hormonal status in protracted critical illness and in-hospital mortality.

INTRODUCTION: The aim of this study was to determine the relationship between hormonal status and mortality in patients with protracted critical illness. METHODS: We conducted a prospective observational study in four medical and surgical intensive care units (ICUs). ICU patients who regained consciousness after 7 days of mechanical ventilation were included. Plasma levels of insulin-like growth factor 1 (IGF-1), prolactin, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and cortisol were measured on the first day patients were awake and cooperative (day 1). Mean blood glucose from admission to day 1 was calculated. RESULTS: We studied 102 patients: 65 men and 37 women (29 of the women were postmenopausal). Twenty-four patients (24%) died in the hospital. The IGF-1 levels were higher and the cortisol levels were lower in survivors. Mean blood glucose was lower in women who survived, and DHEA and DHEAS were higher in men who survived. CONCLUSIONS: These results suggest that, on the basis of sex, some endocrine or metabolic markers measured in the postacute phase of critical illness might have a prognostic value.

Hyperglycaemia and apoptosis of microglial cells in human septic shock.

INTRODUCTION: The effect of hyperglycaemia on the brain cells of septic shock patients is unknown. The objective of this study was to evaluate the relationship between hyperglycaemia and apoptosis in the brains of septic shock patients. METHODS: In a prospective study of 17 patients who died from septic shock, hippocampal tissue was assessed for neuronal ischaemia, neuronal and microglial apoptosis, neuronal Glucose Transporter (GLUT) 4, endothelial inducible Nitric Oxide Synthase (iNOS), microglial GLUT5 expression, microglial and astrocyte activation. Blood glucose (BG) was recorded five times a day from ICU admission to death. Hyperglycaemia was defined as a BG 200 mg/dL g/l and the area under the BG curve (AUBGC) > 2 g/l was assessed. RESULTS: Median BG over ICU stay was 2.2 g/l. Neuronal apoptosis was correlated with endothelial iNOS expression (rho = 0.68, P = 0.04), while microglial apoptosis was associated with AUBGC > 2 g/l (rho = 0.70; P = 0.002). Neuronal and microglial apoptosis correlated with each other (rho = 0.69, P = 0.006), but neither correlated with the duration of septic shock, nor with GLUT4 and 5 expression. Neuronal apoptosis and ischaemia tended to correlate with duration of hypotension. CONCLUSIONS: In patients with septic shock, neuronal apoptosis is rather associated with iNOS expression and microglial apoptosis with hyperglycaemia, possibly because GLUT5 is not downregulated. These data provide a mechanistic basis for understanding the neuroprotective effects of glycemic control.

Characteristics and prognosis of bloodstream infection in patients with COVID-19 admitted in the ICU: an ancillary study of the COVID-ICU study.

BACKGROUND: Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-COV 2) and requiring intensive care unit (ICU) have a high incidence of hospital-acquired infections; however, data regarding hospital acquired bloodstream infections (BSI) are scarce. We aimed to investigate risk factors and outcome of BSI in critically ill coronavirus infectious disease-19 (COVID-19) patients. PATIENTS AND METHODS: We performed an ancillary analysis of a multicenter prospective international cohort study (COVID-ICU study) that included 4010 COVID-19 ICU patients. For the present analysis, only those with data regarding primary outcome (death within 90 days from admission) or BSI status were included. Risk factors for BSI were analyzed using Fine and Gray competing risk model. Then, for outcome comparison, 537 BSI-patients were matched with 537 controls using propensity score matching. RESULTS: Among 4010 included patients, 780 (19.5%) acquired a total of 1066 BSI (10.3 BSI per 1000 patients days at risk) of whom 92% were acquired in the ICU. Higher SAPS II, male gender, longer time from hospital to ICU admission and antiviral drug before admission were independently associated with an increased risk of BSI, and interestingly, this risk decreased over time. BSI was independently associated with a shorter time to death in the overall population (adjusted hazard ratio (aHR) 1.28, 95% CI 1.05-1.56) and, in the propensity score matched data set, patients with BSI had a higher mortality rate (39% vs 33% p = 0.036). BSI accounted for 3.6% of the death of the overall population. CONCLUSION: COVID-19 ICU patients have a high risk of BSI, especially early after ICU admission, risk that increases with severity but not with corticosteroids use. BSI is associated with an increased mortality rate.

Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial.

BACKGROUND: Critically ill patients often require emergency intubation. The use of etomidate as the sedative agent in this context has been challenged because it might cause a reversible adrenal insufficiency, potentially associated with increased in-hospital morbidity. We compared early and 28-day morbidity after a single dose of etomidate or ketamine used for emergency endotracheal intubation of critically ill patients. METHODS: In this randomised, controlled, single-blind trial, 655 patients who needed sedation for emergency intubation were prospectively enrolled from 12 emergency medical services or emergency departments and 65 intensive care units in France. Patients were randomly assigned by a computerised random-number generator list to receive 0.3 mg/kg of etomidate (n=328) or 2 mg/kg of ketamine (n=327) for intubation. Only the emergency physician enrolling patients was aware of group assignment. The primary endpoint was the maximum score of the sequential organ failure assessment during the first 3 days in the intensive care unit. We excluded from the analysis patients who died before reaching the hospital or those discharged from the intensive care unit before 3 days (modified intention to treat). This trial is registered with ClinicalTrials.gov, number NCT00440102. FINDINGS: 234 patients were analysed in the etomidate group and 235 in the ketamine group. The mean maximum SOFA score between the two groups did not differ significantly (10.3 [SD 3.7] for etomidate vs 9.6 [3.9] for ketamine; mean difference 0.7 [95% CI 0.0-1.4], p=0.056). Intubation conditions did not differ significantly between the two groups (median intubation difficulty score 1 [IQR 0-3] in both groups; p=0.70). The percentage of patients with adrenal insufficiency was significantly higher in the etomidate group than in the ketamine group (OR 6.7, 3.5-12.7). We recorded no serious adverse events with either study drug. INTERPRETATION: Our results show that ketamine is a safe and valuable alternative to etomidate for endotracheal intubation in critically ill patients, and should be considered in those with sepsis. FUNDING: French Ministry of Health.

Osmoregulation of vasopressin secretion is altered in the postacute phase of septic shock.

OBJECTIVE: To determine whether septic shock patients have an abnormal reponse to increasing osmolarity. DESIGN: Prospective interventional study. SETTING: Intensive care unit at Raymond Poincaré and Etampes Hospitals. PATIENTS: Normonatremic patients at > 72 hrs from septic shock onset. INTERVENTION: Osmotic challenge consisting of infusing 500 mL of hypertonic saline solution (with cumulative amount of sodium not exceeding 24 g) over 120 mins. MEASUREMENTS AND MAIN RESULTS: Plasma arginine vasopressin levels were measured 15 mins before the test and then four times every 30 mins. A slope of the relation between arginine vasopressin and plasma sodium levels of < 0.5 pg/mEq defined nonresponders. Among the 33 included patients, 17 (52%) were nonresponders. During osmotic challenge, variations throughout the test in plasma sodium levels, blood pressure, and central venous pressure were comparable between the two groups. Arginine vasopressin increased from 4.8 pg/mL [3.3-6.4 pg/mL] to 14.4 pg/mL [11.2-23.3 pg/mL] in responders but only from 2.8 pg/mL [2.3-4.0 pg/mL] to 4.0 pg/mL [3.1-5.3 pg/mL] in nonresponders (p < .0001). Responders had a higher plasma arginine vasopressin levels at baseline and a more severe hematosis alteration. Nonresponders had more frequently bacteremia and liver dysfunction, been referred from the ward and undergone surgery. Critical illness severity, hemodynamic alteration, hydroelectrolytic disturbances, treatment, and outcome did not differ between the two groups. CONCLUSION: Osmoregulation is dramatically altered in half of patients with prolonged septic shock.

Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial.

CONTEXT: Corticosteroid therapy induces potentially detrimental hyperglycemia in septic shock. In addition, the benefit of adding fludrocortisone in this setting is unclear. OBJECTIVES: To test the efficacy of intensive insulin therapy in patients whose septic shock was treated with hydrocortisone and to assess, as a secondary objective, the benefit of fludrocortisone. DESIGN, SETTING, AND PATIENTS: A multicenter, 2 x 2 factorial, randomized trial, involving 509 adults with septic shock who presented with multiple organ dysfunction, as defined by a Sequential Organ Failure Assessment score of 8 or more, and who had received hydrocortisone treatment was conducted from January 2006 to January 2009 in 11 intensive care units in France. INTERVENTIONS: Patients were randomly assigned to 1 of 4 groups: continuous intravenous insulin infusion with hydrocortisone alone, continuous intravenous insulin infusion with hydrocortisone plus fludrocortisone, conventional insulin therapy with hydrocortisone alone, or conventional insulin therapy with intravenous hydrocortisone plus fludrocortisone. Hydrocortisone was administered in a 50-mg bolus every 6 hours, and fludrocortisone was administered orally in 50-microg tablets once a day, each for 7 days. MAIN OUTCOME MEASURE: In-hospital mortality. RESULTS: Of the 255 patients treated with intensive insulin, 117 (45.9%), and 109 of 254 (42.9%) treated with conventional insulin therapy died (relative risk [RR], 1.07; 95% confidence interval [CI], 0.88-1.30; P = .50). Patients treated with intensive insulin experienced significantly more episodes of severe hypoglycemia (<40 mg/dL) than those in the conventional-treatment group, with a difference in mean number of episodes per patient of 0.15 (95% CI, 0.02-0.28; P = .003). At hospital discharge, 105 of 245 patients treated with fludrocortisone (42.9%) died and 121 of 264 (45.8%) in the control group died (RR, 0.94; 95% CI, 0.77-1.14; P = .50). CONCLUSIONS: Compared with conventional insulin therapy, intensive insulin therapy did not improve in-hospital mortality among patients who were treated with hydrocortisone for septic shock. The addition of oral fludrocortisone did not result in a statistically significant improvement in in-hospital mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00320099.

Expert consensus-based clinical practice guidelines management of intravascular catheters in the intensive care unit.

The French Society of Intensive Care Medicine (SRLF), jointly with the French-Speaking Group of Paediatric Emergency Rooms and Intensive Care Units (GFRUP) and the French-Speaking Association of Paediatric Surgical Intensivists (ADARPEF), worked out guidelines for the management of central venous catheters (CVC), arterial catheters and dialysis catheters in intensive care unit. For adult patients: Using GRADE methodology, 36 recommendations for an improved catheter management were produced by the 22 experts. Recommendations regarding catheter-related infections' prevention included the preferential use of subclavian central vein (GRADE 1), a one-step skin disinfection(GRADE 1) using 2% chlorhexidine (CHG)-alcohol (GRADE 1), and the implementation of a quality of care improvement program. Antiseptic- or antibiotic-impregnated CVC should likely not be used (GRADE 2, for children and adults). Catheter dressings should likely not be changed before the 7th day, except when the dressing gets detached, soiled or impregnated with blood (GRADE 2- adults). CHG dressings should likely be used (GRADE 2+). For adults and children, ultrasound guidance should be used to reduce mechanical complications in case of internal jugular access (GRADE 1), subclavian access (Grade 2) and femoral venous, arterial radial and femoral access (Expert opinion). For children, an ultrasound-guided supraclavicular approach of the brachiocephalic vein was recommended to reduce the number of attempts for cannulation and mechanical complications. Based on scarce publications on diagnostic and therapeutic strategies and on their experience (expert opinion), the panel proposed definitions, and therapeutic strategies.