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Purpose: We aimed to determine whether interferon gamma-1b prevents hospital-acquired pneumonia in mechanically ventilated patients., Methods: In a multicenter, placebo-controlled, randomized trial conducted in 11 European hospitals, we randomly assigned critically ill adults, with one or more acute organ failures, under mechanical ventilation to receive interferon gamma-1b (100 µg every 48 h from day 1 to 9) or placebo (following the same regimen). The primary outcome was a composite of hospital-acquired pneumonia or all-cause mortality on day 28. The planned sample size was 200 with interim safety analyses after enrolling 50 and 100 patients., Results: The study was discontinued after the second safety analysis for potential harm with interferon gamma-1b, and the follow-up was completed in June 2022. Among 109 randomized patients (median age, 57 (41-66) years; 37 (33.9%) women; all included in France), 108 (99%) completed the trial. Twenty-eight days after inclusion, 26 of 55 participants (47.3%) in the interferon-gamma group and 16 of 53 (30.2%) in the placebo group had hospital-acquired pneumonia or died (adjusted hazard ratio (HR) 1.76, 95% confidence interval (CI) 0.94-3.29; P = 0.08). Serious adverse events were reported in 24 of 55 participants (43.6%) in the interferon-gamma group and 17 of 54 (31.5%) in the placebo group (P = 0.19). In an exploratory analysis, we found that hospital-acquired pneumonia developed in a subgroup of patients with decreased CCL17 response to interferon-gamma treatment., Conclusions: Among mechanically ventilated patients with acute organ failure, treatment with interferon gamma-1b compared with placebo did not significantly reduce the incidence of hospital-acquired pneumonia or death on day 28. Furthermore, the trial was discontinued early due to safety concerns about interferon gamma-1b treatment., (© 2023. The Author(s).)

Purpose: In the critically ill, hospital-acquired bloodstream infections (HA-BSI) are associated with significant mortality. Granular data are required for optimizing management, and developing guidelines and clinical trials., Methods: We carried out a prospective international cohort study of adult patients (≥ 18 years of age) with HA-BSI treated in intensive care units (ICUs) between June 2019 and February 2021., Results: 2600 patients from 333 ICUs in 52 countries were included. 78% HA-BSI were ICU-acquired. Median Sequential Organ Failure Assessment (SOFA) score was 8 [IQR 5; 11] at HA-BSI diagnosis. Most frequent sources of infection included pneumonia (26.7%) and intravascular catheters (26.4%). Most frequent pathogens were Gram-negative bacteria (59.0%), predominantly Klebsiella spp. (27.9%), Acinetobacter spp. (20.3%), Escherichia coli (15.8%), and Pseudomonas spp. (14.3%). Carbapenem resistance was present in 37.8%, 84.6%, 7.4%, and 33.2%, respectively. Difficult-to-treat resistance (DTR) was present in 23.5% and pan-drug resistance in 1.5%. Antimicrobial therapy was deemed adequate within 24 h for 51.5%. Antimicrobial resistance was associated with longer delays to adequate antimicrobial therapy. Source control was needed in 52.5% but not achieved in 18.2%. Mortality was 37.1%, and only 16.1% had been discharged alive from hospital by day-28., Conclusions: HA-BSI was frequently caused by Gram-negative, carbapenem-resistant and DTR pathogens. Antimicrobial resistance led to delays in adequate antimicrobial therapy. Mortality was high, and at day-28 only a minority of the patients were discharged alive from the hospital. Prevention of antimicrobial resistance and focusing on adequate antimicrobial therapy and source control are important to optimize patient management and outcomes., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Nangibotide is a specific TREM-1 inhibitor that tempered deleterious host-pathogens interactions, restored vascular function, and improved survival, in animal septic shock models. This study evaluated the safety and pharmacokinetics of nangibotide and its effects on clinical and pharmacodynamic parameters in septic shock patients., Methods: This was a multicenter randomized, double-blind, two-stage study. Patients received either continuous infusion of nangibotide (0.3, 1.0, or 3.0 mg/kg/h) or placebo. Treatment began < 24 h after shock onset and continued for up to 5 days. Safety primary outcomes were adverse events (AEs), whether serious or not, and death. Exploratory endpoints evaluated nangibotide effects on pharmacodynamics, organ function, and mortality, and were analyzed according to baseline sTREM-1 concentrations., Results: Forty-nine patients were randomized. All treatment emergent AEs (TEAEs) were collected until Day 28. No significant differences were observed in TEAEs between treatment groups. No drug withdrawal linked to TEAE nor appearance of anti-drug antibodies were reported. Nangibotide pharmacokinetics appeared to be dose-proportional and clearance was dose-independent. Nangibotide did not significantly affect pharmacodynamic markers. Decrease in SOFA score LS mean change (± SE) from baseline to Day 5 in pooled nangibotide groups versus placebo was - 0.7 (± 0.85) in the randomized population and - 1.5 (± 1.12) in patients with high baseline plasma sTREM-1 concentrations (non-significant). This pattern was similar to organ support end points., Conclusion: No significant increases in TEAEs were detected in nangibotide-treated patients versus placebo. These results encourage further evaluation of nangibotide and further exploration of plasma sTREM-1 concentrations as a predictive efficacy biomarker.

To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients.

Objective: To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI)., Participants: A multispecialty task force of international experts in critical care medicine and endocrinology and members of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)., Data Sources: Medline, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews., Results: Three major pathophysiologic events were considered to constitute CIRCI: dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids. The dysregulation of the HPA axis is complex, involving multidirectional crosstalk between the CRH/ACTH pathways, autonomic nervous system, vasopressinergic system, and immune system. Recent studies have demonstrated that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the primary cortisol-metabolizing enzymes in the liver and kidney. Despite the elevated cortisol levels during critical illness, tissue resistance to glucocorticoids is believed to occur due to insufficient glucocorticoid alpha-mediated anti-inflammatory activity., Conclusions: Novel insights into the pathophysiology of CIRCI add to the limitations of the current diagnostic tools to identify at-risk patients and may also impact how corticosteroids are used in patients with CIRCI.

Objective: To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients., Participants: A multispecialty task force of 16 international experts in Critical Care Medicine, endocrinology, and guideline methods, all of them members of the Society of Critical Care Medicine and/or the European Society of Intensive Care Medicine., Design/methods: The recommendations were based on the summarized evidence from the 2008 document in addition to more recent findings from an updated systematic review of relevant studies from 2008 to 2017 and were formulated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The strength of each recommendation was classified as strong or conditional, and the quality of evidence was rated from high to very low based on factors including the individual study design, the risk of bias, the consistency of the results, and the directness and precision of the evidence. Recommendation approval required the agreement of at least 80% of the task force members., Results: The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol at 60 min of <9 µg/dl) after cosyntropin (250 µg) administration and a random plasma cortisol of <10 µg/dl may be used by clinicians. We suggest against using plasma free cortisol or salivary cortisol level over plasma total cortisol (conditional, very low quality of evidence). For treatment of specific conditions, we suggest using intravenous (IV) hydrocortisone <400 mg/day for ≥3 days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy (conditional, low quality of evidence). We suggest not using corticosteroids in adult patients with sepsis without shock (conditional recommendation, moderate quality of evidence). We suggest the use of IV methylprednisolone 1 mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO 2 /FiO 2  < 200 and within 14 days of onset) (conditional, moderate quality of evidence). Corticosteroids are not suggested for patients with major trauma (conditional, low quality of evidence)., Conclusions: Evidence-based recommendations for the use of corticosteroids in critically ill patients with sepsis and septic shock, acute respiratory distress syndrome, and major trauma have been developed by a multispecialty task force.

Objective: To assess the value of monitoring abdominal and rib cage tidal displacement as an indicator of optimal mean airway pressure (Paw) during high-frequency oscillatory ventilation (HFOV)., Design and Setting: Prospective observational study in a university research laboratory., Animals: Eight piglets weighing 12.0+/-0.5 kg, surfactant depleted by lung lavage., Interventions: Compliance of the respiratory system (C(rs)) was calculated from a quasistatic pressure volume loop. After initiation of HFOV lung volume was recruited by increasing Paw to 40 cmH(2)O. Then mean Paw was decreased in steps until PaO(2)/FIO(2) was below 100 mmHg. Proximal pressure amplitude remained constant., Measurements and Results: Abdominal and rib cage tidal displacement was determined using respiratory inductive plethysmography. During HFOV there was maximum in tidal volume (Vt) in seven of eight piglets. At maximal mean Paw abdominal and rib cage displacement were in phase. Phase difference between abdominal and rib cage displacement increased to a maximum of 178+/-28 degrees at minimum mean Paw. A minimum in abdominal displacement and a maximum of Vt was found near the optimal mean Paw, defined as the lowest mean Paw where shunt fraction is below 0.1., Conclusions: During HFOV abdominal and rib cage displacement displayed mean Paw dependent asynchrony. Maximal Vt and minimal abdominal displacement coincided with optimal C(rs), oxygenation, and ventilation, suggesting potential clinical relevance of monitoring Vt and abdominal displacement during HFOV.

Objective: More than one-half the deaths of patients admitted to intensive care units (ICUs) occur after a decision to forgo life-sustaining therapy (DFLST). Although DFLSTs typically occur in patients with severe comorbidities and intractable acute medical disorders, other factors may influence the likelihood of DFLSTs. The objectives of this study were to describe the factors and mortality associated with DFLSTs and to evaluate the potential independent impact of DFLSTs on hospital mortality., Design and Setting: Prospective multicenter 2-year study in six ICUs in France., Patients: The 1,698 patients admitted to the participating ICUs during the study period, including 295 (17.4%) with DFLSTs., Measurements and Results: The impact of DFLSTs on hospital mortality was evaluated using a model that incorporates changes in daily logistic organ dysfunction scores during the first ICU week. Univariate predictors of death included demographic factors (age, gender), comorbidities, reasons for ICU admission, severity scores at ICU admission, and DFLSTs. In a stepwise Cox model five variables independently predicted mortality: good chronic health status (hazard ratio, 0.479), SAPS II score higher than 39 (2.05), chronic liver disease (1.463), daily logistic organ dysfunction score (1.357 per point), and DFLSTs (1.887)., Conclusions: DFLSTs remain independently associated with death after adjusting on comorbidities and severity at ICU admission and within the first ICU week. This highlights the need for further clarifying the many determinants of DFLSTs and for routinely collecting DFLSTs in studies with survival as the outcome variable of interest.

Objective: Noninvasive ventilation may reduce the endotracheal intubation rate in patients with acute cardiogenic pulmonary edema. However, criteria for selecting candidates for this technique are not well established. We analyzed a cohort of patients with severe acute cardiogenic pulmonary edema managed by conventional therapy to identify risk factors for intubation. These factors were used as guide for indications for noninvasive ventilation., Design and Setting: Observational cohort registry in the ICU and emergency and cardiology departments in a community teaching hospital., Patients: . 110 consecutive patients with acute cardiogenic pulmonary edema, 80 of whom received conventional oxygen therapy., Interventions: Physiological measurements and blood gas samples registered upon admission., Measurements and Results: Twenty-one patients (26%) treated with conventional oxygen therapy needed intubation. Acute myocardial infarction, pH below 7.25, low ejection fraction (<30%), hypercapnia, and systolic blood pressure below 140 mmHg were independent predictors for intubation. Conversely, systolic blood pressure of 180 mmHg or higher showed to be a protective factor since only two patients with this blood pressure value required intubation (8%)], both presenting with a pH lower than 7.25. Considering systolic blood pressure lower than 180 mmHg, patients who showed hypercapnia presented a high intubation rate (13/21, 62%) whereas the rate of intubation in patients with normocapnia was intermediate (6/23, 26%). All normocapnic patients with pH less than 7.25 required intubation. No patient with hypocapnia was intubated regardless the level of blood pressure., Conclusions: Patients with pH less than 7.25 or systolic blood pressure less than 180 mmHg associated with hypercapnia should be promptly considered for noninvasive ventilation. With this strategy about 40% of the patients would be initially treated with this technique, which would involve nearly 90% of the patients that require intubation.

Objective: To evaluate the time-course of two organ failure scores (SOFA and Goris) after surgery for postoperative peritonitis in critically ill patients according to the persistence/nonpersistence of intraabdominal sepsis (IAS)., Design: Retrospective study., Patients: Sixty-two consecutive patients (SAPSII = 38+/-14) admitted in the surgical ICU., Methods: Patients were classified according to the persistence of IAS (IAS+, n=36) confirmed by a second laparotomy or the lack of IAS (IAS-, n=26) assessed by a favorable 30-day evolution without reintervention. Scores were calculated daily from day 0 preoperatively to postoperative day 5., Results: In both groups, SOFA scores were higher on day 1 when compared to day 0 (8.3+/-3.1 vs 6.1+/-3.7 in the IAS+ group and 5.2+/-3.4 vs 2.7+/-2.7 in the IAS- group). In the IAS- patients, the SOFA score displayed a decrease starting on day 2 when compared to day 1 (4.4+/-3.6 vs 5.2+/-3.4, P=0.03). In contrast, in the IAS+ patients, the SOFA score remained unchanged until day 5. The time course of the Goris score was strictly similar to the SOFA scores., Conclusion: In critically ill patients with postoperative peritonitis, the postoperative time course of the SOFA and the Goris organ failure scores was different between patients with or without intra-abdominal persistent sepsis. The lack of improvement of one of these scores on postoperative day 2 may suggest persistent intraabdominal sepsis and supports the need for a new surgical exploration.