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Background: Single nucleotide polymorphisms in the myosin light chain kinase (MYLK) gene have been implicated in the risk of sepsis-related acute lung injury and asthma. MYLK encodes protein isoforms involved in multiple components of the inflammatory response, including apoptosis, vascular permeability, and leukocyte diapedesis. We tested the association of MYLK gene variation in the development of acute lung injury in major trauma patients.Methods: We conducted a prospective cohort study of 273 subjects with major trauma (injury severity score > or = 16). All x-rays and clinical data were reviewed by three clinicians for acute lung injury classification. A total of 17 tagging single nucleotide polymorphisms in MYLK were genotyped. Single nucleotide polymorphisms were individually assessed at the genotype level, and multiple logistic regression models were used to adjust for baseline variables. Haplotype analyses of sliding windows including 2-5 single nucleotide polymorphisms were conducted.Results: Ninety-one of the 273 subjects (33%) met criteria for acute lung injury within 5 days of traumatic insult. Three informative MYLK coding single nucleotide polymorphisms were individually associated with acute lung injury, with two informative risk-conferring genotypes His21Pro (CC genotype, odds ratio = 1.87, 95% confidence interval 1.06-3.33; p = 0.022) and Pro147Ser (TT, odds ratio = 2.13, 95% confidence interval 1.14-4.10; p = 0.011) more frequent than the noninformative Thr335Thr CC genotype (odds ratio = 0.42, 95% confidence interval 0.20-0.85; p = 0.010). Each of these genotypic associations was more pronounced in African Americans with trauma. Multivariate analyses demonstrated the association of each MYLK single nucleotide polymorphism with acute lung injury to be independent of age, injury severity score, Acute Physiology and Chronic Health Evaluation III, and the mechanism of trauma. Finally, haplotype analyses revealed strong acute lung injury associations with 2-4 single nucleotide polymorphism haplotypes, all involving His21Pro (p < 0.008).Conclusions: Three MYLK coding single nucleotide polymorphisms previously associated with sepsis-induced acute lung injury and severe asthma in African Americans were associated with acute lung injury development after trauma in African Americans, although effect directions differed. These results confirm our prior studies implicating MYLK as a susceptibility gene in a distinct acute lung injury subset other than sepsis. [ABSTRACT FROM AUTHOR]

Objectives: Multiple organ failure in critically ill patients is associated with poor prognosis, but biomarkers contributory to pathogenesis are unknown. Previous studies support a role for Fas cell surface death receptor (Fas)-mediated apoptosis in organ dysfunction. Our objectives were to test for associations between soluble Fas and multiple organ failure, identify protein quantitative trait loci, and determine associations between genetic variants and multiple organ failure., Design: Retrospective observational cohort study., Setting: Four academic ICUs at U.S. hospitals., Patients: Genetic analyses were completed in a discovery (n = 1,589) and validation set (n = 863). Fas gene expression and flow cytometry studies were completed in outpatient research participants (n = 250)., Interventions: None., Measurements and Main Results: In discovery and validation sets of critically ill patients, we tested for associations between enrollment plasma soluble Fas concentrations and Sequential Organ Failure Assessment score on day 3. We conducted a genome-wide association study of plasma soluble Fas (discovery n = 1,042) and carried forward a single nucleotide variant in the FAS gene, rs982764, for validation (n = 863). We further tested whether the single nucleotide variant in FAS (rs982764) was associated with Sequential Organ Failure Assessment score, FAS transcriptional isoforms, and Fas cell surface expression. Higher plasma soluble Fas was associated with higher day 3 Sequential Organ Failure Assessment scores in both the discovery (β = 4.07; p < 0.001) and validation (β = 6.96; p < 0.001) sets. A single nucleotide variant in FAS (rs982764G) was associated with lower plasma soluble Fas concentrations and lower day 3 Sequential Organ Failure Assessment score in meta-analysis (-0.21; p = 0.02). Single nucleotide variant rs982764G was also associated with a lower relative expression of the transcript for soluble as opposed to transmembrane Fas and higher cell surface expression of Fas on CD4+ T cells., Conclusions: We found that single nucleotide variant rs982764G was associated with lower plasma soluble Fas concentrations in a discovery and validation population, and single nucleotide variant rs982764G was also associated with lower organ dysfunction on day 3. These findings support further study of the Fas pathway as a potential mediator of organ dysfunction in critically ill patients., Competing Interests: Dr. Mikacenic’s institution received funding from the National Center for Advancing Translational Sciences (UL1 TR002319), the National Heart, Lung, and Blood Institute (NHLBI) (R01HL060710, RC2 HL101779), the National Institute on Aging (U19AG023122), the National Institute of allergy and Infectious Diseases (AI101990, AI083455), and the National Institute of Diabetes and Digestive and Kidney Issues (DK097672). Drs. Mikacenic, Bhatraju, Robinson-Cohen, Long, Cerosaletti, Calfee, Matthay, Christie, Meyer, Christiani, and Wurfel received support for article research from the National Institutes of Health (NIH). Drs. Cerosaletti’s, Calfee’s, and Meyer’s institutions received funding from the NIH. Dr. Cerosaletti’s institution received funding from the Department of Defense, the American Diabetes Association, and the Juvenile Diabetes Research Foundation. Drs. Calfee’s and Matthay’s institutions received funding from Gentech/Roche. Dr. Calfee’s institution received funding from Bayer; she received funding from Quark, Vasomune, Gen1e Life Sciences, and Prometic. Dr. Matthay received funding from Novartis and Citius Pharmaceuticals. Dr. Russell received funding from Asahi Kesai Pharmaceuticals of America, IB Therapeutics LLC, and Ferring Pharmaceuticals; he received funding from Grifols; he disclosed that he is the inventor of two patents owned by the University of British Colombia and Ferring, that he is a founder, director, and shareholder in Cyon Therapetutics Inc and a shareholder in Molecular You Corp, and that he is a member of the Data Safety Monitoring Board of an NIH-sponsored trial of plasma in coronavirus disease 2019 (Passive Immunity Trial for Our Nation to Treat COVID-19 in Hospitalized Adults [PassItOn]). Dr. Meyer’s institution received funding from the NHLBI (HL137006, HL137915), Quantum Leap Healthcare Collaborative, Biomarck, Inc, Athersys, Inc, and The Marcus Foundation. Dr. Wurfel’s institution received funding from the NHLBI. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objectives: Circulating nucleosomes and their component histones have been implicated as pathogenic in sepsis and acute respiratory distress syndrome in adults. However, their role in pediatric acute respiratory distress syndrome is unknown., Design: We performed a prospective cohort study in children with acute respiratory distress syndrome, with plasma collection within 24 hours of acute respiratory distress syndrome onset. We associated nucleosome levels with severity of acute respiratory distress syndrome and with nonpulmonary organ failures and tested for association of nucleosomes with PICU mortality and ventilator-free days at 28 days in univariate and multivariable analyses. We also performed proteomics of DNA-bound plasma proteins in a matched case-control study of septic children with and without acute respiratory distress syndrome in order to identify specific histone proteins elevated in acute respiratory distress syndrome., Setting: Large academic tertiary-care PICU., Patients: Intubated children meeting Berlin criteria for acute respiratory distress syndrome., Interventions: None., Measurements and Main Results: We enrolled 333 children with acute respiratory distress syndrome, with 69 nonsurvivors (21%). Plasma nucleosomes were correlated with acute respiratory distress syndrome severity and with the number of nonpulmonary organ failures at acute respiratory distress syndrome onset. Nucleosomes were higher (p < 0.001) in nonsurvivors (0.40 [interquartile range, 0.20-0.71] arbitrary units) relative to survivors (0.10 [interquartile range, 0.04-0.25] arbitrary units). Nucleosomes were associated with PICU mortality in multivariable analysis (adjusted odds ratio 1.84 per 1 sd increase; 95% CI, 1.38-2.45; p < 0.001). Nucleosomes were also associated with a lower probability of being extubated alive by day 28 after multivariable adjustment (adjusted subdistribution hazard ratio, 0.74; 95% CI, 0.63-0.88; p = 0.001). Proteomic analysis demonstrated higher levels of the core nucleosome histones H2A, H2B, H3, and H4 in septic children with acute respiratory distress syndrome, relative to septic children without acute respiratory distress syndrome., Conclusions: Plasma nucleosomes are associated with acute respiratory distress syndrome severity, nonpulmonary organ failures, and worse outcomes in pediatric acute respiratory distress syndrome., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objective: Plasma interleukin-1 beta may influence sepsis mortality, yet recombinant human interleukin-1 receptor antagonist did not reduce mortality in randomized trials. We tested for heterogeneity in the treatment effect of recombinant human interleukin-1 receptor antagonist by baseline plasma interleukin-1 beta or interleukin-1 receptor antagonist concentration., Design: Retrospective subgroup analysis of randomized controlled trial., Setting: Multicenter North American and European clinical trial., Patients: Five hundred twenty-nine subjects with sepsis and hypotension or hypoperfusion, representing 59% of the original trial population., Interventions: Random assignment of placebo or recombinant human interleukin-1 receptor antagonist × 72 hours., Measurements and Main Results: We measured prerandomization plasma interleukin-1 beta and interleukin-1 receptor antagonist and tested for statistical interaction between recombinant human interleukin-1 receptor antagonist treatment and baseline plasma interleukin-1 receptor antagonist or interleukin-1 beta concentration on 28-day mortality. There was significant heterogeneity in the effect of recombinant human interleukin-1 receptor antagonist treatment by plasma interleukin-1 receptor antagonist concentration whether plasma interleukin-1 receptor antagonist was divided into deciles (interaction p = 0.046) or dichotomized (interaction p = 0.028). Interaction remained present across different predicted mortality levels. Among subjects with baseline plasma interleukin-1 receptor antagonist above 2,071 pg/mL (n = 283), recombinant human interleukin-1 receptor antagonist therapy reduced adjusted mortality from 45.4% to 34.3% (adjusted risk difference, -0.12; 95% CI, -0.23 to -0.01), p = 0.044. Mortality in subjects with plasma interleukin-1 receptor antagonist below 2,071 pg/mL was not reduced by recombinant human interleukin-1 receptor antagonist (adjusted risk difference, +0.07; 95% CI, -0.04 to +0.17), p = 0.230. Interaction between plasma interleukin-1 beta concentration and recombinant human interleukin-1 receptor antagonist treatment was not statistically significant., Conclusions: We report a heterogeneous effect of recombinant human interleukin-1 receptor antagonist on 28-day sepsis mortality that is potentially predictable by plasma interleukin-1 receptor antagonist in one trial. A precision clinical trial of recombinant human interleukin-1 receptor antagonist targeted to septic patients with high plasma interleukin-1 receptor antagonist may be worthy of consideration.

Objectives: There are no current pharmacological therapies for the prevention or treatment of acute respiratory distress syndrome. Early dysregulated inflammation likely plays a role in acute respiratory distress syndrome development and possibly acute respiratory distress syndrome outcomes. p38 mitogen-activated protein kinase is central to the regulation of multiple inflammatory mediators implicated in acute organ dysfunction and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. In preclinical models, p38 inhibitors reduce lung injury following pancreatitis and burn injury., Design: We conducted a phase IIa, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and tolerability of dilmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in patients at risk for developing acute respiratory distress syndrome admitted with an Injury Severity Score more than 16, excluding head trauma. Enrolled patients received 4- or 24-hour IV dilmapimod infusions at different doses or placebo, daily for 3 days, in four separate cohorts., Setting: Multicenter randomized clinical trial of large, academic trauma centers., Measurements and Main Results: Seventy-seven patients were enrolled. Although adverse events were common in this critically ill population, dilmapimod was well tolerated, with no clinically relevant safety findings. Pharmacokinetic models indicated that the higher dose of 10 mg given as continuous infusion over 24 hours had the most favorable plasma concentration profile. Likewise, measures of soluble inflammatory markers including interleukin-6, C-reactive peptide, interleukin-8, and soluble tumor necrosis factor receptor 1 were most different between this dosing arm and placebo. Although the study was not specifically designed with acute respiratory distress syndrome as an outcome, the number of patients who developed acute respiratory distress syndrome was small (2/77)., Conclusions: The novel p38 mitogen-activated protein kinase inhibitor dilmapimod appears well tolerated and may merit further evaluation for prevention of acute respiratory distress syndrome and other organ injury in larger clinical trials. Furthermore, results of this early-phase trial may aid in design of future studies aimed at prevention of acute respiratory distress syndrome and other organ injury.

Objectives: Septic shock is associated with increased long-term morbidity and mortality. However, little is known about the use of hospital-based acute care in survivors after hospital discharge. The objectives of the study were to examine the frequency, timing, causes, and risk factors associated with emergency department visits and hospital readmissions within 30 days of discharge., Design: Retrospective cohort study., Setting: Tertiary, academic hospital in the United States., Patients: Patients admitted with septic shock (serum lactate≥4 mmol/L or refractory hypotension) and discharged alive to a nonhospice setting between 2007 and 2010., Interventions: None., Measurements and Main Results: The coprimary outcomes were all-cause hospital readmission and emergency department visits (treat-and-release encounters) within 30 days to any of the three health system hospitals. Of 269 at-risk survivors, 63 (23.4%; 95% CI, 18.2-28.5) were readmitted within 30 days of discharge and another 12 (4.5%; 95% CI, 2.3-7.7) returned to the emergency department for a treat-and-release visit. Readmissions occurred within 15 days of discharge in 75% of cases and were more likely in oncology patients (p=0.001) and patients with a longer hospital length of stay (p=0.04). Readmissions were frequently due to another life-threatening condition and resulted in death or discharge to hospice in 16% of cases. The reasons for readmission were deemed potentially related to the index septic shock hospitalization in 78% (49 of 63) of cases. The most common cause was infection related, accounting for 46% of all 30-day readmissions, followed by cardiovascular or thromboembolic events (18%)., Conclusions: The use of hospital-based acute care appeared to be common in septic shock survivors. Encounters often led to readmission within 15 days of discharge, were frequently due to another acute condition, and appeared to result in substantial morbidity and mortality. Given the potential public health implications of these findings, validation studies are needed.

Objectives: Higher body mass index is associated with increased risk of acute kidney injury after major trauma. Since body mass index is nonspecific, reflecting lean, fluid, and adipose mass, we evaluated the use of CT to determine if abdominal adiposity underlies the body mass index-acute kidney injury association., Design: Prospective cohort study., Setting: Level I Trauma Center of a university hospital., Patients: Patients older than 13 years with an Injury Severity Score greater than or equal to 16 admitted to the trauma ICU were followed for development of acute kidney injury over 5 days. Those with isolated severe head injury or on chronic dialysis were excluded., Interventions: None., Measurements and Main Results: Clinical, anthropometric, and demographic variables were collected prospectively. CT images at the level of the L4-5 intervertebral disc space were extracted from the medical record and used by two operators to quantitate visceral adipose tissue and subcutaneous adipose tissue areas. Acute kidney injury was defined by Acute Kidney Injury Network creatinine and dialysis criteria. Of 400 subjects, 327 (81.8%) had CT scans suitable for analysis: 264 of 285 (92.6%) blunt trauma subjects and 63 of 115 (54.8%) penetrating trauma subjects. Visceral adipose tissue and subcutaneous adipose tissue areas were highly correlated between operators (intraclass correlation > 0.99, p < 0.001 for each) and within operator (intraclass correlation > 0.99, p < 0.001 for each). In multivariable analysis, the standardized risk of acute kidney injury was 15.1% (95% CI, 10.6-19.6%), 18.1% (14-22.2%), and 23.1% (18.3-27.9%) at the 25th, 50th, and 75th percentiles of visceral adipose tissue area, respectively (p = 0.001), with similar findings when using subcutaneous adipose tissue area as the adiposity measure., Conclusions: Quantitation of abdominal adiposity using CT scans obtained for clinical reasons is feasible and highly reliable in critically ill trauma patients. Abdominal adiposity is independently associated with acute kidney injury in this population, confirming that excess adipose tissue contributes to the body mass index-acute kidney injury association. Further studies of the potential mechanisms linking adiposity with acute kidney injury are warranted.

Objectives: Clinical trials in septic shock continue to fail due, in part, to inequitable and sometimes unknown distribution of baseline mortality risk between study arms. Investigators advocate that interventional trials in septic shock require effective outcome risk stratification. We derived and tested a multibiomarker-based approach to estimate mortality risk in adults with septic shock., Design: Previous genome-wide expression studies identified 12 plasma proteins as candidates for biomarker-based risk stratification. The current analysis used banked plasma samples and clinical data from existing studies. Biomarkers were assayed in plasma samples obtained from 341 subjects with septic shock within 24 hours of admission to the ICU. Classification and regression tree analysis was used to generate a decision tree predicting 28-day mortality based on a combination of both biomarkers and clinical variables. The derived tree was first tested in an independent cohort of 331 subjects, then calibrated using all subjects (n = 672), and subsequently validated in another independent cohort (n = 209)., Setting: Multiple ICUs in Canada, Finland, and the United States., Subjects: Eight hundred eighty-one adults with septic shock or severe sepsis., Intervention: None., Measurements and Main Results: The derived decision tree included five candidate biomarkers, admission lactate concentration, age, and chronic disease burden. In the derivation cohort, sensitivity for mortality was 94% (95% CI, 87-97), specificity was 56% (50-63), positive predictive value was 50% (43-57), and negative predictive value was 95% (89-98). Performance was comparable in the test cohort. The calibrated decision tree had the following test characteristics in the validation cohort: sensitivity 85% (76-92), specificity 60% (51-69), positive predictive value 61% (52-70), and negative predictive value 85% (75-91)., Conclusions: We have derived, tested, calibrated, and validated a risk stratification tool and found that it reliably estimates the probability of mortality in adults with septic shock.

Objectives: Formal guidelines recommend that therapeutic hypothermia be considered after in-hospital cardiac arrest. The rate of therapeutic hypothermia use after in-hospital cardiac arrest and details about its implementation are unknown. We aimed to determine the use of therapeutic hypothermia for adult in-hospital cardiac arrest, whether use has increased over time, and to identify factors associated with its use., Design: Multicenter, prospective cohort study., Setting: A total of 538 hospitals participating in the Get With the Guidelines-Resuscitation database (2003-2009)., Patients: A total of 67,498 patients who had return of spontaneous circulation after in-hospital cardiac arrest., Interventions: None., Measurements and Main Results: The primary outcome was the initiation of therapeutic hypothermia. We measured the proportion of therapeutic hypothermia patients who achieved target temperature (32-34 °C) and were overcooled. Of 67,498 patients, therapeutic hypothermia was initiated in 1,367 patients (2.0%). The target temperature (32-34 °C) was not achieved in 44.3% of therapeutic hypothermia patients within 24 hours and 17.6% were overcooled. The use of therapeutic hypothermia increased from 0.7% in 2003 to 3.3% in 2009 (p < 0.001). We found that younger age (p < 0.001) and occurrence in a non-ICU location (p < 0.001), on a weekday (p = 0.005), and in a teaching hospital (p = 0.001) were associated with an increased likelihood of therapeutic hypothermia being initiated., Conclusions: After in-hospital cardiac arrest, therapeutic hypothermia was used rarely. Once initiated, the target temperature was commonly not achieved. The frequency of use increased over time but remained low. Factors associated with therapeutic hypothermia use included patient age, time and location of occurrence, and type of hospital.

Objectives: : To examine the association of the resident work-hours reform with mortality for patients in medical and surgical intensive care units. The United States instituted restrictions on resident work-hours in July 2003. The clinical impact of this reform on critically ill patients is unknown., Design: : A retrospective cohort study, comparing mortality trends before and after July 1, 2003, in teaching and nonteaching hospitals., Setting and Patients: : The study included 230,151 adult patients admitted to 104 different intensive care units at 40 hospitals participating in the Acute Physiology and Chronic Health Evaluation IV clinical information system from July 1, 2001, to June 30, 2005., Interventions: : None., Measurements and Main Results: : The primary exposure was the date of admission, relative to the implementation of the work-hours regulations. The primary outcome was in-hospital mortality; a secondary outcome was intensive care unit mortality. The analysis included 79,377 patients in 12 academic hospitals; 73,580 patients in 12 community hospitals with residents; and 77,194 patients in 16 nonteaching hospitals. Risk-adjusted mortality improved in hospitals of all teaching levels during the study period. There were no significant differences in the mortality trends between hospitals of different teaching intensities, as demonstrated by nonsignificant interaction between time and teaching status (global test of interaction, p = .56)., Conclusions: : There was a decrease in in-hospital mortality in intensive care unit patients during the years of observation. This decrease was not associated with hospital teaching status, suggesting no net positive or negative association of the resident work-hours regulations with a major patient-centered outcome.

Objective: We sought to develop a simple point score that would accurately capture the risk of hospital death for patients with acute lung injury (ALI)., Design: This is a secondary analysis of data from two randomized trials. Baseline clinical variables collected within 24 hours of enrollment were modeled as predictors of hospital mortality using logistic regression and bootstrap resampling to arrive at a parsimonious model. We constructed a point score based on regression coefficients., Setting: Medical centers participating in the Acute Respiratory Distress Syndrome Clinical Trials Network (ARDSnet)., Patients: Model development: 414 patients with nontraumatic ALI participating in the low tidal volume arm of the ARDSnet Acute Respiratory Management in ARDS study. Model validation: 459 patients participating in the ARDSnet Assessment of Low tidal Volume and elevated End-expiratory volume to Obviate Lung Injury study. Model Validation: 459 patients participating in the ARDSnet Assessment of Low tidal Volume and elevated End-expiratory volume to Obviate Lung Injury trial., Interventions: None., Measurements and Main Results: Variables comprising the prognostic model were hematocrit <26% (1 point), bilirubin >or=2 mg/dL (1 point), fluid balance >2.5 L positive (1 point), and age (1 point for age 40-64 years, 2 points for age >or=65 years). Predicted mortality (95% confidence interval) for 0, 1, 2, 3, and 4+ point totals was 8% (5% to 14%), 17% (12% to 23%), 31% (26% to 37%), 51% (43% to 58%), and 70% (58% to 80%), respectively. There was an excellent agreement between predicted and observed mortality in the validation cohort. Observed mortality for 0, 1, 2, 3, and 4+ point totals in the validation cohort was 12%, 16%, 28%, 47%, and 67%, respectively. Compared with the Acute Physiology Assessment and Chronic Health Evaluation III score, areas under the receiver operating characteristic curve for the point score were greater in the development cohort (0.72 vs. 0.67, p = 0.09) and lower in the validation cohort (0.68 vs. 0.75, p = 0.03)., Conclusions: Mortality in patients with ALI can be predicted using an index of four readily available clinical variables with good calibration. This index may help inform prognostic discussions, but validation in nonclinical trial populations is necessary before widespread use.

Principle: Serum lactate is a potentially useful biomarker to risk-stratify patients with severe sepsis; however, it is plausible that elevated serum lactate is simply a manifestation of clinically apparent organ dysfunction and/or shock (i.e., refractory hypotension)., Objective: To test whether the association between initial serum lactate level and mortality in patients presenting to the emergency department (ED) with severe sepsis is independent of organ dysfunction and shock., Design: Single-center cohort study. The primary outcome was 28-day mortality and the risk factor variable was initial venous lactate (mmol/L), categorized as low (< 2), intermediate (2-3.9), or high (> or = 4). Potential covariates included age, sex, race, acute and chronic organ dysfunction, severity of illness, and initiation of early goal-directed therapy. Multivariable logistic regression analyses were stratified on the presence or absence of shock., Setting: The ED of an academic tertiary care center from 2005 to 2007., Patients: Eight hundred thirty adults admitted with severe sepsis in the ED., Interventions: None., Measurements and Main Results: Mortality at 28 days was 22.9% and median serum lactate was 2.9 mmol/L. Intermediate (odds ratio [OR] = 2.05, p = 0.024) and high serum lactate levels (OR = 4.87, p < 0.001) were associated with mortality in the nonshock subgroup. In the shock subgroup, intermediate (OR = 3.27, p = 0.022) and high serum lactate levels (OR = 4.87, p = 0.001) were also associated with mortality. After adjusting for potential confounders, intermediate and high serum lactate levels remained significantly associated with mortality within shock and nonshock strata., Conclusions: Initial serum lactate was associated with mortality independent of clinically apparent organ dysfunction and shock in patients admitted to the ED with severe sepsis. Both intermediate and high serum lactate levels were independently associated with mortality.

Objective: The additional impact of development of acute lung injury on mortality in severely-injured trauma patients beyond baseline severity of illness has been questioned. We assessed the contribution of acute lung injury to in-hospital mortality in critically ill trauma patients., Design: Prospective cohort study. The contribution of acute lung injury to in-hospital mortality was evaluated in two ways. First, multivariable logistic regression models were used to test the independent association of acute lung injury with in-hospital mortality while adjusting for baseline confounding variables. Second, causal pathway models were used to estimate the amount of the overall association of baseline severity of illness with in-hospital mortality that is attributable to the interval development of acute lung injury., Setting: Academic level 1 trauma center., Patients: Two hundred eighty-three critically ill trauma patients without isolated head injury and with an Injury Severity Score > or = 16 were evaluated for development of acute lung injury in the first 5 days after trauma., Measurements and Main Results: Of the 283 patients, 38 (13.4%) died. The unadjusted mortality rate was nearly three-fold greater in the acute lung injury group (23.9% vs. 8.4%; odds ratio = 3.36; 95% confidence interval 1.67-6.77; p = 0.001). Acute lung injury remained an independent risk factor for death after adjustment for age, baseline Acute Physiologic and Chronic Health Evaluation III score, Injury Severity Score, and blunt mechanism of injury (odds ratio = 2.87; 95% confidence interval 1.29-6.37; p = 0.010). Forty percent of the total association of the baseline Acute Physiologic and Chronic Health Evaluation III score with mortality occurred via an indirect association through acute lung injury, and the remaining 60% via a direct effect., Conclusions: Development of acute lung injury in critically ill trauma patients without isolated head injury contributes independently to in-hospital mortality beyond baseline severity of illness measures. In addition, a significant portion of the association between baseline illness severity and risk of death in these patients might be explained by the interval development of acute lung injury.