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Despite the almost universal administration of supplemental oxygen in patients presenting in the emergency department 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.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 (PaOA total of 910 patients were included. In unadjusted (crude) analysis, a PaOHigh 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.

Cellular lipid metabolism has been linked to immune responses; however, the precise mechanisms by which de novo fatty acid synthesis can regulate inflammatory responses remain unclear. The NLRP3 inflammasome serves as a platform for caspase-1–dependent maturation and secretion of proinflammatory cytokines. Here, we demonstrated that the mitochondrial uncoupling protein-2 (UCP2) regulates NLRP3-mediated caspase-1 activation through the stimulation of lipid synthesis in macrophages. UCP2-deficient mice displayed improved survival in a mouse model of polymicrobial sepsis. Moreover, UCP2 expression was increased in human sepsis. Consistently, UCP2-deficient mice displayed impaired lipid synthesis and decreased production of IL-1β and IL-18 in response to LPS challenge. In macrophages, UCP2 deficiency suppressed NLRP3-mediated caspase-1 activation and NLRP3 expression associated with inhibition of lipid synthesis. In UCP2-deficient macrophages, inhibition of lipid synthesis resulted from the downregulation of fatty acid synthase (FASN), a key regulator of fatty acid synthesis. FASN inhibition by shRNA and treatment with the chemical inhibitors C75 and cerulenin suppressed NLRP3-mediated caspase-1 activation and inhibited NLRP3 and pro–IL-1β gene expression in macrophages. In conclusion, our results suggest that UCP2 regulates the NLRP3 inflammasome by inducing the lipid synthesis pathway in macrophages. These results identify UCP2 as a potential therapeutic target in inflammatory diseases such as sepsis.

Optimal timing of intubation is controversial. We attempted to investigate the association between timing of intubation and clinical outcomes of critically ill patients.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).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).Avoiding late intubation may be associated with lower mortality in critically ill patients without COVID-19.

We attempted to investigate the change in mortality of intubated patients with coronavirus disease (COVID-19) from first to subsequent waves across several countries. 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). 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. 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.

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.

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 (PaO2:FiO2) greater than 300 on the first day following intubation. We defined persistent severe ARDS as PaO2:FiO2 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 PaO2:FiO2 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.

OBJECTIVES:. Since changes in pharmacological treatments for severely ill patients with coronavirus disease 2019 have been incorporated into clinical practice, both by their use (corticosteroids and remdesivir) and by stopping them (e.g., hydroxychloroquine), we sought to compare the rate of intubation and mortality of intubated patients in our ICUs between the first and second waves of the pandemic. DESIGN:. Single-center, observational. SETTING:. Four coronavirus disease 2019 designated ICUs at an urban Greek teaching hospital. PATIENTS:. All adult patients with coronavirus disease 2019 consecutively admitted to ICU during the first (n = 50) and second (n = 212) waves of the pandemic. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. The percentage of intubated ICU patients dropped from 82% during the first wave to 66% during the second wave (p = 0.042). However, the absolute number of intubated ICU patients was lower during the first than the second wave (41 vs 140 patients). ICU or hospital mortality of intubated patients increased from 39% during the first wave to 60% during the second wave (p = 0.028). The binary logistic regression for hospital mortality as the dependent variable in intubated patients and covariates the age, Acute Physiology and Chronic Health Evaluation II score, cardiovascular comorbidity, lactate, positive end-expiratory pressure, Sequential Organ Failure Assessment score, and wave, distinguished only Acute Physiology and Chronic Health Evaluation II (odds ratio, 1.40 with 95% CI, 1.14—1.72; p = 0.001) as the sole independent predictor of hospital mortality. CONCLUSIONS:. Pharmacological adaptations and other measures may have led to fewer intubations over time. However, these changes do not seem to be translated into improved outcomes of intubated patients. Perhaps the same change in the use of drugs and protocols that could cause fewer intubations of ICU patients might be a reason of increased mortality in those patients who are eventually intubated. Furthermore, the relative staff inexperience and overall increase in patients’ comorbidities during the second wave could have contributed to increased Acute Physiology and Chronic Health Evaluation II score and mortality of intubated patients.

ImportanceAlthough 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.ObjectiveTo 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 ParticipantsThis 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.ExposuresPatients 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 5 months before intubation) comprised the control group.Main Outcomes and MeasuresThe 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.ResultsA 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 RelevanceIn 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.

BackgroundAlthough 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.ObjectiveTo estimate the attributable mortality, if any, of ARDS.DesignFirst, 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.ResultsIn 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; pConclusionsARDS 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 NumberCRD42017078313

COVID-19 outcomes like mortality have been associated with albumin alteration. However, it is unclear whether albumin changes in COVID-19 are pathogen specific or not. To this end, we characterized the kinetics of serum albumin in mechanically ventilated patients with COVID-19 compared to mechanically ventilated patients with sepsis-induced Acute Respiratory Distress Syndrome (ARDS). We discovered two phases of alterations in albumin levels during the course of Covid-19 critical illness, but not for the sepsis-induced ARDS. Our findings suggest the metabolic effects of COVID-19 are pathogen-specific and albumin recovery may signal the cessation of a deleterious immune response in this disease.

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

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.

Background According to the literature, 20–30% of intubated patients are difficult to wean off mechanical ventilation and have a prolonged intensive care unit (ICU) stay with detrimental effects on muscle strength, functional ability and quality of life. Inspiratory muscle training (IMT) via a threshold device has been proposed as an effective exercise for minimising the effects of mechanical ventilation on respiratory muscles of critically ill patients with prolonged weaning. In addition, high-flow nasal cannula (HFNC) oxygen has been proved to provide efficient support for both high- and low-risk patients after extubation, thus preventing re-intubation. Material and methods A randomised controlled trial was designed to assess the efficacy of combining IMT and HFNC as therapeutic strategies for patients with high risk for weaning failure. Once patients with prognostic factors of difficult weaning are awake, ventilated with support settings and cooperative, they will be randomised to one of the two following study groups: intervention group (IMT and HFNC) and control group (IMT and Venturi mask). IMT will start as soon as possible. Each allocated oxygen delivery device will be applied immediately after extubation. IMT intervention will continue until patients' discharge from ICU. The primary outcome is the rate of weaning failure. Secondary outcomes are maximal inspiratory and expiratory strength, endurance of respiratory muscles, global muscle strength, functional ability and quality of life along with duration of ventilation (days) and ICU and hospital length of stay. Conclusion The present study could significantly contribute to knowledge of how best to treat patients with difficult weaning and high risk of re-intubation., This RCT will provide a therapeutic strategic plan for difficult-to-wean patients, minimising their intubation period and length of ICU stay https://bit.ly/37CkxTB

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 versus 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” versus the “delayed or no 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, 62% with at least one comorbidity, 14% never intubated) were admitted in the ICU; all with acute hypoxemic respiratory failure. Early intubation was not associated with higher ICU-mortality (21% versus 33%), fewer ventilator-free days (3 versus 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.

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 hours) (p

Rationale: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a major public health concern with high mortality and morbidity. Although inflammatory responses triggered by infection are crucial for host defense against invading microbes, the excessive inflammation often causes tissue damage leading to organ dysfunction. Resolution of inflammation, an active immune process mediated by endogenous lipid mediators (LMs), is important to maintain host homeostasis.Objectives: We sought to determine the role of the nucleotide-binding domain, leucine-rich repeat–containing receptor, pyrin domain–containing-3 (NLRP3) inflammasome in polymicrobial sepsis and regulation of LM biosynthesis.Methods: We performed cecal ligation and puncture (CLP) using mice lacking NLRP3 inflammasome-associated molecules to assess mortality. Inflammation was evaluated by using biologic fluids including plasma, bronchoalveolar, and peritoneal lavage fluid. Local acting LMs in peritoneal ...

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.

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 (

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.

BackgroundAcute 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.MethodsA 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.ResultsOf 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%); pConclusionsPatients 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.

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.

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 Pao2 to Fio2 ratio (Pao2:Fio2) > 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 1 day. Pao2:Fio2 at screening, change in Pao2:Fio2 from screening to enrollment, use of vasopressor agents, Fio2 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.

Background Acute respiratory distress syndrome (ARDS) is potentially underrecognized by clinicians. Early recognition and subsequent optimal treatment of patients with ARDS may be facilitated by usage of biomarkers. Surfactant protein D (SP-D), a marker of alveolar epithelial injury, has been proposed as a potentially useful biomarker for diagnosis of ARDS in a few studies. We tried to validate the performance of plasma SP-D levels for diagnosis of ARDS. Methods We conducted a retrospective analysis using data from three (two in USA and one in Korea) prospective biobank cohorts involving 407 critically ill patients admitted to medical intensive care unit (ICU). A propensity score matched analysis (patients with versus without ARDS, matched 1:1) was carried out using significant variables from multiple logistic regression. The diagnostic accuracy of plasma SP-D as a diagnostic marker of ARDS was assessed by receiver operating characteristic curve analysis. Results Out of the 407 subjects included in this study, 39 (10%) patients fulfilled ARDS criteria. Patients with ARDS had higher SP-D levels in plasma (p

Summary Background Delay of tracheostomy for roughly 2 weeks after translaryngeal intubation of critically ill patients is the presently recommended practice and is supported by findings from large trials. However, these trials were suboptimally powered to detect small but clinically important effects on mortality. We aimed to assess the benefit of early versus late or no tracheostomy on mortality and pneumonia in critically ill patients who need mechanical ventilation. Methods We systematically searched PubMed, CINAHL, Embase, Web of Science, DOAJ, the Cochrane Library, references of relevant articles, scientific conference proceedings, and grey literature up to Aug 31, 2013, to identify randomised controlled trials comparing early tracheostomy (done within 1 week after translaryngeal intubation) with late (done any time after the first week of mechanical ventilation) or no tracheostomy and reporting on mortality or incidence of pneumonia in critically ill patients under mechanical ventilation. Our primary outcomes were all-cause mortality during the stay in the intensive-care unit and incidence of ventilator-associated pneumonia. Mortality during the stay in the intensive-care unit was a composite endpoint of definite intensive-care-unit mortality, presumed intensive-care-unit mortality, and 28-day mortality. We calculated pooled odds ratios (OR), pooled risk ratios (RR), and 95% CIs with a random-effects model. All but complications analyses were done on an intention-to-treat basis. Findings Analyses of 13 trials (2434 patients, 648 deaths) showed that all-cause mortality in the intensive-care unit was not significantly lower in patients assigned to the early versus the late or no tracheostomy group (OR 0·80, 95% CI 0·59–1·09; p=0·16). This result persisted when we considered only trials with a low risk of bias (511 deaths; OR 0·80, 95% CI 0·59–1·09; p=0·16; eight trials with 1934 patients). Incidence of ventilator-associated pneumonia was lower in mechanically ventilated patients assigned to the early versus the late or no tracheostomy group (691 cases; OR 0·60, 95% CI 0·41–0·90; p=0·01; 13 trials with 1599 patients). There was no evidence of a difference between the compared groups for 1-year mortality (788 deaths; RR 0·93, 95% CI 0·85–1·02; p=0·14; three trials with 1529 patients). Interpretation The synthesised evidence suggests that early tracheostomy is not associated with lower mortality in the intensive-care unit than late or no tracheostomy. However, early, compared with late or no, tracheostomy might be associated with a lower incidence of pneumonia; a finding that could question the present practice of delaying tracheostomy beyond the first week after translaryngeal intubation in mechanically ventilated patients. Nevertheless, the scarcity of a beneficial effect on long-term mortality and the potential complications associated with tracheostomy need careful consideration; thus, further studies focusing on long-term outcomes are warranted. Funding None.