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RationaleFollowing acute respiratory distress syndrome (ARDS), joblessness is common but poorly understood.ObjectivesTo evaluate the timing of return to work after ARDS, and associated risk factors, lost earnings, and changes in healthcare coverage Methods: Over 12-month longitudinal follow-up, ARDS survivors from 43 U.S. ARDSNet hospitals provided employment and healthcare coverage data via structured telephone interviews. Factors associated with the timing of return to work were assessed using Fine and Gray regression analysis. Lost earnings were estimated using Bureau of Labor Statistics data.Measurements and main resultsOf 922 consenting survivors, 386 (42%) were employed before ARDS (56% male; mean ± SD age, 45 ± 13 yr), with seven dying by 12-month follow-up. Of 379 previously employed 12-month survivors, 166 (44%) were jobless at 12-month follow-up. Accounting for competing risks of death and retirement, half of enrolled and previously employed survivors returned to work by 13 weeks after hospital discharge, with 68% ever returning by 12 months. Delays in return to work were associated with longer hospitalization and older age among nonwhite survivors. Over 12-month follow-up, 274 (71%) survivors accrued lost earnings, averaging $26,949 ± $22,447 (60% of pre-ARDS annual earnings). Jobless survivors experienced a 14% (95% confidence interval, 5-22%; P = 0.002) absolute decrease in private health insurance (from 44% pre-ARDS) and a 16% (95% confidence interval, 7-24%; P

Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates., Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo., Design, Setting, and Participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation., Intervention: Patients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days., Main Outcome and Measures: The primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL., Results: Of 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P = .56; difference, 0.6; 95% CI, -1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P = .01; difference, -6.3; 95% CI, -10.8 to -1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen., Conclusions and Relevance: Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients., Trial Registration: ClinicalTrials.gov Identifier: NCT04291508.

Background: Delirium is common during critical illness and is associated with long-term cognitive impairment and disability. Antipsychotics are frequently used to treat delirium, but their effects on long-term outcomes are unknown. We aimed to investigate the effects of antipsychotic treatment of delirious, critically ill patients on long-term cognitive, functional, psychological, and quality-of-life outcomes., Methods: This prespecified, long-term follow-up to the randomised, double-blind, placebo-controlled phase 3 MIND-USA Study was conducted in 16 hospitals throughout the USA. Adults (aged ≥18 years) who had been admitted to an intensive care unit with respiratory failure or septic or cardiogenic shock were eligible for inclusion in the study if they had delirium. Participants were randomly assigned-using a computer-generated, permuted-block randomisation scheme with stratification by trial site and age-in a 1:1:1 ratio to receive intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Investigators and participants were masked to treatment group assignment. 3 months and 12 months after randomisation, we assessed survivors' cognitive, functional, psychological, quality-of-life, and employment outcomes using validated telephone-administered tests and questionnaires. This trial was registered with ClinicalTrials.gov, NCT01211522, and is complete., Findings: Between Dec 7, 2011, and Aug 12, 2017, we screened 20 914 individuals, of whom 566 were eligible and consented or had consent provided to participate. Of these 566 patients, 184 were assigned to the placebo group, 192 to the haloperidol group, and 190 to the ziprasidone group. 1-year survival and follow-up rates were similar between groups. Cognitive impairment was common in all three treatment groups, with a third of survivors impaired at both 3-month and 12-month follow-up in all groups. More than half of the surveyed survivors in each group had cognitive or physical limitations (or both) that precluded employment at both 3-month and 12-month follow-up. At both 3 months and 12 months, neither haloperidol (adjusted odds ratio 1·22 [95% CI 0·73-2.04] at 3 months and 1·12 [0·60-2·11] at 12 months) nor ziprasidone (1·07 [0·59-1·96] at 3 months and 0·94 [0·62-1·44] at 12 months) significantly altered cognitive outcomes, as measured by the Telephone Interview for Cognitive Status T score, compared with placebo. We also found no evidence that functional, psychological, quality-of-life, or employment outcomes improved with haloperidol or ziprasidone compared with placebo., Interpretation: In delirious, critically ill patients, neither haloperidol nor ziprasidone had a significant effect on cognitive, functional, psychological, or quality-of-life outcomes among survivors. Our findings, along with insufficient evidence of short-term benefit and frequent inappropriate continuation of antipsychotics at hospital discharge, indicate that antipsychotics should not be used routinely to treat delirium in critically ill adults., Funding: National Institutes of Health and the US Department of Veterans Affairs., Competing Interests: Declaration of interests The following declarations of interest are reported outside of the submitted work. MFM reports grants from the National Institutes of Health (NIH) and the US Department of Veterans Affairs. LMB reports grants from the NIH and the American Association of Critical Care Nurses. MNG reports grants from the NIH, the Agency for Healthcare Research and Quality, and the US Centers for Disease Control and Prevention; consulting fees for a role as scientific advisor for Endpoint Health; honoraria for grand rounds presentation at Yale University (New Haven, CT, USA); travel support from the American Thoracic Society executive committee; and participation on the data safety monitoring board for a trial on monoclonal antibodies for COVID-19, funded by Regeneron (NCT04452318). AM reports consulting fees from Zoll, Eli Lilly, LivaNova, and Jazz Pharmaceuticals; and a philanthropic contribution from ResMed to the University of California San Diego (La Jolla, CA, USA). BAK reports grants from the NIH, payment for expert testimony for a medicolegal case in the state of Indiana (USA), payment for participation on a data safety monitoring board for the PANDORA trial, and a leadership role as president of the American Delirium Society. SSC reports grants from the NIH and direct payments for participation on the data safety monitoring board of an NIH-funded study unrelated to delirium. CLH reports grants from the NIH. PR reports grants from the NIH and the US Department of Defense, payment and travel support for a continuing medical education event at the Johns Hopkins School of Medicine, and previous leadership of the Association of Academic Anesthesiology Chairs and Society of Academic Associations of Anesthesiology and Perioperative Medicine. BTP reports leadership as co-chair of the Society of Critical Care Medicine ICU Liberation Committee. PPP reports grants from the NIH. NEB reports grants from the NIH and travel support for the Society of Intensive Care Medicine Singapore annual meeting. CGH reports consulting fees for Sedana Medical. MBP reports grants from CSL Behring, the NIH, and the US Department of Defense; royalties for serving as an associate editor with Elsevier on a surgical textbook; travel support for continuing medical education events with the Eastern Association for the Surgery of Trauma, Society of University Surgeons, and American College of Surgeons; a patent for image-derived prognostic models unrelated to this work; participation on a data safety monitoring board for Liberate Medical; and leadership as treasurer for the Eastern Association for the Surgery of Trauma. JLS reports honoria for presentations for the Society of Critical Care Medicine, American College of Chest Physicians, the Chilean Society of Critical Care Medicine, and the Spanish Society of Hospital Pharmacy; travel support for meetings with the Society of Critical Care Medicine, the Saudi Society of Clinical Pharmacy, and the Chilean Society of Critical Care Medicine; and leadership on committees with the Society of Critical Care Medicine. EWE reports grant support from the NIH and the US Department of Veterans Affairs, honoraria for continuing medical education lectures sponsored by Pfizer, and study support (investigational drug provision, no direct payments) from Eli Lilly. TDG reports grants from the NIH, research funding from Ceribell, and personal fees from Haisco Pharmaceutical and Lungpacer Medical. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

(1) Background: The disease-modifying mechanisms of high-dose intravenous vitamin C (HDIVC) in sepsis induced acute respiratory distress syndrome (ARDS) is unclear. (2) Methods: We performed a post hoc study of plasma biomarkers from subjects enrolled in the randomized placebo-controlled trial CITRIS-ALI. We explored the effects of HDIVC on cell-free DNA (cfDNA) and syndecan-1, surrogates for neutrophil extracellular trap (NET) formation and degradation of the endothelial glycocalyx, respectively. (3) Results: In 167 study subjects, baseline cfDNA levels in HDIVC (84 subjects) and placebo (83 subjects) were 2.18 ng/µL (SD 4.20 ng/µL) and 2.65 ng/µL (SD 3.87 ng/µL), respectively, p = 0.45. At 48-h, the cfDNA reduction was 1.02 ng/µL greater in HDIVC than placebo, p = 0.05. Mean baseline syndecan-1 levels in HDIVC and placebo were 9.49 ng/mL (SD 5.57 ng/mL) and 10.83 ng/mL (SD 5.95 ng/mL), respectively, p = 0.14. At 48 h, placebo subjects exhibited a 1.53 ng/mL (95% CI, 0.96 to 2.11) increase in syndecan-1 vs. 0.75 ng/mL (95% CI, 0.21 to 1.29, p = 0.05), in HDIVC subjects. (4) Conclusions: HDIVC infusion attenuated cell-free DNA and syndecan-1, biomarkers associated with sepsis-induced ARDS. Improvement of these biomarkers suggests amelioration of NETosis and shedding of the vascular endothelial glycocalyx, respectively.

The acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation (MV) maintains gas exchange in patients with ARDS but exposes lung cells to physical forces that exacerbate injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during MV impairs lung function. We found that mTORC1 is activated in lung epithelial cells following volutrauma and atelectrauma in mice and humanized in vitro models of the lung microenvironment. mTORC1 is also activated in lung tissue of mechanically ventilated patients with ARDS. Deletion of Tsc2, a negative regulator of mTORC1, in epithelial cells impairs lung compliance during MV. Conversely, treatment with rapamycin at the time MV is initiated improves lung compliance without altering lung inflammation or barrier permeability. mTORC1 inhibition mitigates physiologic lung injury by preventing surfactant dysfunction during MV. Our data demonstrate that, in contrast to canonical mTORC1 activation under favorable growth conditions, activation of mTORC1 during MV exacerbates lung injury and inhibition of this pathway may be a novel therapeutic target to mitigate ventilator-induced lung injury during ARDS.

There is an urgent need for new drugs for patients with acute respiratory distress syndrome (ARDS), including those with coronavirus disease (COVID-19). ARDS in influenza-infected mice is associated with reduced concentrations of liponucleotides (essential precursors for de novo phospholipid synthesis) in alveolar type II (ATII) epithelial cells. Because surfactant phospholipid synthesis is a primary function of ATII cells, we hypothesized that disrupting this process could contribute significantly to the pathogenesis of influenza-induced ARDS. The goal of this study was to determine whether parenteral liponucleotide supplementation can attenuate ARDS. C57BL/6 mice inoculated intranasally with 10,000 plaque-forming units/mouse of H1N1 influenza A/WSN/33 virus were treated with CDP (cytidine 5'-diphospho)-choline (100 μg/mouse i.p.) ± CDP -diacylglycerol 16:0/16:0 (10 μg/mouse i.p.) once daily from 1 to 5 days after inoculation (to model postexposure influenza prophylaxis) or as a single dose on Day 5 (to model treatment of patients with ongoing influenza-induced ARDS). Daily postexposure prophylaxis with CDP-choline attenuated influenza-induced hypoxemia, pulmonary edema, alterations in lung mechanics, impairment of alveolar fluid clearance, and pulmonary inflammation without altering viral replication. These effects were not recapitulated by the daily administration of CTP (cytidine triphosphate) and/or choline. Daily coadministration of CDP-diacylglycerol significantly enhanced the beneficial effects of CDP-choline and also modified the ATII cell lipidome, reversing the infection-induced decrease in phosphatidylcholine and increasing concentrations of most other lipid classes in ATII cells. Single-dose treatment with both liponucleotides at 5 days after inoculation also attenuated hypoxemia, altered lung mechanics, and inflammation. Overall, our data show that liponucleotides act rapidly to reduce disease severity in mice with severe influenza-induced ARDS.

The mechanisms responsible for driving endogenous airway hyperresponsiveness (AHR) in the form of exercise-induced bronchoconstriction (EIB) are not fully understood. We examined alterations in airway phospholipid hydrolysis, surfactant degradation, and lipid mediator release in relation to AHR severity and changes induced by exercise challenge. Paired induced sputum ( n = 18) and bronchoalveolar lavage (BAL) fluid ( n = 11) were obtained before and after exercise challenge in asthmatic subjects. Samples were analyzed for phospholipid structure, surfactant function, and levels of eicosanoids and secreted phospholipase A 2 group 10 (sPLA 2 -X). A primary epithelial cell culture model was used to model effects of osmotic stress on sPLA 2 -X. Exercise challenge resulted in increased surfactant degradation, phospholipase activity, and eicosanoid production in sputum samples of all patients. Subjects with EIB had higher levels of surfactant degradation and phospholipase activity in BAL fluid. Higher basal sputum levels of cysteinyl leukotrienes (CysLTs) and prostaglandin D 2 (PGD 2 ) were associated with direct AHR, and both the postexercise and absolute change in CysLTs and PGD 2 levels were associated with EIB severity. Surfactant function either was abnormal at baseline or became abnormal after exercise challenge. Baseline levels of sPLA 2 -X in sputum and the absolute change in amount of sPLA 2 -X with exercise were positively correlated with EIB severity. Osmotic stress ex vivo resulted in movement of water and release of sPLA 2 -X to the apical surface. In summary, exercise challenge promotes changes in phospholipid structure and eicosanoid release in asthma, providing two mechanisms that promote bronchoconstriction, particularly in individuals with EIB who have higher basal levels of phospholipid turnover.

Background: Treatments for ARDS that improve patient outcomes include use of lung-protective ventilation, prone ventilation, and conservative fluid management. Implementation of ARDS protocols via educational programs might improve adherence and outcomes. The objective of this study was to investigate the effects of an ARDS protocol implementation on outcomes and adherence with ARDS guidelines., Methods: This was a single-center, interventional, comparative study before and after protocol implementation. Staff education for the ARDS protocol was implemented between June 2014 and May 2015. A retrospective cohort analysis was conducted during between January 2012 and May 2014 (pre-protocol) and between June 2015 and June 2017 (post-protocol). A total of 450 subjects with ARDS were included. After propensity score matching, 432 subjects were analyzed. Of those, 330 subjects were treated after protocol implementation., Results: The median (interquartile range [IQR]) plateau pressure and tidal volume over the first 3 d decreased significantly after protocol implementation (30.5 [IQR 24.2-33] vs 25.5 [IQR 21.7-30], P = .01 and 7.65 vs 7.4 mL/kg predicted body weight, P = .032, respectively). The percentage of subjects with unsafe tidal volume (> 10 mL/kg predicted body weight) decreased (14.4% vs 5.8%, P = .02). The percentage of subjects with safe plateau pressure (≤ 30 cm H 2 O) increased (47.4% vs 76.5%, P < .001). PEEP deviation from the ARDSNet PEEP/[Formula: see text] table was significantly lower after the implementation. Mortality at 28 and 90 days improved after implementation (53.9% vs 41.8% and 61.8% vs 48.2%, respectively). Adjusted odds ratios for 28-d and 90-d mortality were 0.47 (95% CI 0.28-0.78) and 0.45 (95% CI 0.27-0.76), respectively., Conclusions: ARDS protocol implementation was associated with improved survival and rate of adherence., Competing Interests: The authors have disclosed no conflicts of interest. Supplementary material related to this paper is available at http://www.rcjournal.com., (Copyright © 2021 by Daedalus Enterprises.)

Importance: Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed., Objective: To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19., Design, Setting, and Participants: This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients., Interventions: Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237)., Main Outcomes and Measures: The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality., Results: Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, -0.2% [95% CI, -5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09])., Conclusions and Relevance: Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults., Trial Registration: ClinicalTrials.gov: NCT04332991.

Mechanical ventilation is an essential lifesaving therapy in acute respiratory distress syndrome (ARDS) that may cause ventilator-induced lung injury (VILI) through a positive feedback between altered alveolar mechanics, edema, surfactant inactivation, and injury. Although the biophysical forces that cause VILI are well documented, a knowledge gap remains in the quantitative link between altered parenchymal structure (namely alveolar derecruitment and flooding), pulmonary function, and VILI. This information is essential to developing diagnostic criteria and ventilation strategies to reduce VILI and improve ARDS survival. To address this unmet need, we mechanically ventilated mice to cause VILI. Lung structure was measured at three air inflation pressures using design-based stereology, and the mechanical function of the pulmonary system was measured with the forced oscillation technique. Assessment of the pulmonary surfactant included total surfactant, distribution of phospholipid aggregates, and surface tension lowering activity. VILI-induced changes in the surfactant included reduced surface tension lowering activity in the typically functional fraction of large phospholipid aggregates and a significant increase in the pool of surface-inactive small phospholipid aggregates. The dominant alterations in lung structure at low airway pressures were alveolar collapse and flooding. At higher airway pressures, alveolar collapse was mitigated and the flooded alveoli remained filled with proteinaceous edema. The loss of ventilated alveoli resulted in decreased alveolar gas volume and gas-exchange surface area. These data characterize three alveolar phenotypes in murine VILI: flooded and non-recruitable alveoli, unstable alveoli that derecruit at airway pressures below 5 cmH 2 O, and alveoli with relatively normal structure and function. The fraction of alveoli with each phenotype is reflected in the proportional changes in pulmonary system elastance at positive end expiratory pressures of 0, 3, and 6 cmH 2 O., (Copyright © 2020 Smith, Roy, Cleveland, Mattson, Okamura, Charlebois, Hamlington, Novotny, Knudsen, Ochs, Hite and Bates.)

Importance: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS)., Objective: To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS., Design, Setting, and Participants: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018., Interventions: Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours., Main Outcomes and Measures: The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours., Results: Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hours., Conclusions and Relevance: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS., Trial Registration: ClinicalTrials.gov Identifier: NCT02106975.

Background: The benefits of early continuous neuromuscular blockade in patients with acute respiratory distress syndrome (ARDS) who are receiving mechanical ventilation remain unclear., Methods: We randomly assigned patients with moderate-to-severe ARDS (defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of <150 mm Hg with a positive end-expiratory pressure [PEEP] of ≥8 cm of water) to a 48-hour continuous infusion of cisatracurium with concomitant deep sedation (intervention group) or to a usual-care approach without routine neuromuscular blockade and with lighter sedation targets (control group). The same mechanical-ventilation strategies were used in both groups, including a strategy involving a high PEEP. The primary end point was in-hospital death from any cause at 90 days., Results: The trial was stopped at the second interim analysis for futility. We enrolled 1006 patients early after the onset of moderate-to-severe ARDS (median, 7.6 hours after onset). During the first 48 hours after randomization, 488 of the 501 patients (97.4%) in the intervention group started a continuous infusion of cisatracurium (median duration of infusion, 47.8 hours; median dose, 1807 mg), and 86 of the 505 patients (17.0%) in the control group received a neuromuscular blocking agent (median dose, 38 mg). At 90 days, 213 patients (42.5%) in the intervention group and 216 (42.8%) in the control group had died before hospital discharge (between-group difference, -0.3 percentage points; 95% confidence interval, -6.4 to 5.9; P = 0.93). While in the hospital, patients in the intervention group were less physically active and had more adverse cardiovascular events than patients in the control group. There were no consistent between-group differences in end points assessed at 3, 6, and 12 months., Conclusions: Among patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, there was no significant difference in mortality at 90 days between patients who received an early and continuous cisatracurium infusion and those who were treated with a usual-care approach with lighter sedation targets. (Funded by the National Heart, Lung, and Blood Institute; ROSE ClinicalTrials.gov number, NCT02509078.)., (Copyright © 2019 Massachusetts Medical Society.)

OBJECTIVE To evaluate the lipidomic profile of surfactant obtained from horses with asthma at various clinical stages and to compare results with findings for healthy horses exposed to the same conditions. SAMPLE Surfactant samples obtained from 6 horses with severe asthma and 7 healthy horses. PROCEDURES Clinical evaluation of horses and surfactant analysis were performed. Samples obtained from horses with severe asthma and healthy horses before (baseline), during, and after exposure to hay were analyzed. Crude surfactant pellets were dried prior to dissolution in a solution of isopropanol:methanol:chloroform (4:2:1) containing 7.5mM ammonium acetate. Shotgun lipidomics were performed by use of high-resolution data acquisition on an ion-trap mass spectrometer. Findings were analyzed by use of an ANOVA with a Tukey-Kramer post hoc test. RESULTS Results of lipidomic analysis were evaluated to detect significant differences between groups of horses and among exposure statuses within groups of horses. Significantly increased amounts of cyclic phosphatidic acid (cPA) and diacylglycerol (DAG) were detected in surfactant from severely asthmatic horses during exposure to hay, compared with baseline and postexposure concentrations. Concentrations of cPA and DAG did not change significantly in healthy horses regardless of exposure status. CONCLUSIONS AND CLINICAL RELEVANCE cPA 16:0 and DAG 36:2 were 2 novel lipid mediators identified in surfactant obtained from asthmatic horses with clinical disease. These molecules were likely biomarkers of sustained inflammation. Further studies are needed to evaluate a possible correlation with disease severity and potential alterations in the plasma lipidomic profile of horses with asthma.

Background: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU)., Methods: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation., Results: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms., Conclusions: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .).

Objective: Academic medical centers in North America are expanding their missions from the traditional triad of patient care, research, and education to include the broader issue of healthcare delivery improvement. In recent years, integrated Critical Care Organizations have developed within academic centers to better meet the challenges of this broadening mission. The goal of this article was to provide interested administrators and intensivists with the proper resources, lines of communication, and organizational approach to accomplish integration and Critical Care Organization formation effectively., Design: The Academic Critical Care Organization Building section workgroup of the taskforce established regular monthly conference calls to reach consensus on the development of a toolkit utilizing methods proven to advance the development of their own academic Critical Care Organizations. Relevant medical literature was reviewed by literature search. Materials from federal agencies and other national organizations were accessed through the Internet., Setting: The Society of Critical Care Medicine convened a taskforce entitled "Academic Leaders in Critical Care Medicine" on February 22, 2016 at the 45th Critical Care Congress using the expertise of successful leaders of advanced governance Critical Care Organizations in North America to develop a toolkit for advancing Critical Care Organizations., Measurements and Main Results: Key elements of an academic Critical Care Organization are outlined. The vital missions of multidisciplinary patient care, safety, and quality are linked to the research, education, and professional development missions that enhance the value of such organizations. Core features, benefits, barriers, and recommendations for integration of academic programs within Critical Care Organizations are described. Selected readings and resources to successfully implement the recommendations are provided. Communication with medical school and hospital leadership is discussed., Conclusions: We present the rationale for critical care programs to transition to integrated Critical Care Organizations within academic medical centers and provide recommendations and resources to facilitate this transition and foster Critical Care Organization effectiveness and future success.

Ventilator-associated bacterial pneumonia (VABP) is a difficult therapeutic problem. Considerable controversy exists regarding the optimal chemotherapy for this entity. The recent guidelines of the Infectious Diseases Society of America and the American Thoracic Society recommend a 7-day therapeutic course for VABP based on the balance of no negative impact on all-cause mortality, less resistance emergence, and fewer antibiotic treatment days, counterbalanced with a higher relapse rate for patients whose pathogen is a nonfermenter. The bacterial burden causing an infection has a substantial impact on treatment outcome and resistance selection. We describe the baseline bronchoalveolar lavage (BAL) fluid burden of organisms in suspected VABP patients screened for inclusion in a clinical trial. We measured the urea concentrations in plasma and BAL fluid to provide an index of the dilution of the bacterial and drug concentrations in the lung epithelial lining fluid introduced by the BAL procedure. We were then able to calculate the true bacterial burden as the diluted colony count times the dilution factor. The median dilution factor was 28.7, with the interquartile range (IQR) being 11.9 to 53.2. Median dilution factor-corrected colony counts were 6.18 log 10 (CFU/ml) [IQR, 5.43 to 6.46 log 10 (CFU/ml)]. In a subset of patients, repeat BAL on day 5 showed a good stability of the dilution factor. We previously showed that large bacterial burdens reduce or stop bacterial killing by granulocytes. (This study has been registered at ClinicalTrials.gov under registration no. NCT01570192.)., (Copyright © 2017 American Society for Microbiology.)

Objective: To determine if the length of stay at a referring institution intensive care unit (ICU) before transfer to a tertiary/quaternary care facility is a risk factor for mortality., Design: We performed a retrospective chart review of patients transferred to our ICU from referring institution ICUs over a 3-year period. Logistical regression analysis was performed to determine which factors were independently associated with increased mortality. The primary outcomes were ICU and hospital mortality., Main Results: A total of 1248 patients were included in our study. Length of stay at the referring institution was an independent risk factor for both ICU and hospital mortality (P<.0001), with increasing lengths of stay correlating with increased mortality. Each additional day at the referring institution was associated with a 1.04 increase in likelihood of ICU mortality (95% confidence interval, 1.02-1.06; P =0.001) and a 1.029 (95% confidence interval, 1.01-1.05; P .005) increase in likelihood of hospital mortality., Conclusions: Length of stay at the referring institution before transfer is a risk factor for worse outcomes, with longer stays associated with increased likelihood of mortality. Further studies delineating which factors most affect length of stay at referring institutions, though a difficult task, should be pursued., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial is a multicenter, randomized trial designed to assess the efficacy and safety of early neuromuscular blockade in patients with moderate to severe acute respiratory distress syndrome. This document provides background for interpretation of the trial results, and highlights unique design approaches that may inform future trials of acute illness. We describe the process by which ROSE was chosen as the inaugural trial of the multidisciplinary Prevention and Early Treatment of Acute Lung Injury Network, provide the trial methodology using the Consolidated Standards of Reporting Trials framework, and discuss key design challenges and their resolution. Four key design issues proved challenging-feasibility, choice of sedation depth in the control group, impact of emphasizing early treatment on enrollment criteria and protocol execution, and choice of positive end-expiratory pressure strategy. We used literature, an iterative consensus model, and internal surveys of current practice to inform design choice. ROSE will provide definitive, Consolidated Standards of Reporting Trials adherent data on early neuromuscular blockade for future patients with acute respiratory distress syndrome. Our multidisciplinary approach to trial design may be of use to other trials of acute illness. Clinical trial registered with www.clinicaltrials.gov (NCT02509078).

Importance: Physical rehabilitation in the intensive care unit (ICU) may improve the outcomes of patients with acute respiratory failure., Objective: To compare standardized rehabilitation therapy (SRT) to usual ICU care in acute respiratory failure., Design, Setting, and Participants: Single-center, randomized clinical trial at Wake Forest Baptist Medical Center, North Carolina. Adult patients (mean age, 58 years; women, 55%) admitted to the ICU with acute respiratory failure requiring mechanical ventilation were randomized to SRT (n=150) or usual care (n=150) from October 2009 through May 2014 with 6-month follow-up., Interventions: Patients in the SRT group received daily therapy until hospital discharge, consisting of passive range of motion, physical therapy, and progressive resistance exercise. The usual care group received weekday physical therapy when ordered by the clinical team. For the SRT group, the median (interquartile range [IQR]) days of delivery of therapy were 8.0 (5.0-14.0) for passive range of motion, 5.0 (3.0-8.0) for physical therapy, and 3.0 (1.0-5.0) for progressive resistance exercise. The median days of delivery of physical therapy for the usual care group was 1.0 (IQR, 0.0-8.0)., Main Outcomes and Measures: Both groups underwent assessor-blinded testing at ICU and hospital discharge and at 2, 4, and 6 months. The primary outcome was hospital length of stay (LOS). Secondary outcomes were ventilator days, ICU days, Short Physical Performance Battery (SPPB) score, 36-item Short-Form Health Surveys (SF-36) for physical and mental health and physical function scale score, Functional Performance Inventory (FPI) score, Mini-Mental State Examination (MMSE) score, and handgrip and handheld dynamometer strength., Results: Among 300 randomized patients, the median hospital LOS was 10 days (IQR, 6 to 17) for the SRT group and 10 days (IQR, 7 to 16) for the usual care group (median difference, 0 [95% CI, -1.5 to 3], P = .41). There was no difference in duration of ventilation or ICU care. There was no effect at 6 months for handgrip (difference, 2.0 kg [95% CI, -1.3 to 5.4], P = .23) and handheld dynamometer strength (difference, 0.4 lb [95% CI, -2.9 to 3.7], P = .82), SF-36 physical health score (difference, 3.4 [95% CI, -0.02 to 7.0], P = .05), SF-36 mental health score (difference, 2.4 [95% CI, -1.2 to 6.0], P = .19), or MMSE score (difference, 0.6 [95% CI, -0.2 to 1.4], P = .17). There were higher scores at 6 months in the SRT group for the SPPB score (difference, 1.1 [95% CI, 0.04 to 2.1, P = .04), SF-36 physical function scale score (difference, 12.2 [95% CI, 3.8 to 20.7], P = .001), and the FPI score (difference, 0.2 [95% CI, 0.04 to 0.4], P = .02)., Conclusions and Relevance: Among patients hospitalized with acute respiratory failure, SRT compared with usual care did not decrease hospital LOS., Trial Registration: clinicaltrials.gov Identifier: NCT00976833.

Macrophage phagocytosis of particles and pathogens is an essential aspect of innate host defense. Phagocytic function requires cytoskeletal rearrangements that depend on the interaction between macrophage surface receptors, particulates/pathogens, and the extracellular matrix. In the present study we determine the role of a mechanosensitive ion channel, transient receptor potential vanilloid 4 (TRPV4), in integrating the LPS and matrix stiffness signals to control macrophage phenotypic change for host defense and resolution from lung injury. We demonstrate that active TRPV4 mediates LPS-stimulated murine macrophage phagocytosis of nonopsonized particles (Escherichia coli) in vitro and opsonized particles (IgG-coated latex beads) in vitro and in vivo in intact mice. Intriguingly, matrix stiffness in the range seen in inflamed or fibrotic lung is required to sensitize the TRPV4 channel to mediate the LPS-induced increment in macrophage phagocytosis. Furthermore, TRPV4 is required for the LPS induction of anti-inflammatory/proresolution cytokines. These findings suggest that signaling through TRPV4, triggered by changes in extracellular matrix stiffness, cooperates with LPS-induced signals to mediate macrophage phagocytic function and lung injury resolution. These mechanisms are likely to be important in regulating macrophage function in the context of pulmonary infection and fibrosis., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Objectives: In the Fluid and Catheter Treatment Trial (FACTT) of the National Institutes of Health Acute Respiratory Distress Syndrome Network, a conservative fluid protocol (FACTT Conservative) resulted in a lower cumulative fluid balance and better outcomes than a liberal fluid protocol (FACTT Liberal). Subsequent Acute Respiratory Distress Syndrome Network studies used a simplified conservative fluid protocol (FACTT Lite). The objective of this study was to compare the performance of FACTT Lite, FACTT Conservative, and FACTT Liberal protocols., Design: Retrospective comparison of FACTT Lite, FACTT Conservative, and FACTT Liberal. Primary outcome was cumulative fluid balance over 7 days. Secondary outcomes were 60-day adjusted mortality and ventilator-free days through day 28. Safety outcomes were prevalence of acute kidney injury and new shock., Setting: ICUs of Acute Respiratory Distress Syndrome Network participating hospitals., Patients: Five hundred three subjects managed with FACTT Conservative, 497 subjects managed with FACTT Liberal, and 1,124 subjects managed with FACTT Lite., Interventions: Fluid management by protocol., Measurements and Main Results: Cumulative fluid balance was 1,918 ± 323 mL in FACTT Lite, -136 ± 491 mL in FACTT Conservative, and 6,992 ± 502 mL in FACTT Liberal (p < 0.001). Mortality was not different between groups (24% in FACTT Lite, 25% in FACTT Conservative and Liberal, p = 0.84). Ventilator-free days in FACTT Lite (14.9 ± 0.3) were equivalent to FACTT Conservative (14.6 ± 0.5) (p = 0.61) and greater than in FACTT Liberal (12.1 ± 0.5, p < 0.001 vs Lite). Acute kidney injury prevalence was 58% in FACTT Lite and 57% in FACTT Conservative (p = 0.72). Prevalence of new shock in FACTT Lite (9%) was lower than in FACTT Conservative (13%) (p = 0.007 vs Lite) and similar to FACTT Liberal (11%) (p = 0.18 vs Lite)., Conclusions: FACTT Lite had a greater cumulative fluid balance than FACTT Conservative but had equivalent clinical and safety outcomes. FACTT Lite is an alternative to FACTT Conservative for fluid management in Acute Respiratory Distress Syndrome.

Background: In the acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in patients with sepsis. We hypothesized that rosuvastatin therapy would improve clinical outcomes in critically ill patients with sepsis-associated ARDS., Methods: We conducted a multicenter trial in which patients with sepsis-associated ARDS were randomly assigned to receive either enteral rosuvastatin or placebo in a double-blind manner. The primary outcome was mortality before hospital discharge home or until study day 60 if the patient was still in a health care facility. Secondary outcomes included the number of ventilator-free days (days that patients were alive and breathing spontaneously) to day 28 and organ-failure-free days to day 14., Results: The study was stopped because of futility after 745 of an estimated 1000 patients had been enrolled. There was no significant difference between study groups in 60-day in-hospital mortality (28.5% with rosuvastatin and 24.9% with placebo, P=0.21) or in mean (±SD) ventilator-free days (15.1±10.8 with rosuvastatin and 15.1±11.0 with placebo, P=0.96). The groups were well matched with respect to demographic and key physiological variables. Rosuvastatin therapy, as compared with placebo, was associated with fewer days free of renal failure to day 14 (10.1±5.3 vs. 11.0±4.7, P=0.01) and fewer days free of hepatic failure to day 14 (10.8±5.0 vs. 11.8±4.3, P=0.003). Rosuvastatin was not associated with an increased incidence of serum creatine kinase levels that were more than 10 times the upper limit of the normal range., Conclusions: Rosuvastatin therapy did not improve clinical outcomes in patients with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction. (Funded by the National Heart, Lung, and Blood Institute and the Investigator-Sponsored Study Program of AstraZeneca; ClinicalTrials.gov number, NCT00979121.).

Background: Aspiration of colonized oropharyngeal secretions is a major factor in the pathogenesis of ventilator-associated pneumonia (VAP). A tapered-cuff endotracheal tube (ETT) has been demonstrated to reduce aspiration around the cuff. Whether these properties are efficacious in reducing VAP is not known., Methods: This 2-period, investigator-initiated observational study was designed to assess the efficacy of a tapered-cuff ETT to reduce the VAP rate. All intubated, mechanically ventilated patients over the age of 18 were included. During the baseline period a standard, barrel-shaped-cuff ETT (Mallinckrodt Hi-Lo) was used. All ETTs throughout the hospital were then replaced with a tapered-cuff ETT (TaperGuard). The primary outcome variable was the incidence of VAP per 1,000 ventilator days., Results: We included 2,849 subjects, encompassing 15,250 ventilator days. The mean ± SD monthly VAP rate was 3.29 ± 1.79/1,000 ventilator days in the standard-cuff group and 2.77 ± 2.00/1,000 ventilator days in the tapered-cuff group (P = .65). While adherence to the VAP prevention bundle was high throughout the study, bundle adherence was significantly higher during the standard-cuff period (96.5 ± 2.7%) than in the tapered-cuff period (90.3 ± 3.5%, P = .01)., Conclusions: In the setting of a VAP rate very near the average of ICUs in the United States, and where there was high adherence to a VAP prevention bundle, the use of a tapered-cuff ETT was not associated with a reduction in the VAP rate.

Introduction: Secretory phospholipases A2 (sPLA2) hydrolyze phospholipids in cell membranes and extracellular structures such as pulmonary surfactant. This study tests the hypothesis that sPLA2 are elevated in human lungs during acute respiratory distress syndrome (ARDS) and that sPLA2 levels are associated with surfactant injury by hydrolysis of surfactant phospholipids., Methods: Bronchoalveolar lavage (BAL) fluid was obtained from 18 patients with early ARDS (<72 hours) and compared with samples from 10 healthy volunteers. Secreted phospholipase A2 levels were measured (enzyme activity and enzyme immunoassay) in conjunction with ARDS subjects' surfactant abnormalities including surfactant phospholipid composition, large and small aggregates distribution and surface tension function., Results: BAL sPLA2 enzyme activity was markedly elevated in ARDS samples relative to healthy subjects when measured by ex vivo hydrolysis of both phosphatidylglycerol (PG) and phosphatidylcholine (PC). Enzyme immunoassay identified increased PLA2G2A protein in the ARDS BAL fluid, which was strongly correlated with the sPLA2 enzyme activity against PG. Of particular interest, the authors demonstrated an average depletion of 69% of the PG in the ARDS sample large aggregates relative to the normal controls. Furthermore, the sPLA2 enzyme activity against PG and PC ex vivo correlated with the BAL recovery of in vivo PG and PC, respectively, and also correlated with the altered distribution of the large and small surfactant aggregates., Conclusions: These results support the hypothesis that sPLA2-mediated hydrolysis of surfactant phospholipid, especially PG by PLA2G2A, contributes to surfactant injury during early ARDS.

Context: The amount of enteral nutrition patients with acute lung injury need is unknown., Objective: To determine if initial lower-volume trophic enteral feeding would increase ventilator-free days and decrease gastrointestinal intolerances compared with initial full enteral feeding., Design, Setting, and Participants: The EDEN study, a randomized, open-label, multicenter trial conducted from January 2, 2008, through April 12, 2011. Participants were 1000 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network., Interventions: Participants were randomized to receive either trophic or full enteral feeding for the first 6 days. After day 6, the care of all patients who were still receiving mechanical ventilation was managed according to the full feeding protocol., Main Outcome Measures: Ventilator-free days to study day 28., Results: Baseline characteristics were similar between the trophic-feeding (n = 508) and full-feeding (n = 492) groups. The full-feeding group received more enteral calories for the first 6 days, about 1300 kcal/d compared with 400 kcal/d (P < .001). Initial trophic feeding did not increase the number of ventilator-free days (14.9 [95% CI, 13.9 to 15.8] vs 15.0 [95% CI, 14.1 to 15.9]; difference, -0.1 [95% CI, -1.4 to 1.2]; P = .89) or reduce 60-day mortality (23.2% [95% CI, 19.6% to 26.9%] vs 22.2% [95% CI, 18.5% to 25.8%]; difference, 1.0% [95% CI, -4.1% to 6.3%]; P = .77) compared with full feeding. There were no differences in infectious complications between the groups. Despite receiving more prokinetic agents, the full-feeding group experienced more vomiting (2.2% vs 1.7% of patient feeding days; P = .05), elevated gastric residual volumes (4.9% vs 2.2% of feeding days; P < .001), and constipation (3.1% vs 2.1% of feeding days; P = .003). Mean plasma glucose values and average hourly insulin administration were both higher in the full-feeding group over the first 6 days., Conclusion: In patients with acute lung injury, compared with full enteral feeding, a strategy of initial trophic enteral feeding for up to 6 days did not improve ventilator-free days, 60-day mortality, or infectious complications but was associated with less gastrointestinal intolerance., Trial Registration: clinicaltrials.gov Identifiers: NCT00609180 and NCT00883948.

Hydrolysis of surfactant phospholipids (PL) by secretory phospholipases A(2) (sPLA(2)) contributes to surfactant damage in inflammatory airway diseases such as acute lung injury/acute respiratory distress syndrome. We and others have reported that each sPLA(2) exhibits specificity in hydrolyzing different PLs in pulmonary surfactant and that the presence of hydrophilic surfactant protein A (SP-A) alters sPLA(2)-mediated hydrolysis. This report tests the hypothesis that hydrophobic SP-B also inhibits sPLA(2)-mediated surfactant hydrolysis. Three surfactant preparations were used containing varied amounts of SP-B and radiolabeled tracers of phosphatidylcholine (PC) or phosphatidylglycerol (PG): 1) washed ovine surfactant (OS) (pre- and postorganic extraction) compared with Survanta (protein poor), 2) Survanta supplemented with purified bovine SP-B (1-5%, wt/wt), and 3) a mixture of dipalmitoylphosphatidylcholine (DPPC), 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC), and 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG) (DPPC:POPC:POPG, 40:40:20) prepared as vesicles and monomolecular films in the presence or absence of SP-B. Hydrolysis of PG and PC by Group IB sPLA(2) (PLA2G1A) was significantly lower in the extracted OS, which contains SP-B, compared with Survanta (P = 0.005), which is SP-B poor. Hydrolysis of PG and PC in nonextracted OS, which contains all SPs, was lower than both Survanta and extracted OS. When Survanta was supplemented with 1% SP-B, PG and PC hydrolysis by PLA2G1B was significantly lower (P < 0.001) than in Survanta alone. When supplemented into pure lipid vesicles and monomolecular films composed of PG and PC mixtures, SP-B also inhibited hydrolysis by both PLA2G1B and Group IIA sPLA2 (PLA2G2A). In films, PLA2G1B hydrolyzed surfactant PL monolayers at surface pressures ≤30 mN/m (P < 0.01), and SP-B lowered the surface pressure range at which hydrolysis can occur. These results suggest the hydrophobic SP, SP-B, protects alveolar surfactant PL from hydrolysis mediated by multiple sPLA(2) in both vesicles (alveolar subphase) and monomolecular films (air-liquid interface).

Introduction: Hospitals are under pressure to provide care that not only shortens hospital length of stay but also reduces subsequent hospital admissions. Hospital readmissions have received increased attention in outcome reporting. The authors identified survivors of acute respiratory failure who then required subsequent hospitalization. A cohort of acute respiratory failure survivors, who participated in an early intensive care unit (ICU) mobility program, was assessed to determine if variables from the index hospitalization predict hospital readmission or death, within 12 months of hospital discharge., Methods: Hospital database and responses to letters mailed to 280 acute respiratory failure survivors. Univariate predictor variables shown to be associated with hospital readmission or death (P < 0.1) were included in a multiple logistic regression. A stepwise selection procedure was used to identify significant variables (P < 0.05)., Results: Of the 280 survivors, 132 (47%) had at least 1 readmission or died within the first year, 126 (45%) were not readmitted and 22 (8%) were lost to follow-up. Tracheostomy [odds ratio (OR), 4.02 (95%CI, 1.72-9.40)], female gender [OR, 1.94 (95%CI, 1.13-3.32)], a higher Charlson Comorbidity Index assessed upon index hospitalization discharge [OR, 1.15 (95%CI, 1.01-1.31)] and lack of early ICU mobility therapy [OR, 1.77 (95%CI, 1.04-3.01)] predicted readmission or death in the first year postindex hospitalization., Conclusions: Tracheostomy, female gender, higher Charlson Comorbidity Index and lack of early ICU mobility were associated with readmissions or death during the first year. Although the mechanisms of increased hospital readmission are unclear, these findings may provide further support for early ICU mobility for patients with acute respiratory failure.

Introduction: Conservative fluid management in patients with acute lung injury (ALI) increases time alive and free from mechanical ventilation. Vascular pedicle width (VPW) is a non-invasive measurement of intravascular volume status. The VPW was studied in ALI patients to determine the correlation between VPW and intravascular pressure measurements and whether VPW could predict fluid status., Methods: This retrospective cohort study involved 152 patients with ALI enrolled in the Fluid and Catheter Treatment Trial (FACTT) from five NHLBI ARDS (Acute Respiratory Distress Syndrome) Network sites. VPW and central venous pressure (CVP) or pulmonary artery occlusion pressure (PAOP) from the first four study days were correlated. The relationships between VPW, positive end-expiratory pressure (PEEP), cumulative fluid balance, and PAOP were also evaluated. Receiver operator characteristic (ROC) curves were used to determine the ability of VPW to detect PAOP < 8 mmHg and PAOP ≥ 18 mm Hg., Results: A total of 71 and 152 patients provided 118 and 276 paired VPW/PAOP and VPW/CVP measurements, respectively. VPW correlated with PAOP (r = 0.41; P < 0.001) and less well with CVP (r = 0.21; P = 0.001). In linear regression, VPW correlated with PAOP 1.5-fold better than cumulative fluid balance and 2.5-fold better than PEEP. VPW discriminated achievement of PAOP < 8 mm Hg (AUC = 0.73; P = 0.04) with VPW ≤67 mm demonstrating 71% sensitivity (95% CI 30 to 95%) and 68% specificity (95% CI 59 to 75%). For discriminating a hydrostatic component of the edema (that is, PAOP ≥ 18 mm Hg), VPW ≥ 72 mm demonstrated 61.4% sensitivity (95% CI 47 to 74%) and 61% specificity (49 to 71%) (area under the curve (AUC) 0.69; P = 0.001)., Conclusions: VPW correlates with PAOP better than CVP in patients with ALI. Due to its only moderate sensitivity and specificity, the ability of VPW to discriminate fluid status in patients with acute lung injury is limited and should only be considered when intravascular pressures are unavailable.

Objective: To evaluate the phospholipid composition and function of surfactant in horses with recurrent airway obstruction (RAO) at various clinical stages and compare these properties with findings in horses without RAO., Animals: 7 horses with confirmed RAO and 7 without RAO (non-RAO horses)., Procedures: Pairs of RAO-affected and non-RAO horses were evaluated before, during, and after exposure to hay. Evaluations included clinical scoring, lung function testing, airway endoscopy, and bronchoalveolar lavage fluid (BALF) absolute and differential cell counts. Cell-free BALF was separated into crude surfactant pellet and supernatant by ultracentrifugation, and phospholipid and protein concentrations were determined. Phospholipid composition of crude surfactant pellets and surface tension were evaluated with high-performance liquid chromatography and a pulsating bubble surfactometer, respectively. Findings were compared statistically via mixed-effects, repeated-measures ANOVA., Results: Total phospholipid concentration in BALF was lower in RAO-affected versus non-RAO horses at all sample collection times. In the RAO-affected group, total phospholipid concentration was lower during exposure to hay than before or after exposure. There were no significant differences in BALF protein concentration, percentages of phospholipid classes, or surface tension between or within groups of horses., Conclusions and Clinical Relevance: All clinical stages of RAO-affected horses were characterized by low surfactant concentration in BALF. Exacerbation of RAO led to an additional decrease in surfactant concentration. Causes for low surfactant concentration in RAO-affected horses remain to be determined. Low phospholipid concentration may render RAO-affected horses more susceptible than unaffected horses to surfactant alterations and contribute to clinical disease status and progression.

Background: Surfactant alterations are described in horses after exercise, anesthesia, and prolonged transport, in horses with recurrent airway obstruction, and in neonatal foals. The effect of horse age or bronchoalveolar lavage fluid (BALF) sample characteristics on surfactant is unknown., Objectives: To evaluate surfactant phospholipid composition and function in healthy horses, and to investigate the influence of age and BALF sample characteristics on surfactant., Animals: Seventeen healthy horses 6-25 years of age maintained on pasture year-round., Methods: BALF was collected by standard procedures and was assessed for recovery volume, nucleated cell count (NCC), and cytology. Cell-free BALF was separated into crude surfactant pellet (CSP) and surfactant supernatant (Supe) by ultracentrifugation. Phospholipid and protein content were determined from both fractions. CSP phospholipid composition was analyzed by high-performance liquid chromatography with an evaporative light scatter detector. Surface tension of CSP was evaluated with a pulsating bubble surfactometer. Regression analysis was used to evaluate associations between age, BALF sample characteristics, and surfactant variables., Results: Results and conclusions were derived from 15 horses. Increasing age was associated with decreased phospholipid content in CSP but not Supe. Age did not affect protein content of CSP or Supe, or surfactant phospholipid composition or function. Age-related surfactant changes were unaffected by BALF recovery percentage, NCC, and cytological profile., Conclusions and Clinical Importance: Older horses have decreased surfactant phospholipid content, which might be because of age-related pulmonary changes. Surfactant composition is unaffected by BALF sample characteristics at a BALF recovery percentage of at least 50%.

Lung surfactant is produced by type II alveolar cells as a mixture of phospholipids, surfactant proteins, and neutral lipids. Surfactant lowers alveolar surface tension and is crucial for the prevention of alveolar collapse. In addition, surfactant contributes to smaller airway patency and improves mucociliary clearance. Surfactant-specific proteins are part of the innate immune defense mechanisms of the lung. Lung surfactant alterations have been described in a number of respiratory diseases. Surfactant deficiency (quantitative deficit of surfactant) in premature animals causes neonatal respiratory distress syndrome. Surfactant dysfunction (qualitative changes in surfactant) has been implicated in the pathophysiology of acute respiratory distress syndrome and asthma. Analysis of surfactant from amniotic fluid allows assessment of fetal lung maturity (FLM) in the human fetus and exogenous surfactant replacement therapy is part of the standard care in premature human infants. In contrast to human medicine, use and success of FLM testing or surfactant replacement therapy remain limited in veterinary medicine. Lung surfactant has been studied in large animal models of human disease. However, only a few reports exist on lung surfactant alterations in naturally occurring respiratory disease in large animals. This article gives a general review on the role of lung surfactant in respiratory disease followed by an overview of our current knowledge on surfactant in large animal veterinary medicine.

Background: Abnormalities in lung surfactant are well described in human respiratory diseases including asthma, but are poorly described in horses., Hypothesis: Lung surfactant is abnormal in horses with clinical signs of recurrent airway obstruction (RAO)., Animals: Six healthy horses and 5 horses with RAO., Methods: Bronchoalveolar lavage fluid (BALF) was obtained from all horses by standard procedures. Cell-free BALF was separated into crude surfactant pellets (CSP) and supernatant via ultracentrifugation. Phospholipid and protein content was analyzed from both of these fractions. Phospholipid composition of CSP was determined using high-performance liquid chromatography with an evaporative light scatter detector. Surface tension of CSP was measured with a pulsating bubble surfactometer., Results: Compared with healthy horses, surfactant from RAO-affected horses was characterized by significantly decreased phospholipid content in total surfactant (median; range: 23.2; 14.7-62.2 microg/mL BALF versus 172; 111-267 microg/mL BALF, P = .0062) and CSP (20.2; 6.4-48.9 microL/mL BALF versus 155; 94.4-248 microg/mL BALF, P = .0062), and a significantly lower percentage of phosphatidylglycerol (PG) (4.5; 3.6-5.6% versus 6.6; 4.1-7.6%, P = .028). Furthermore, the ratio between the percentages of phosphatidylcholine and PG was significantly higher in RAO-affected horses than in healthy horses (20.9; 16.6: 25.9 versus 13.9; 11.8-22.8, P = .045)., Conclusions and Clinical Importance: This study demonstrates that surfactant from RAO-affected horses is abnormal. Further studies are needed to determine if these abnormalities are related to an increased tendency for bronchoconstriction and to a decreased ability to clear airway mucus in RAO-affected horses.

Background: Lung surfactant function and composition are varied and adapted to the specific respiratory physiology of all mammalian species., Hypothesis: Lung surfactant function and composition are different in neonatal foals as compared to adult horses., Animals: Six adult horses, 7 term foals (<24 hours old), and 4 premature foals were used. Animals were part of the Auburn University teaching herd except for 3 client-owned premature foals., Methods: Bronchoalveolar lavage fluid (BALF) was obtained from all animals. Ultracentrifugation of cell-free BALF separated surfactant into crude surfactant pellets (CSP) and supernatant. Both fractions were analyzed for phospholipid and protein content with the Bartlett and bicinchoninic acid method, respectively. Phospholipid composition of the CSP was determined by using high-performance liquid chromatography with an evaporative light scatter detector. Surface tension of the CSP was measured with a pulsating bubble surfactometer. Results from term foals (<24 hours old) were compared statistically to those from adult horses. Values of P < .05 were considered significant., Results: BALF phospholipid content was similar between adult horses and term foals, but BALF protein content was significantly decreased in term foals. Phosphatidylglycerol was significantly decreased, phosphatidylinositol was significantly increased, and the minimum surface tension was significantly increased in the CSP from term foals compared to adult horses., Conclusions and Clinical Importance: Surface tension and phospholipid composition of surfactant in neonatal foals are significantly different compared to adult horses. These changes may influence biophysical and immunologic functions of surfactant.

Background: Optimal fluid management in patients with acute lung injury is unknown. Diuresis or fluid restriction may improve lung function but could jeopardize extrapulmonary-organ perfusion., Methods: In a randomized study, we compared a conservative and a liberal strategy of fluid management using explicit protocols applied for seven days in 1000 patients with acute lung injury. The primary end point was death at 60 days. Secondary end points included the number of ventilator-free days and organ-failure-free days and measures of lung physiology., Results: The rate of death at 60 days was 25.5 percent in the conservative-strategy group and 28.4 percent in the liberal-strategy group (P=0.30; 95 percent confidence interval for the difference, -2.6 to 8.4 percent). The mean (+/-SE) cumulative fluid balance during the first seven days was -136+/-491 ml in the conservative-strategy group and 6992+/-502 ml in the liberal-strategy group (P<0.001). As compared with the liberal strategy, the conservative strategy improved the oxygenation index ([mean airway pressure x the ratio of the fraction of inspired oxygen to the partial pressure of arterial oxygen]x100) and the lung injury score and increased the number of ventilator-free days (14.6+/-0.5 vs. 12.1+/-0.5, P<0.001) and days not spent in the intensive care unit (13.4+/-0.4 vs. 11.2+/-0.4, P<0.001) during the first 28 days but did not increase the incidence or prevalence of shock during the study or the use of dialysis during the first 60 days (10 percent vs. 14 percent, P=0.06)., Conclusions: Although there was no significant difference in the primary outcome of 60-day mortality, the conservative strategy of fluid management improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing nonpulmonary-organ failures. These results support the use of a conservative strategy of fluid management in patients with acute lung injury. (ClinicalTrials.gov number, NCT00281268 [ClinicalTrials.gov].)., (Copyright 2006 Massachusetts Medical Society.)

Background: The balance between the benefits and the risks of pulmonary-artery catheters (PACs) has not been established., Methods: We evaluated the relationship of benefits and risks of PACs in 1000 patients with established acute lung injury in a randomized trial comparing hemodynamic management guided by a PAC with hemodynamic management guided by a central venous catheter (CVC) using an explicit management protocol. Mortality during the first 60 days before discharge home was the primary outcome., Results: The groups had similar baseline characteristics. The rates of death during the first 60 days before discharge home were similar in the PAC and CVC groups (27.4 percent and 26.3 percent, respectively; P=0.69; absolute difference, 1.1 percent; 95 percent confidence interval, -4.4 to 6.6 percent), as were the mean (+/-SE) numbers of both ventilator-free days (13.2+/-0.5 and 13.5+/-0.5; P=0.58) and days not spent in the intensive care unit (12.0+/-0.4 and 12.5+/-0.5; P=0.40) to day 28. PAC-guided therapy did not improve these measures for patients in shock at the time of enrollment. There were no significant differences between groups in lung or kidney function, rates of hypotension, ventilator settings, or use of dialysis or vasopressors. Approximately 90 percent of protocol instructions were followed in both groups, with a 1 percent rate of crossover from CVC- to PAC-guided therapy. Fluid balance was similar in the two groups, as was the proportion of instructions given for fluid and diuretics. Dobutamine use was uncommon. The PAC group had approximately twice as many catheter-related complications (predominantly arrhythmias)., Conclusions: PAC-guided therapy did not improve survival or organ function but was associated with more complications than CVC-guided therapy. These results, when considered with those of previous studies, suggest that the PAC should not be routinely used for the management of acute lung injury. (ClinicalTrials.gov number, NCT00281268.)., (Copyright 2006 Massachusetts Medical Society.)

Secretory A(2) phospholipases (sPLA(2)) hydrolyze surfactant phospholipids cause surfactant dysfunction and are elevated in lung inflammation. Phospholipase-mediated surfactant hydrolysis may disrupt surfactant function by generation of lysophospholipids and free fatty acids and/or depletion of native phospholipids. In this study, we quantitatively assessed multiple mechanisms of sPLA(2)-mediated surfactant dysfunction using non-enzymatic models including supplementation of surfactants with exogenous lysophospholipids and free fatty acids. Our data demonstrated lysophospholipids at levels >or=10 mol% of total phospholipid (i.e., >or=10% hydrolysis) led to a significant increase in minimum surface tension and increased the time to achieve a normal minimum surface tension. Lysophospholipid inhibition of surfactant function was independent of the lysophospholipid head group or total phospholipid concentration. Free fatty acids (palmitic acid, oleic acid) alone had little effect on minimum surface tension, but did increase the maximum surface tension and the time to achieve normal minimum surface tension. The combined effect of equimolar free fatty acids and lysophospholipids was not different from the effect of lysophospholipids alone for any measurement of surfactant function. Surfactant proteins did not change the percent lysophospholipids required to increase minimum surface tension. As a mechanism that causes surfactant dysfunction, depletion of native phospholipids required much greater change (equivalent to >80% hydrolysis) than generation of lysophospholipids. In summary, generation of lysophospholipids is the principal mechanism of phospholipase-mediated surfactant injury in our non-enzymatic models. These models and findings will assist in understanding more complex in vitro and in vivo studies of phospholipase-mediated surfactant injury.