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OBJECTIVE: There is controversy on whether catheter-related bloodstream infections (CR-BSI) affect the mortality of critically ill patients. DESIGN: Meta-analysis of comparative studies that reported on mortality of intensive care unit (ICU) adult patients with and without CR-BSI. METHODS: PubMed, Current Contents, and reference lists of retrieved publications were searched with no language or time restrictions. Heterogeneity was assessed by means of I-statistic and chi-square test. Publication bias was detected by the funnel plot method using Egger's test. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated by implementing both the Mantel-Haenszel fixed effect and the DerSimonian-Laird random effects model. RESULTS: Eight studies, involving 2,540 ICU patients, were included. Heterogeneity was detected (I = 0.67, 95% CI 0.32-0.85, p = 0.003). Publication bias was not found (Egger's test, p = 0.28). All-cause in-hospital mortality was higher in ICU patients with CR-BSI than in those without CR-BSI (fixed effect model: OR = 1.81, 95% CI 1.44-2.28; random effects model: OR = 1.96, 95% CI 1.25-3.09). This was also the case for the subgroup analysis of the studies that were matched for severity of illness (fixed effect model: OR = 1.65, 95% CI 1.28-2.13; random effects model: OR = 1.70, 95% CI 1.00-2.90). CONCLUSION: Presence, as opposed to absence, of CR-BSI is associated with higher mortality in critically ill adult patients. This finding seems to justify and may enhance efforts to prevent CR-BSI in such patients. [ABSTRACT FROM AUTHOR]

Summary: Linezolid has been approved for the treatment of patients with infections caused by Gram-positive cocci that are resistant to traditionally used antibiotics, including glycopeptides. This oxazolidinone antibiotic has been reported to have excellent pharmacokinetics and effectiveness. We did a meta-analysis of randomised controlled trials (RCTs) to clarify whether linezolid is superior to glycopeptides or β-lactams for the treatment of Gram-positive infections. 12 RCTs, involving 6093 patients, were included. Overall, with respect to treatment success, linezolid was more effective than glycopeptides or β-lactams (odds ratio [OR] 1·41 [95% CI 1·11–1·81]). Mortality was similar between the groups (OR 0·97 [0·79–1·19]). Linezolid was more effective than comparators in patients with skin and soft-tissue infections (OR 1·67 [1·31–2·12]) and bacteraemia (OR 2·07 [1·13–3·78]). However, there was no difference in treatment success for patients with pneumonia (OR 1·03 [0·75–1·42]). Treatment with linezolid was not associated with more adverse effects in general (OR 1·40 [0·95–2·06]); however, thrombocytopenia was recorded more commonly in patients receiving linezolid (OR 11·72 [3·66–37·57]). Although linezolid is more effective than its comparators for the empirical treatment of selected patients, several points, such as the use of less potent antistaphylococcal β-lactams, the same all-cause mortality, and the higher probability of thrombocytopenia, should be taken into account and may limit the use of linezolid to specific patient populations or infections that are difficult to treat with other antibiotics. [Copyright &y& Elsevier]

Objective: Previous meta-analyses reported advantages of passive (i.e., heat and moisture exchangers, or HMEs) compared with active (i.e., heated humidifiers, or HHs) humidifiers in reducing the incidence of ventilator-associated pneumonia, but they did not examine the effect of these devices on mortality, length of intensive care unit stay, and duration of mechanical ventilation. In addition, relevant data were recently published.Design: Meta-analysis of randomized controlled trials comparing HMEs with HHs for the management of mechanically ventilated patients to determine the impact of these devices on clinical outcomes of such patients.Methods: We searched PubMed and the Cochrane Central Register of Controlled Trials as well as reference lists from publications, with no language restrictions. We estimated pooled odds ratios (ORs) and 95% confidence intervals (CIs), using a random effects model.Results: Thirteen randomized controlled trials, studying 2,580 patients, were included. There was no difference in incidence of ventilator-associated pneumonia among patients managed with HMEs and HHs (OR 0.85, 95% CI 0.62-1.16). There was no difference between the compared groups regarding mortality (OR 0.98, 95% CI 0.80-1.20), length of intensive care unit stay (weighted mean differences, -0.68 days, 95% CI -3.65 to 2.30), duration of mechanical ventilation (weighted mean differences, 0.11 days, 95% CI -0.90 to 1.12), or episodes of airway occlusion (OR 2.26, 95% CI 0.55-9.28). HMEs were cheaper than HHs in each of the randomized controlled trials.Conclusion: The available evidence does not support the preferential performance of either passive or active humidifiers in mechanical ventilation patients in terms of ventilator-associated pneumonia incidence, mortality, or morbidity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although acute exacerbations of chronic bronchitis (AECBs) are common, there has been no metaanalysis that focused on the optimum regimen. METHODS: To evaluate the comparative effectiveness and safety of first-line antimicrobial agents (ie, amoxicillin, ampicillin, pivampicillin, trimethoprim/sulfamethoxazole, and doxycycline) and second-line antimicrobial agents (ie, amoxicillin/clavulanic acid, macrolides, second-generation or third-generation cephalosporins, and quinolones) for the treatment of patients with AECB, in an era of increasing antimicrobial resistance among the microbes responsible for AECB, we performed a metaanalysis of randomized controlled trials (RCTs) retrieved through searches of the PubMed and the Cochrane databases. RESULTS: Twelve RCTs were included in the metaanalysis. First-line antibiotics were associated with lower treatment success compared to second-line antibiotics in the clinically evaluable patients (odds ratio [OR], 0.51; 95% confidence interval [CI], 0.34 to 0.75). There were no differences among the compared regimens regarding mortality (OR, 0.64; 95% CI, 0.25 to 1.66) or treatment success (OR, 0.56; 95% CI, 0.22 to 1.43) in microbiologically evaluable patients, or adverse effects in general (OR, 0.75; 95% CI, 0.39 to 1.45) or diarrhea in particular (OR, 1.58; 95% CI, 0.74 to 3.35). CONCLUSIONS: Compared to first-line antibiotics, second-line antibiotics are more effective, but not less safe, when administered to patients with AECB. The available data did not allow for stratified analyses according to the presence of risk factors for poor outcome, such as increased age, impaired lung function, airway obstruction, and frequency of exacerbations; this fact should be taken into consideration when interpreting the findings of this metaanalysis. [ABSTRACT FROM AUTHOR]

Rationale: Because of the effects of aging on the respiratory system, it is conceivable that the association between driving pressure and mortality depends on age. Objectives: We endeavored to evaluate whether the association between driving pressure and mortality of patients with acute respiratory distress syndrome (ARDS) varies across the adult lifespan, hypothesizing that it is stronger in older, including very old (⩾80 yr), patients. Methods: We performed a secondary analysis of individual patient-level data from seven ARDS Network and PETAL Network randomized controlled trials ("ARDSNet cohort"). We tested our hypothesis in a second, independent, national cohort ("Hellenic cohort"). We performed both binary logistic and Cox regression analyses including the interaction term between age (as a continuous variable) and driving pressure at baseline (i.e., the day of trial enrollment) as the predictor and 90-day mortality as the dependent variable. Measurements and Main Results: On the basis of data from 4,567 patients with ARDS included in the ARDSNet cohort, we found that the effect of driving pressure on mortality depended on age ( P  = 0.01 for the interaction between age as a continuous variable and driving pressure). The difference in driving pressure between survivors and nonsurvivors significantly changed across the adult lifespan ( P  < 0.01). In both cohorts, a driving pressure threshold of 11 cm H 2 O was associated with mortality in very old patients. Conclusions: Data from randomized controlled trials with strict inclusion criteria suggest that the effect of driving pressure on the mortality of patients with ARDS may depend on age. These results may advocate for a personalized age-dependent mechanical ventilation approach.

Objectives: Optimal timing of tracheostomy in severe traumatic brain injury (TBI) is unknown due to lack of clinical trials. We emulated a target trial to estimate the effect of early vs. delayed tracheostomy strategy on functional outcome of patients with severe TBI., Design: Target trial emulation using 1:1 balanced risk-set matching., Setting: North American hospitals participating in the TBI Hypertonic Saline randomized controlled trial of the Resuscitation Outcomes Consortium., Patients: The prematching population consisted of patients with TBI and admission Glasgow Coma Scale less than or equal to 8, who were alive and on mechanical ventilation on the fourth day following trial enrollment, and stayed in the ICU for at least 5 days. Patients with absolute indication for tracheostomy and patients who died during the first 28 days with a decision to withdraw care were excluded., Interventions: We matched patients who received tracheostomy at a certain timepoint (early group) with patients who had not received tracheostomy at the same timepoint but were at-risk of tracheostomy in the future (delayed group). The primary outcome was a poor 6-month functional outcome, defined as Glasgow Outcome Scale-Extended less than or equal to 4., Measurements and Main Results: Out of 1282 patients available for analysis, 275 comprised the prematching population, with 75 pairs being created postmatching. Median time of tracheostomy differed significantly in the early vs. the delayed group (7.0 d [6.0-10.0 d] vs. 12.0 d [9.8-18.3 d]; p < 0.001). Only 40% of patients in the delayed group received tracheostomy. There was no statistically significant difference between groups regarding poor 6-month functional outcome (early: 68.0% vs. delayed: 72.0%; p = 0.593)., Conclusions: In a target trial emulation, early as opposed to delayed tracheostomy strategy was not associated with differences in 6-month functional outcome following severe TBI. Considering the limitations of target trial emulations, delaying tracheostomy through a "watchful waiting" approach may be appropriate., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Abstract: Background: Systemic venous congestion, assessed by the venous excess ultrasound (VExUS) score, has been associated with adverse effects, including acute kidney injury (AKI), in patients with cardiac disease. In general intensive care unit (ICU) patients, the association between VExUS score and outcomes is understudied. We aimed to investigate the association between the trajectory of VExUS score within the first 3 days of ICU admission and the composite clinical outcome of major adverse kidney events within 30 days (MAKE30). Methods: In this prospective observational study, including patients consecutively admitted to the ICU, VExUS score was calculated within 24 h after ICU admission (day 1) and at 48 to 72 h (day 3). D-VExUS was calculated as the difference between the VExUS score on day 3 minus that on day 1. Development of AKI within 7 days and all-cause mortality within 30 days were recorded. Results: A total of 89 patients (62% men; median age, 62 years; median Acute Physiology and Chronic Health Evaluation II score, 24) were included. Sixty (67%) patients developed AKI within 7 days, and 17 (19%) patients died within 30 days after ICU admission. D-VExUS was associated with MAKE30, even after adjustment for confounders (hazard ratio, 2.07; 95% confidence interval, 1.17-3.66; P = 0.01). VExUS scores on days 1 or 3 were not associated with MAKE30. Also, VExUS scores on day 1 or on day 3 and D-VExUS were not associated with development of AKI or mortality. Conclusions: In a general ICU cohort, early trajectory of VExUS score, but not individual VExUS scores at different time points, was associated with the patient-centered MAKE30 outcome. Dynamic changes rather than snapshot measurements may unmask the adverse effects of systemic venous congestion on important clinical outcomes., (Copyright © 2024 by the Shock Society.)

Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19., Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care)., Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61-1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64-1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09-0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality., Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19., Funding: Hellenic Foundation for Research and Innovation., Competing Interests: ACK was investigator for the National Institutes of Health Adaptive COVID-19 Treatment Trial. WBE was the site Principal Investigator for a therapeutics study funded by Gilead Sciences (funds to institution) during the past three years. WBE also reports grant funding support from the VA Health Services Research and Development Service (VA HSRD IIR 20-101, 20-076) and from the VA National Artificial Intelligence Institute. OH reports research funds from Roche. The remaining authors (IIS, DB, VCV, ABC, EP, KG, NAX, AK, RP, XM) report no conflicts of interest., (© 2024 The Authors.)

Abstract: Purpose: Trajectory of acute respiratory distress syndrome (ARDS) spans from rapidly improving cases to cases receiving prolonged mechanical ventilation (PMV). We attempted to estimate temporal trends of prevalence and mortality of PMV and to identify risk factors associated with mortality of patients with ARDS receiving PMV. Methods: We performed a secondary analysis of individual patient data from six randomized controlled clinical trials conducted by the ARDS Network. Prolonged mechanical ventilation was defined as the need for mechanical ventilation for >21 consecutive days. Results: Of 4,216 patients with ARDS, 646 (15.3%) received PMV. Prevalence of PMV gradually declined from 18.4% in the ARDS Network: Low-Tidal-Volume Trial (published in 2000) trial to 10.9% in the SAILS (2014) trial ( R2 = 0.728, P = 0.031). Ninety-day mortality of patients receiving PMV did not change over time ( R2 = 0.271, P = 0.290) and remained as high as 36.8%. Ιn the three most recent trials, risk factors associated with mortality among the 250 patients with ARDS receiving PMV included age, malignancy, pneumonia as the cause of ARDS, coagulation dysfunction, and hepatic dysfunction during the first 21 days after trial enrollment. Conclusion: Although prevalence of PMV among patients enrolled in ARDS Network trials gradually declined, mortality did not change. Risk factors associated with mortality were mostly nonmodifiable., Competing Interests: BTT received grants from the National Heart, Lung, and Blood Institute and personal fees from Bayer, Novartis, and Genentech outside the submitted work. The other authors report no conflict of interests., (Copyright © 2023 by the Shock Society.)

Background: The Acute Respiratory Distress Syndrome (ARDS) is characterized by lung inflammation and edema, impairing both oxygenation and lung compliance. Recent studies reported a dissociation between oxygenation and compliance (severe hypoxemia with preserved compliance) in early ARDS and COVID-19-related-ARDS (CARDS). During the pandemic, in patients requiring prolonged mechanical ventilation, we observed the opposite combination (mild-moderate hypoxemia but significantly impaired compliance). The purpose of our study was to investigate the prevalence of this combination of mild-moderate hypoxemia and impaired compliance in persistent ARDS and CARDS., Methods: For this retrospective study, we used individual patient-level data from two independent cohorts of ARDS patients. The ARDSNet cohort included patients from four ARDS Network randomized controlled trials. The CARDS cohort included patients with ARDS due to COVID-19 hospitalized in two intensive care units in Greece. We used a threshold of 150 for PaO 2 /FiO 2 and 30 ml/cmH 2 O for compliance, estimated the prevalence of each of the four combinations of oxygenation and compliance at baseline, and examined the change in its prevalence from baseline to day 21 in the ARDSNet and CARDS cohorts., Results: The ARDSNet cohort included 2909 patients and the CARDS cohort included 349 patients. The prevalence of the combination of mild-moderate hypoxemia and low compliance increased from baseline to day 21 both in the ARDSNet cohort (from 22.2 to 42.7%) and in the CARDS cohort (from 3.1 to 33.3%). Among surviving patients with low compliance, oxygenation improved over time. The 60-day mortality rate was higher for patients who had mild-moderate hypoxemia and low compliance on day 21 (28% and 56% in ARDSNet and CARDS), compared to those who had mild-moderate hypoxemia and high compliance (20% and 50%, respectively)., Conclusions: Among patients with ARDS who require prolonged controlled mechanical ventilation, regardless of ARDS etiology, a dissociation between oxygenation and compliance characterized by mild-moderate hypoxemia but low compliance becomes increasingly prevalent. The findings of this study highlight the importance of monitoring mechanics in patients with persistent ARDS., (© 2023. The Author(s).)

Purpose: There is growing interest in improving the inclusiveness of racial and ethnic minority participants in trials of acute respiratory distress syndrome (ARDS). With our study we aimed to examine temporal trends of representation and mortality of racial and ethnic minority participants in randomized controlled trials of ARDS., Methods: We performed a secondary analysis of eight ARDS Network and PETAL Network therapeutic clinical trials, published between 2000 and 2019. We classified race/ethnicity into "White", "Black", "Hispanic", or "Other" (including Asian, American Indian or Alaskan Native, Native Hawaiian, or other Pacific Islander participants)., Results: Of 5375 participants with ARDS, 1634 (30.4%) were Black, Hispanic, or Other race participants. Representation of racial and ethnic minority participants in trials did not change significantly over time (p = 0.257). However, among participants with moderate to severe ARDS (i.e., partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 150), the difference in mortality between racial and ethnic minority participants and White participants decreased over time. In the five most recent trials, including 2923 participants with ARDS, there were no statistically significant differences in mortality between racial/ethnic groups, even after adjusting for potential confounders. In these five most recent trials, mortality was 31% for White, 31.9% for Black, 30.3% for Hispanic, and 37.1% for Other race participants (p = 0.633)., Conclusion: Representation of racial and ethnic minority participants in ARDS trials from North America, published between 2000 and 2019, did not change over time. Black and Hispanic participants with ARDS may have similar mortality as White participants within trials., (© 2023. The Author(s).)

Background: Acute respiratory distress syndrome is a potentially fatal postoperative complication. We aimed to estimate temporal trends of the representation of patients with postoperative acute respiratory distress syndrome in clinical trials, determine their distinct clinical features, and identify predictors of mortality., Methods: This is a secondary analysis of 7 randomized controlled clinical trials conducted by the Acute Respiratory Distress Syndrome Network and the Clinical Trials Network for the Prevention and Early Treatment of Acute Lung Injury. Patients with acute respiratory distress syndrome were classified into a postoperative acute respiratory distress syndrome group (ie, patients who had undergone elective surgery in the immediate period before trial enrollment) and a non-postoperative acute respiratory distress syndrome group., Results: Out of 5,316 patients with acute respiratory distress syndrome, 256 (4.8%) had postoperative acute respiratory distress syndrome. Representation of postoperative acute respiratory distress syndrome in trials gradually declined from 2000 to 2011, but it remained stable afterward at 2.7%. Postoperative acute respiratory distress syndrome was associated with lower 90-day mortality (24.6% vs 30.9%, P = .032) than non-postoperative acute respiratory distress syndrome, even after adjusting for age, acute respiratory distress syndrome severity, usage of vasopressors at baseline, and the study publication year (hazard ratio 0.63, 95% confidence interval 0.49-0.82). Age (odds ratio 1.07, 95% confidence interval 1.04-1.09), immunosuppression (odds ratio 4.12, 95% confidence interval 1.43-11.86), and positive fluid balance (odds ratio 1.09, 95% confidence interval 1.04-1.14) were associated with 90-day mortality among patients with postoperative acute respiratory distress syndrome., Conclusion: Representation of postoperative acute respiratory distress syndrome in trials of the Acute Respiratory Distress Syndrome Network and the Clinical Trials Network for the Prevention and Early Treatment of Acute Lung Injury gradually declined from 2000 to 2011 but remained stable afterward. Postoperative acute respiratory distress syndrome was associated with lower mortality than non-postoperative acute respiratory distress syndrome. These findings may put both temporal trends and the prognosis of postoperative acute respiratory distress syndrome in perspective. Also, positive fluid balance was associated with the mortality of patients with postoperative acute respiratory distress syndrome., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Study Objective: Despite the almost universal administration of supplemental oxygen in patients presenting in the emergency department (ED) with severe traumatic brain injury, optimal early oxygenation levels are unknown. Therefore, we aimed to examine the effect of different early oxygenation levels on the clinical outcomes of patients presenting in the emergency department with severe traumatic brain injury., Methods: We performed a secondary analysis of the Resuscitation Outcomes Consortium Traumatic Brain Injury Hypertonic Saline randomized controlled trial by including patients with Glasgow Coma Scale ≤8. Early oxygenation levels were assessed by the worst value of arterial partial pressure of oxygen (PaO 2 ) during the first 4 hours of presentation in the emergency department. The primary outcome was 6-month neurologic status, as assessed by the Extended Glasgow Outcome Scale. A binary logistic regression was utilized, and an odds ratio (OR) with 95% (95% confidence intervals) was calculated., Results: A total of 910 patients were included. In unadjusted (crude) analysis, a PaO 2 of 101 to 250 mmHg (OR, 0.59 [0.38 to 0.91]), or 251 to 400 mmHg (OR, 0.53 [0.34 to 0.83]) or ≥401 mmHg (OR, 0.31 [0.20 to 0.49]) was less likely to be associated with poor neurologic status when compared with a PaO 2 of ≤100 mmHg. This was also the case for adjusted analyses (including age, pupillary reactivity, and Revised Trauma Score)., Conclusion: High oxygenation levels as early as the first 4 hours of presentation in the emergency department may not be adversely associated with the long-term neurologic status of patients with severe traumatic brain injury. Therefore, during the early phase of trauma, clinicians may focus on stabilizing patients while giving low priority to the titration of oxygenation levels., (Copyright © 2022 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Importance: Although vaccination substantially reduces the risk of severe COVID-19, it is yet unknown whether vaccinated patients who develop COVID-19 and require invasive mechanical ventilation have lower mortality than controls., Objective: To examine the association between COVID-19 vaccination status and mortality among critically ill patients who require invasive mechanical ventilation owing to acute respiratory distress syndrome (ARDS) related to COVID-19., Design, Setting, and Participants: This multicenter cohort study was performed between June 7, 2021, and February 1, 2022, among 265 consecutive adult patients with COVID-19 in academic intensive care units who underwent invasive mechanical ventilation owing to ARDS., Exposures: Patients in the full vaccination group had completed the primary COVID-19 vaccination series more than 14 days but less than 5 months prior to intubation. This time threshold was chosen because guidelines from the US Centers for Disease Control and Prevention recommend a booster dose beyond that time. The remaining patients (ie, those who were unvaccinated, partially vaccinated, or fully vaccinated <14 days or >5 months before intubation) comprised the control group., Main Outcomes and Measures: The primary outcome was time from intubation to all-cause intensive care unit mortality. A Cox proportional hazards regression model including vaccination status, age, comorbid conditions, and baseline Sequential Organ Failure Assessment score on the day of intubation was used., Results: A total of 265 intubated patients (170 men [64.2%]; median age, 66.0 years [IQR, 58.0-76.0 years]; 26 [9.8%] in the full vaccination group) were included in the study. A total of 20 patients (76.9%) in the full vaccination group received the BNT162b2 vaccine, and the remaining 6 (23.1%) received the ChAdOx1 nCoV-19 vaccine. Patients in the full vaccination group were older (median age, 72.5 years [IQR, 62.8-80.0 years] vs 66.0 years [IQR, 57.0-75.0 years]) and more likely to have comorbid conditions (24 of 26 [92.3%] vs 160 of 239 [66.9%]), including malignant neoplasm (6 of 26 [23.1%] vs 18 of 239 [7.5%]), than those in the control group. Full vaccination status was significantly associated with lower mortality compared with controls (16 of 26 patients [61.5%] died in the full vaccination group vs 163 of 239 [68.2%] in the control group; hazard ratio, 0.55 [95% CI, 0.32-0.94]; P = .03)., Conclusions and Relevance: In this cohort study, full vaccination status was associated with lower mortality compared with controls, which suggests that vaccination might be beneficial even among patients who were intubated owing to COVID-19-related ARDS. These results may inform discussions with families about prognosis.

Background: Although older adults are at high risk for severe coronavirus disease 2019 (COVID-19) requiring intensive care unit (ICU) admission, age is often used as a selection criterion in case of ICU beds scarcity. We sought to compare the proportion, clinical features and mortality between patients ≥70 years old and younger ICU patients with COVID-19., Methods: All patients, consecutively admitted to our COVID ICU, where age was not used as an admission criterion, from March 2020 through April 2021, were included. Demographics, clinical and laboratory characteristics were recorded. Illness severity and Charlson comorbidity Index (CCI) were calculated. Patients≥70 years old were compared to youngers., Results: Of 458 patients (68 [59-76] years, 70% males), 206 (45%) were ≥70 years old. Compared to younger, older patients had higher illness severity scores (APACHE II 18 [14-23] versus 12 [9-16], P<0.001, SOFA 8 [6-10] versus 6 [2-8], P<0.001, CCI 5 [4-6] versus 2 [1-3], P<0.001), increased need for mechanical ventilation (92% vs. 72%, P<0.001) and ICU mortality (74% versus. 29%, P<0.001). Age (HR: 1.045, CI: 1.02-1.07, P=0.001), CCI (HR: 1.135, CI: 1.037-1.243, P=0.006) and APACHE II (HR: 1.070, CI: 1.013-1.130, P=0.015) were independently associated with mortality. Among comorbidities, obesity, chronic pulmonary disease and chronic kidney disease were independent risk factors for death., Conclusions: When age is not used as criterion for admission to COVID ICU, patients ≥70 years old represent a considerable proportion and, compared to younger ones, they have higher mortality. Age, severity of illness and CCI, and certain comorbidities are independent risk factors for mortality.

Background: We attempted to investigate the change in mortality of intubated patients with coronavirus disease (COVID-19) from first to subsequent waves across several countries., Methods: We pre-registered our meta-analysis with PROSPERO [Anonymized]. We searched PubMed, Scopus, and gray literature for observational studies reporting data on all-cause mortality of intubated patients with COVID-19 recruited both during first and subsequent waves of the pandemic. We considered studies published after 31 August 2020 up to 12 July 2021. The primary outcome of the meta-analysis was all-cause mortality. We used a random effects model to calculate pooled risk ratio (RR) and 95% confidence intervals (CI)., Results: By incorporating data of 363,660 patients from 43 countries included in 28 studies, we found that all-cause mortality of intubated patients with COVID-19 increased from first to subsequent waves (from 62.2% to 72.6%; RR 0.90, 95% CI 0.85-0.94, p < 0.00001). This finding was independent of the geo-economic variation of the included studies and persisted in several pre-specified subgroup and sensitivity analyses., Conclusions: The robust finding of this meta-analysis suggests that mortality of intubated patients with COVID-19 did not improve over time. Future research should target this group of patients to further optimize their management.

Purpose: Optimal timing of intubation is controversial. We attempted to investigate the association between timing of intubation and clinical outcomes of critically ill patients., Methods: PubMed was systematically searched for studies reporting on mortality of critically ill patients undergoing early versus late intubation. Studies involving patients with new coronavirus disease (COVID-19) were excluded because a relevant meta-analysis has been published. "Early" intubation was defined according to the authors of the included studies. All-cause mortality was the primary outcome. Pooled risk ratio (RR) and 95% confidence intervals (CI) were calculated using a random effects model. The meta-analysis was registered with PROSPERO (CRD42021284850)., Results: In total, 27 studies involving 15,441 intubated patients (11,943 early, 3498 late) were included. All-cause mortality was lower in patients undergoing early versus late intubation (7338 deaths; 45.8% versus 53.5%; RR 0.92, 95% CI 0.87-0.97; p = 0.001). This was also the case in the sensitivity analysis of studies defining "early" as intubation within 24 h from admission in the intensive care unit (6279 deaths; 45.8% versus 53.6%; RR 0.93, 95% CI 0.89-0.98; p = 0.005)., Conclusion: Avoiding late intubation may be associated with lower mortality in critically ill patients without COVID-19., Competing Interests: Declaration of Competing Interest None declared for all authors., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Before the pandemic of coronavirus disease (COVID-19), rapidly improving acute respiratory distress syndrome (ARDS), mostly defined by early extubation, had been recognized as an increasingly prevalent subphenotype (making up 15-24% of all ARDS cases), associated with good prognosis (10% mortality in ARDSNet trials). We attempted to determine the prevalence and prognosis of rapidly improving ARDS and of persistent severe ARDS related to COVID-19., Methods: We included consecutive patients with COVID-19 receiving invasive mechanical ventilation in three intensive care units (ICU) during the second pandemic wave in Greece. We defined rapidly improving ARDS as extubation or a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO 2 :FiO 2 ) greater than 300 on the first day following intubation. We defined persistent severe ARDS as PaO 2 :FiO 2  of equal to or less than 100 on the second day following intubation., Results: A total of 280 intubated patients met criteria of ARDS with a median PaO 2 :FiO 2  of 125.0 (interquartile range 93.0-161.0) on day of intubation, and overall ICU-mortality of 52.5% (ranging from 24.3 to 66.9% across the three participating sites). Prevalence of rapidly improving ARDS was 3.9% (11 of 280 patients); no extubation occurred on the first day following intubation. ICU-mortality of patients with rapidly improving ARDS was 54.5%. This low prevalence and high mortality rate of rapidly improving ARDS were consistent across participating sites. Prevalence of persistent severe ARDS was 12.1% and corresponding mortality was 82.4%., Conclusions: Rapidly improving ARDS was not prevalent and was not associated with good prognosis among patients with COVID-19. This is starkly different from what has been previously reported for patients with ARDS not related to COVID-19. Our results on both rapidly improving ARDS and persistent severe ARDS may contribute to our understanding of trajectory of ARDS and its association with prognosis in patients with COVID-19., (© 2022. The Author(s).)

Background: Whether vitamin C provides any benefit when administered in critically ill patients, including those with coronavirus disease (COVID-19), is controversial. We endeavored to estimate the effect of administration of vitamin C on clinical outcomes of critically ill patients with COVID-19 by performing an observational study and subsequent meta-analysis., Methods: Firstly, we conducted an observational study of critically ill patients with laboratory-confirmed COVID-19 who consecutively underwent invasive mechanical ventilation in an academic intensive care unit (ICU) during the second pandemic wave. We compared all-cause mortality of patients receiving vitamin C ("vitamin C" group) or not ("control" group) on top of standard-of-care. Subsequently, we systematically searched PubMed and CENTRAL for relevant studies, which reported on all-cause mortality (primary outcome) and/or morbidity of critically ill patients with COVID-19 receiving vitamin C or not treatment. Pooled risk ratio (RR) and 95% confidence intervals (CI) were calculated using a random effects model. The meta-analysis was registered with PROSPERO., Results: In the observational study, baseline characteristics were comparable between the two groups. Mortality was 20.0% (2/10) in the vitamin C group vs. 47.6% (49/103; p = 0.11) in the control group. Subsequently, the meta-analysis included 11 studies (6 observational; five randomized controlled trials) enrolling 1,807 critically ill patients with COVID-19. Mortality of patients receiving vitamin C on top of standard-of-care was not lower than patients receiving standard-of-care alone (25.8 vs. 34.7%; RR 0.85, 95% CI 0.57-1.26; p = 0.42)., Conclusions: After combining results of our observational cohort with those of relevant studies into a meta-analysis of data from 1,807 patients, we found that administration vitamin C as opposed to standard-of-care alone might not be associated with lower of mortality among critically ill patients with COVID-19. Additional evidence is anticipated from relevant large randomized controlled trials which are currently underway., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42021276655., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gavrielatou, Xourgia, Xixi, Mantelou, Ischaki, Kanavou, Zervakis, Routsi, Kotanidou and Siempos.)

We investigated the effect of prone ventilation on right ventricular (RV) function of intubated patients with COVID-19-associated acute respiratory distress syndrome by measuring both conventional RV functional variables (namely, tricuspid annular peak systolic velocity, tricuspid annular plane systolic excursion, and fractional area change) and right ventricular free wall strain (RVFWS) using transthoracic speckle-tracking echocardiography at baseline (before prone positioning), 18 hours after prone positioning, and 1 hour after supine repositioning. We found that transthoracic echocardiography was feasible in a considerable proportion (nine patients, 75% of our cohort) of patients undergoing prone ventilation. Also, abnormal as opposed to normal RVFWS values (in the absence of conventional variables of RV dysfunction) at baseline were associated with higher mortality (100% vs 20%; p = 0.048). Finally, we found that, among patients without acute cor pulmonale or conventional markers of RV dysfunction, one session of prone ventilation may not affect right myocardial strain., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Objectives: This report aims to characterize the kinetics of serum albumin in critically ill patients with coronavirus disease 2019 compared with critically ill patients with sepsis-induced acute respiratory distress syndrome., Design: Retrospective analysis., Setting: We analyzed two critically ill cohorts, one with coronavirus disease 2019 and another with sepsis-induced acute respiratory distress syndrome, treated in the New York Presbyterian Hospital-Weill Cornell Medical Center., Patients: Adult patients in the coronavirus disease 2019 cohort, diagnosed through reverse transcriptase-polymerase chain reaction assays performed on nasopharyngeal swabs, were admitted from March 3, 2020, to July 10, 2020. Adult patients in the sepsis-induced acute respiratory distress syndrome cohort, defined by Sepsis III criteria receipt of invasive mechanical ventilation and a Pao 2 /Fio 2 ratio less than 300 were admitted from December 12, 2006, to February 26, 2019., Interventions: None., Measurements and Main Results: We evaluated serial serum albumin levels within 30 days after ICU admission in each cohort. We then examined the albumin progression trajectories, aligned at ICU admission time to test the relationship at a similar point in disease progression, in survivors and nonsurvivors. Albumin trajectory in all critically ill coronavirus disease 2019 patients show two distinct phases: phase I (deterioration) showing rapid albumin loss and phase II (recovery) showing albumin stabilization or improvement. Meanwhile, albumin recovery predicted clinical improvement in critical coronavirus disease 2019. In addition, we found a deterioration and recovery trends in survivors in the sepsis-induced acute respiratory distress syndrome cohort but did not find such two-phase trend in nonsurvivors., Conclusions: The changes in albumin associated with coronavirus disease 2019 associated respiratory failure are transient compared with sepsis-associated acute respiratory distress syndrome and highlight the potential for recovery following a protracted course of severe coronavirus disease 2019., Competing Interests: Dr. Wang is supported by National Science Foundation-Information and Intelligent Systems 2027970, 1750326, Office of Naval Research N00014-18-1-2585. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Although acute respiratory distress syndrome (ARDS) is associated with high mortality, its direct causal link with death is unclear. Clarifying this link is important to justify costly research on prevention of ARDS., Objective: To estimate the attributable mortality, if any, of ARDS., Design: First, we performed a systematic review and meta-analysis of observational studies reporting mortality of critically ill patients with and without ARDS matched for underlying risk factor. Next, we conducted a survival analysis of prospectively collected patient-level data from subjects enrolled in three intensive care unit (ICU) cohorts to estimate the attributable mortality of critically ill septic patients with and without ARDS using a novel causal inference method., Results: In the meta-analysis, 44 studies (47 cohorts) involving 56 081 critically ill patients were included. Mortality was higher in patients with versus without ARDS (risk ratio 2.48, 95% CI 1.86 to 3.30; p<0.001) with a numerically stronger association between ARDS and mortality in trauma than sepsis. In the survival analysis of three ICU cohorts enrolling 1203 critically ill patients, 658 septic patients were included. After controlling for confounders, ARDS was found to increase the mortality rate by 15% (95% CI 3% to 26%; p=0.015). Significant increases in mortality were seen for severe (23%, 95% CI 3% to 44%; p=0.028) and moderate (16%, 95% CI 2% to 31%; p=0.031), but not for mild ARDS., Conclusions: ARDS has a direct causal link with mortality. Our findings provide information about the extent to which continued funding of ARDS prevention trials has potential to impart survival benefit., Prospero Registration Number: CRD42017078313., Competing Interests: Competing interests: AMKC is a cofounder and stock holder of and serves on the Scientific Advisory Board for Proterris, which develops therapeutic uses for carbon monoxide. He also has a use patent on carbon monoxide. He served as a consultant for an advisory board meeting of Teva Pharmaceutical Industries, July 2018. RMB serves on the Advisory Board for Merck. LEF reports clinical trials support from Asahi Kasei Pharma America. None declared: LKT, KH, CO, ID, JSH, EJS, DRP, LG-E, AH, MPV, JWH and IIS., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: The Sequential Organ Failure Assessment (SOFA) tool is a commonly used measure of illness severity. Calculation of the respiratory subscore of SOFA is frequently limited by missing arterial oxygen pressure (Pa O 2 ) data. Although missing Pa O 2 data are commonly replaced with normal values, the performance of different methods of substituting Pa O 2 for SOFA calculation is unclear. Objectives: The study objective was to compare the performance of different substitution strategies for missing Pa O 2 data for SOFA score calculation. Methods: This retrospective cohort study was performed using the Weill Cornell Critical Care Database for Advanced Research from a tertiary care hospital in the United States. All adult patients admitted to an intensive care unit (ICU) from 2011 to 2019 with an available respiratory SOFA score were included. We analyzed the availability of the Pa O 2 /fraction of inspired oxygen (Fi O 2 ) ratio on the first day of ICU admission. In those without a Pa O 2 /Fi O 2 ratio available, the ratio of oxygen saturation as measured by pulse oximetry to Fi O 2 was used to calculate a respiratory SOFA subscore according to four methods (linear substitution [Rice], nonlinear substitution [Severinghaus], modified respiratory SOFA, and multiple imputation by chained equations [MICE]) as well as the missing-as-normal technique. We then compared how well the different total SOFA scores discriminated in-hospital mortality. We performed several subgroup and sensitivity analyses. Results: We identified 35,260 unique visits, of which 9,172 included predominant respiratory failure. Pa O 2 data were available for 14,939 (47%). The area under the receiver operating characteristic curve for each substitution technique for discriminating in-hospital mortality was higher than that for the missing-as-normal technique (0.78 [0.77-0.79]) in all analyses (modified, 0.80 [0.79-0.81]; Rice, 0.80 [0.79-0.81]; Severinghaus, 0.80 [0.79-0.81]; and MICE, 0.80 [0.79-0.81]) ( P < 0.01). Each substitution method had a higher accuracy for discriminating in-hospital mortality (MICE, 0.67; Rice, 0.67; modified, 0.66; and Severinghaus, 0.66) than the missing-as-normal technique. Model calibration for in-hospital mortality was less precise for the missing-as-normal technique than for the other substitution techniques at the lower range of SOFA and among the subgroups. Conclusions: Using physiologic and statistical substitution methods improved the total SOFA score's ability to discriminate mortality compared with the missing-as-normal technique. Treating missing data as normal may result in underreporting the severity of illness compared with using substitution. The simplicity of a direct oxygen saturation as measured by pulse oximetry/Fi O 2 ratio-modified SOFA technique makes it an attractive choice for electronic health record-based research. This knowledge can inform comparisons of severity of illness across studies that used different techniques.

Background: Although several international guidelines recommend early over late intubation of patients with severe coronavirus disease 2019 (COVID-19), this issue is still controversial. We aimed to investigate the effect (if any) of timing of intubation on clinical outcomes of critically ill patients with COVID-19 by carrying out a systematic review and meta-analysis., Methods: PubMed and Scopus were systematically searched, while references and preprint servers were explored, for relevant articles up to December 26, 2020, to identify studies which reported on mortality and/or morbidity of patients with COVID-19 undergoing early versus late intubation. "Early" was defined as intubation within 24 h from intensive care unit (ICU) admission, while "late" as intubation at any time after 24 h of ICU admission. All-cause mortality and duration of mechanical ventilation (MV) were the primary outcomes of the meta-analysis. Pooled risk ratio (RR), pooled mean difference (MD) and 95% confidence intervals (CI) were calculated using a random effects model. The meta-analysis was registered with PROSPERO (CRD42020222147)., Results: A total of 12 studies, involving 8944 critically ill patients with COVID-19, were included. There was no statistically detectable difference on all-cause mortality between patients undergoing early versus late intubation (3981 deaths; 45.4% versus 39.1%; RR 1.07, 95% CI 0.99-1.15, p = 0.08). This was also the case for duration of MV (1892 patients; MD - 0.58 days, 95% CI - 3.06 to 1.89 days, p = 0.65). In a sensitivity analysis using an alternate definition of early/late intubation, intubation without versus with a prior trial of high-flow nasal cannula or noninvasive mechanical ventilation was still not associated with a statistically detectable difference on all-cause mortality (1128 deaths; 48.9% versus 42.5%; RR 1.11, 95% CI 0.99-1.25, p = 0.08)., Conclusions: The synthesized evidence suggests that timing of intubation may have no effect on mortality and morbidity of critically ill patients with COVID-19. These results might justify a wait-and-see approach, which may lead to fewer intubations. Relevant guidelines may therefore need to be updated.

Background: Optimal timing of initiation of invasive mechanical ventilation in patients with acute hypoxemic respiratory failure due to COVID-19 is unknown. Thanks to early flattening of the epidemiological curve, ventilator demand in Greece was kept lower than supply throughout the pandemic, allowing for unbiased comparison of the outcomes of patients undergoing early intubation vs. delayed or no intubation. Methods: We conducted an observational study including all adult patients with laboratory-confirmed COVID-19 consecutively admitted in Evangelismos Hospital, Athens, Greece between March 11, 2020 and April 15, 2020. Patients subsequently admitted in the intensive care unit (ICU) were categorized into the "early intubation" vs. the "delayed or no intubation" group. The "delayed or no intubation" group included patients receiving non-rebreather mask for equal to or more than 24 h or high-flow nasal oxygen for any period of time or non-invasive mechanical ventilation for any period of time in an attempt to avoid intubation. The remaining intubated patients comprised the "early intubation" group. Results: During the study period, a total of 101 patients (37% female, median age 65 years) were admitted in the hospital. Fifty-nine patients (58% of the entire cohort) were exclusively hospitalized in general wards with a mortality of 3% and median length of stay of 7 days. Forty-two patients (19% female, median age 65 years) were admitted in the ICU; all with acute hypoxemic respiratory failure. Of those admitted in the ICU, 62% had at least one comorbidity and 14% were never intubated. Early intubation was not associated with higher ICU-mortality (21 vs. 33%), fewer ventilator-free days (3 vs. 2 days) or fewer ICU-free days than delayed or no intubation. Conclusions: A strategy of early intubation was not associated with worse clinical outcomes compared to delayed or no intubation. Given that early intubation may presumably reduce virus aerosolization, these results may justify further research with a randomized controlled trial., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Siempos, Xourgia, Ntaidou, Zervakis, Magira, Kotanidou, Routsi and Zakynthinos.)

Purpose: To provide clinical practice recommendations and generate a research agenda on mechanical ventilation and respiratory support in patients with acute brain injury (ABI)., Methods: An international consensus panel was convened including 29 clinician-scientists in intensive care medicine with expertise in acute respiratory failure, neurointensive care, or both, and two non-voting methodologists. The panel was divided into seven subgroups, each addressing a predefined clinical practice domain relevant to patients admitted to the intensive care unit (ICU) with ABI, defined as acute traumatic brain or cerebrovascular injury. The panel conducted systematic searches and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method was used to evaluate evidence and formulate questions. A modified Delphi process was implemented with four rounds of voting in which panellists were asked to respond to questions (rounds 1-3) and then recommendation statements (final round). Strong recommendation, weak recommendation, or no recommendation were defined when > 85%, 75-85%, and < 75% of panellists, respectively, agreed with a statement., Results: The GRADE rating was low, very low, or absent across domains. The consensus produced 36 statements (19 strong recommendations, 6 weak recommendations, 11 no recommendation) regarding airway management, non-invasive respiratory support, strategies for mechanical ventilation, rescue interventions for respiratory failure, ventilator liberation, and tracheostomy in brain-injured patients. Several knowledge gaps were identified to inform future research efforts., Conclusions: This consensus provides guidance for the care of patients admitted to the ICU with ABI. Evidence was generally insufficient or lacking, and research is needed to demonstrate the feasibility, safety, and efficacy of different management approaches.

Dermato-neuro syndrome is a potentially fatal neurological complication of scleromyxedema consisting of fever, seizures, and coma. This is an overlooked scleromyxedema case of a 62-year-old female patient from 2-years ago. She was admitted to our ICU because of high fever, colloid speech, muscle ache, and nausea. Molecular methods in the cerebrospinal fluid for neurotropic viruses ruled out acute infectious encephalitis. Her thyroid hormones were within normal values while the serum protein electrophoresis confirmed the monoclonal gammopathy of immunoglobulin G lambda (IgG(λ)), known for the last 2 years. The subsequent bone-marrow biopsy excluded the development of multiple myeloma. The patient fulfilled fundamental diagnostic criteria of scleromyxedema (monoclonal gammopathy, normal thyroid function and the appearance of marked sclerosis and induration of the skin papules on the face, neck, extremities, and skin creases) presenting as dermato-neuro syndrome, which was histologically confirmed. She demonstrated a remarkable improvement after intravenous immunoglobulin treatment during the first 24 hours. Mimics of non-infectious acute encephalitis should include the clinical diagnosis of scleromyxedema, especially when patients present in the emergency department with acute fever, coma, and skin lesions of diffuse sclerodermoid and papular type., (Copyright © 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Purpose: Whether cancer is associated with worse prognosis among patients with COVID-19 is unknown. We aimed to quantify the effect (if any) of the presence as opposed to absence of cancer on important clinical outcomes of patients with COVID-19 by carrying out a systematic review and meta-analysis., Methods: We systematically searched PubMed, medRxiv, COVID-19 Open Research Dataset (CORD-19), and references of relevant articles up to April 27, 2020, to identify observational studies comparing patients with versus without cancer infected with COVID-19 and to report on mortality and/or need for admission to the intensive care unit (ICU). We calculated pooled risk ratios (RR) and 95% CIs with a random-effects model. The meta-analysis was registered with PROSPERO (CRD42020181531)., Results: A total of 32 studies involving 46,499 patients (1,776 patients with cancer) with COVID-19 from Asia, Europe, and the United States were included. All-cause mortality was higher in patients with versus those without cancer (2,034 deaths; RR, 1.66; 95% CI, 1.33 to 2.07; P < .0001; 8 studies with 37,807 patients). The need for ICU admission was also more likely in patients with versus without cancer (3,220 events; RR, 1.56; 95% CI, 1.31 to 1.87; P < .0001; 26 studies with 15,375 patients). However, in a prespecified subgroup analysis of patients > 65 years of age, all-cause mortality was comparable between those with versus without cancer (915 deaths; RR, 1.06; 95% CI, 0.79 to 1.41; P = .71; 8 studies with 5,438 patients)., Conclusion: The synthesized evidence suggests that cancer is associated with worse clinical outcomes among patients with COVID-19. However, elderly patients with cancer may not be at increased risk of death when infected with COVID-19. These findings may inform discussions of clinicians with patients about prognosis and may guide health policies.

Background: Acute respiratory distress syndrome (ARDS) is heterogeneous. As an indication of the heterogeneity of ARDS, there are patients whose syndrome improves rapidly (i.e., within 24 hours), others whose hypoxemia improves gradually and still others whose severe hypoxemia persists for several days. The latter group of patients with persistent severe ARDS poses challenges to clinicians. We attempted to assess the baseline characteristics and outcomes of persistent severe ARDS and to identify which variables are useful to predict it., Methods: A secondary analysis of patient-level data from the ALTA, EDEN and SAILS ARDSNet clinical trials was conducted. We defined persistent severe ARDS as a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) of equal to or less than 100 mmHg on the second study day following enrollment. Regularized logistic regression with an L1 penalty [Least Absolute Shrinkage and Selection Operator (LASSO)] techniques were used to identify predictive variables of persistent severe ARDS., Results: Of the 1531 individuals with ARDS alive on the second study day after enrollment, 232 (15%) had persistent severe ARDS. Of the latter, 100 (43%) individuals had mild or moderate hypoxemia at baseline. Usage of vasopressors was greater [144/232 (62%) versus 623/1299 (48%); p<0.001] and baseline severity of illness was higher in patients with versus without persistent severe ARDS. Mortality at 60 days [95/232 (41%) versus 233/1299 (18%); p<0.001] was higher, and ventilator-free (p<0.001), intensive care unit-free [0 (0-14) versus 19 (7-23); p<0.001] and non-pulmonary organ failure-free [3 (0-21) versus 20 (1-26); p<0.001] days were fewer in patients with versus without persistent severe ARDS. PaO2:FiO2, FiO2, hepatic failure and positive end-expiratory pressure at enrollment were useful predictive variables., Conclusions: Patients with persistent severe ARDS have distinct baseline characteristics and poor prognosis. Identifying such patients at enrollment may be useful for the prognostic enrichment of trials., Competing Interests: The corresponding author has read the journal’s policy and the authors of this manuscript have the following competing interests: AMC is a co-founder of Proterris and serving as a consultant for an advisory board meeting of Teva Pharmaceutical Industries, July 2018. None declared (ES, DRP, KPC, CO, EJS, IIS). This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Background: Despite numerous publications on mitochondrial DNA (mtDNA) in the last decade it remains to be seen whether mtDNA can be used clinically. We conducted a systematic review to assess circulating cell-free mtDNA as a biomarker of mortality in critically ill patients., Methods: This systematic review was registered with PROSPERO (CRD42016046670). PubMed, CINAHL, the Cochrane Library, Embase, Scopus, and Web of Science, and reference lists of retrieved articles were searched. Studies measuring circulating cell-free mtDNA and reporting on all-cause mortality in critically ill adult and pediatric patients were included. The primary and secondary outcomes were mortality and morbidity, respectively., Results: Of the 1,566 initially retrieved publications, 40 studies were included, accounting for 3,450 critically ill patients. Substantial differences between studies were noted in how mtDNA was isolated and measured. Sixteen of the 40 included studies (40%) explored the association between mtDNA levels and mortality; of those 16 studies, 11 (68.8%) reported a statistically significant association. The area under the receiver operating characteristic (AUROC) curve for mtDNA and mortality was calculated for 10 studies and ranged from 0.61 to 0.95., Conclusions: There is growing interest in mtDNA as a predictor of mortality in critically ill patients. Most studies are small, lack validation cohorts, and utilize different protocols to measure mtDNA. When reported, AUROC analysis usually suggests a statistically significant association between mtDNA and mortality. Standardization of mtDNA protocols and the completion of a large, prospective, multicenter trial may be warranted to firmly establish the clinical usefulness of mtDNA., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: In sepsis, there may be dysregulation in programed cell death pathways, typified by apoptosis and necroptosis. Programmed cell death pathways may contribute to variability in the immune response. TRAIL is a potent inducer of apoptosis. Receptor-interacting serine/threonine protein kinase-3 (RIPK3) is integral to the execution of necroptosis. We explored whether plasma TRAIL levels were associated with in-hospital mortality, organ dysfunction, and septic shock. We also explored the relationship between TRAIL and RIPK3., Methods: We performed an observational study of critically ill adults admitted to intensive care units at 3 academic medical centers across 2 continents, using 1 as derivation and the other 2 as validation cohorts. Levels of TRAIL were measured in the plasma of 570 subjects by ELISA., Results: In all cohorts, lower (<28.5 pg/ml) versus higher levels of TRAIL were associated with increased organ dysfunction (P ≤ 0.002) and septic shock (P ≤ 0.004). Lower TRAIL levels were associated with in-hospital mortality in 2 of 3 cohorts (Weill Cornell-Biobank of Critical Illness, P = 0.012; Brigham and Women's Hospital Registry of Critical Illness, P = 0.011; Asan Medical Center, P = 0.369). Lower TRAIL was also associated with increased RIPK3 (P ≤ 0.001)., Conclusion: Lower levels of TRAIL were associated with septic shock and organ dysfunction in 3 independent ICU cohorts. TRAIL was inversely associated with RIPK3 in all cohorts., Funding: NIH (R01-HL055330 and KL2-TR002385).

Background: Observational studies suggest that some patients meeting criteria for ARDS no longer fulfill the oxygenation criterion early in the course of their illness. This subphenotype of rapidly improving ARDS has not been well characterized. We attempted to assess the prevalence, characteristics, and outcomes of rapidly improving ARDS and to identify which variables are useful to predict it., Methods: A secondary analysis was performed of patient level data from six ARDS Network randomized controlled trials. We defined rapidly improving ARDS, contrasted with ARDS > 1 day, as extubation or a Pao 2 to Fio 2 ratio (Pao 2 :Fio 2 ) > 300 on the first study day following enrollment., Results: The prevalence of rapidly improving ARDS was 10.5% (458 of 4,361 patients) and increased over time. Of the 1,909 patients enrolled in the three most recently published trials, 197 (10.3%) were extubated on the first study day, and 265 (13.9%) in total had rapidly improving ARDS. Patients with rapidly improving ARDS had lower baseline severity of illness and lower 60-day mortality (10.2% vs 26.3%; P < .0001) than ARDS > 1 day. Pao 2 :Fio 2 at screening, change in Pao 2 :Fio 2 from screening to enrollment, use of vasopressor agents, Fio 2 at enrollment, and serum bilirubin levels were useful predictive variables., Conclusions: Rapidly improving ARDS, mostly defined by early extubation, is an increasingly prevalent and distinct subphenotype, associated with better outcomes than ARDS > 1 day. Enrollment of patients with rapidly improving ARDS may negatively affect the prognostic enrichment and contribute to the failure of therapeutic trials., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Purpose: We examined whether patients with acute respiratory distress syndrome (ARDS) lacking risk factors are enrolled in therapeutic trials and assessed their clinical characteristics and outcomes., Methods: We performed a secondary analysis of patient-level data pooled from the ARMA, ALVEOLI, FACTT, ALTA and EDEN ARDSNet randomized controlled trials obtained from the Biologic Specimen and Data Repository Information Coordinating Center of the National Heart, Lung and Blood Institute. We compared baseline characteristics and clinical outcomes (before and after adjustment using Poisson regression model) of ARDS patients with versus without risk factors., Results: Of 3733 patients with ARDS, 81 (2.2%) did not have an identifiable risk factor. Patients without risk factors were younger, had lower baseline severity of illness, were more likely to have the ARDS resolve rapidly (i.e., within 24 h) (p < 0.001) and they had more ventilator-free days (median 21; p = 0.003), more intensive care unit-free days (18; p = 0.010), and more non-pulmonary organ failure-free days (24; p < 0.001) than comparators (17, 14 and 18, respectively). Differences persisted after adjustment for potential confounders., Conclusions: Patients with ARDS without identifiable risk factors are enrolled in therapeutic trials and may have better outcomes, including a higher proportion of rapidly resolving ARDS, than those with risk factors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Necroptosis is a form of programmed necrotic cell death that is rapidly emerging as an important pathophysiological pathway in numerous disease states. Necroptosis is dependent on receptor-interacting protein kinase 3 (RIPK3), a protein shown to play an important role in experimental models of critical illness. However, there is limited clinical evidence regarding the role of extracellular RIPK3 in human critical illness., Methods: Plasma RIPK3 levels were measured in 953 patients prospectively enrolled in 5 ongoing intensive care unit (ICU) cohorts in both the USA and Korea. RIPK3 concentrations among groups were compared using prospectively collected phenotypic and outcomes data., Results: In all 5 cohorts, extracellular RIPK3 levels in the plasma were higher in patients who died in the hospital compared with those who survived to discharge. In a combined analysis, increasing RIPK3 levels were associated with elevated odds of in-hospital mortality (odds ratio [OR] 1.7 for each log10-unit increase in RIPK3 level, P < 0.0001). When adjusted for baseline severity of illness, the OR for in-hospital mortality remained statistically significant (OR 1.33, P = 0.007). Higher RIPK3 levels were also associated with more severe organ failure., Conclusions: Our findings suggest that elevated levels of RIPK3 in the plasma of patients admitted to the ICU are associated with in-hospital mortality and organ failure., Funding: Supported by NIH grants P01 HL108801, R01 HL079904, R01 HL055330, R01 HL060234, K99 HL125899, and KL2TR000458-10. Supported by Samsung Medical Center grant SMX1161431.

In patients requiring ventilator support, mechanical ventilation (MV) may induce acute lung injury (ventilator-induced lung injury [VILI]). VILI is associated with substantial morbidity and mortality in mechanically ventilated patients with and without acute respiratory distress syndrome. At the cellular level, VILI induces necrotic cell death. However, the contribution of necroptosis, a programmed form of necrotic cell death regulated by receptor-interacting protein-3 kinase (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), to the development of VILI remains unexplored. Here, we show that plasma levels of RIPK3, but not MLKL, were higher in patients with MV (i.e., those prone to VILI) than in patients without MV (i.e., those less likely to have VILI) in two large intensive care unit cohorts. In mice, RIPK3 deficiency, but not MLKL deficiency, ameliorated VILI. In both humans and mice, VILI was associated with impaired fatty acid oxidation (FAO), but in mice this association was not observed under conditions of RIPK3 deficiency. These findings suggest that FAO-dependent RIPK3 mediates pathogenesis of acute lung injury.