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Three COVID-19 vaccines are authorized or approved for use among adults in the United States (1,2). Two 2-dose mRNA vaccines, mRNA-1273 from Moderna and BNT162b2 from Pfizer-BioNTech, received Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) in December 2020 for persons aged ≥18 years and aged ≥16 years, respectively. A 1-dose viral vector vaccine (Ad26.COV2 from Janssen [Johnson & Johnson]) received EUA in February 2021 for persons aged ≥18 years (3). The Pfizer-BioNTech vaccine received FDA approval for persons aged ≥16 years on August 23, 2021 (4). Current guidelines from FDA and CDC recommend vaccination of eligible persons with one of these three products, without preference for any specific vaccine (4,5). To assess vaccine effectiveness (VE) of these three products in preventing COVID-19 hospitalization, CDC and collaborators conducted a case-control analysis among 3,689 adults aged ≥18 years who were hospitalized at 21 U.S. hospitals across 18 states during March 11-August 15, 2021. An additional analysis compared serum antibody levels (anti-spike immunoglobulin G [IgG] and anti-receptor binding domain [RBD] IgG) to SARS-CoV-2, the virus that causes COVID-19, among 100 healthy volunteers enrolled at three hospitals 2-6 weeks after full vaccination with the Moderna, Pfizer-BioNTech, or Janssen COVID-19 vaccine. Patients with immunocompromising conditions were excluded. VE against COVID-19 hospitalizations was higher for the Moderna vaccine (93%; 95% confidence interval [CI] = 91%-95%) than for the Pfizer-BioNTech vaccine (88%; 95% CI = 85%-91%) (p = 0.011); VE for both mRNA vaccines was higher than that for the Janssen vaccine (71%; 95% CI = 56%-81%) (all p

Rationale: How to provide advanced respiratory support for coronavirus disease (COVID-19) to maximize population-level survival while optimizing mechanical ventilator access is unknown. Objectives: To evaluate the use of high-flow nasal cannula for COVID-19 on population-level mortality and ventilator availability. Methods: We constructed dynamical (deterministic) simulation models of high-flow nasal cannula and mechanical ventilation use for COVID-19 in the United States. Model parameters were estimated through consensus based on published literature, local data, and experience. We had the following two outcomes: 1) cumulative number of deaths and 2) days without any available ventilators. We assessed the impact of various policies for the use of high-flow nasal cannula (with or without “early intubation”) versus a scenario in which high-flow nasal cannula was unavailable. Results: The policy associated with the fewest deaths and the least time without available ventilators combined the use of high-flow nasal cannula for patients not urgently needing ventilators with the use of early mechanical ventilation for these patients when at least 10% of ventilator supply was not in use. At the national level, this strategy resulted in 10,000–40,000 fewer deaths than if high-flow nasal cannula were not available. In addition, with moderate national ventilator capacity (30,000–45,000 ventilators), this strategy led to up to 25 (11.8%) fewer days without available ventilators. For a 250-bed hospital with 100 mechanical ventilators, the availability of 13, 20, or 33 high-flow nasal cannulas prevented 81, 102, and 130 deaths, respectively. Conclusions: The use of high-flow nasal cannula coupled with early mechanical ventilation when supply is sufficient results in fewer deaths and greater ventilator availability.

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.FUNDING: US National Institutes of Health and Operation Warp Speed.

Purpose: Montefiore Medical Center (MMC) in the Bronx, New York, was subjected to an unprecedented surge of critically ill patients with COVID-19 disease during the initial outbreak of the pandemic in New York State in the spring of 2020. It is important to describe our experience in order to assist hospitals in other areas of the country that may soon be subjected to similar surges. Materials and Methods: We retrospectively reviewed the expansion of critical care medicine services at Montefiore during the COVID-19 surge in terms of space, staff, stuff, and systems. In addition, we report on a debriefing session held with a multidisciplinary group of frontline CCM providers at Montefiore. Findings: The surge of critically ill patients from COVID-19 disease necessitated a tripling of critical care bed capacity at (MMC), with attendant increased needs for staffing, equipment, and systematic innovations to increase efficiency and effectiveness. Feedback from a multidisciplinary group of frontline providers revealed multiple opportunities for improvement for the next potential surge at MMC as well as guidance for other hospitals. Conclusions: Given increasing cases and burden of critical illness from COVID-19 across the US, engineering safe and effective expansions of critical care capacity will be crucial. We hope that our description of what worked and what did not at MMC will help guide other hospitals in their pandemic preparedness.

Most persons infected with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), develop virus-specific antibodies within several weeks, but antibody titers might decline over time. Understanding the timeline of antibody decline is important for interpreting SARS-CoV-2 serology results. Serum specimens were collected from a convenience sample of frontline health care personnel at 13 hospitals and tested for antibodies to SARS-CoV-2 during April 3-June 19, 2020, and again approximately 60 days later to assess this timeline. The percentage of participants who experienced seroreversion, defined as an antibody signal-to-threshold ratio >1.0 at baseline and

Objectives The objectives of this study were to: 1) determine the association between vasopressor dosing intensity during the first 6 hours and first 24 hours after the onset of septic shock and 30-day in-hospital mortality; 2) determine whether the effect of vasopressor dosing intensity varies by fluid resuscitation volume; and 3) determine whether the effect of vasopressor dosing intensity varies by dosing titration pattern. Design Multicenter prospective cohort study between September 2017 and February 2018. Vasopressor dosing intensity was defined as the total vasopressor dose infused across all vasopressors in norepinephrine equivalents. Setting Thirty-three hospital sites in the United States (n = 32) and Jordan (n = 1). Patients Consecutive adults requiring admission to the ICU with septic shock treated with greater than or equal to 1 vasopressor within 24 hours of shock onset. Interventions None. Measurements and main results Out of 1,639 patients screened, 616 were included. Norepinephrine (93%) was the most common vasopressor. Patients received a median of 3,400 mL (interquartile range, 1,851-5,338 mL) during the 24 hours after shock diagnosis. The median vasopressor dosing intensity during the first 24 hours of shock onset was 8.5 μg/min norepinephrine equivalents (3.4-18.1 μg/min norepinephrine equivalents). In the first 6 hours, increasing vasopressor dosing intensity was associated with increased odds ratio of 30-day in-hospital mortality, with the strength of association dependent on concomitant fluid administration. Over the entire 24 hour period, every 10 μg/min increase in vasopressor dosing intensity was associated with an increased risk of 30-day mortality (adjusted odds ratio, 1.33; 95% CI, 1.16-1.53), and this association did not vary with the amount of fluid administration. Compared to an early high/late low vasopressor dosing strategy, an early low/late high or sustained high vasopressor dosing strategy was associated with higher mortality. Conclusions Increasing vasopressor dosing intensity during the first 24 hours after septic shock was associated with increased mortality. This association varied with the amount of early fluid administration and the timing of vasopressor titration.

IMPORTANCE: A comprehensive understanding of the benefits of COVID-19 vaccination requires consideration of disease attenuation, determined as whether people who develop COVID-19 despite vaccination have lower disease severity than unvaccinated people. OBJECTIVE: To evaluate the association between vaccination with mRNA COVID-19 vaccines—mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech)—and COVID-19 hospitalization, and, among patients hospitalized with COVID-19, the association with progression to critical disease. DESIGN, SETTING, AND PARTICIPANTS: A US 21-site case-control analysis of 4513 adults hospitalized between March 11 and August 15, 2021, with 28-day outcome data on death and mechanical ventilation available for patients enrolled through July 14, 2021. Date of final follow-up was August 8, 2021. EXPOSURES: COVID-19 vaccination. MAIN OUTCOMES AND MEASURES: Associations were evaluated between prior vaccination and (1) hospitalization for COVID-19, in which case patients were those hospitalized for COVID-19 and control patients were those hospitalized for an alternative diagnosis; and (2) disease progression among patients hospitalized for COVID-19, in which cases and controls were COVID-19 patients with and without progression to death or mechanical ventilation, respectively. Associations were measured with multivariable logistic regression. RESULTS: Among 4513 patients (median age, 59 years [IQR, 45-69]; 2202 [48.8%] women; 23.0% non-Hispanic Black individuals, 15.9% Hispanic individuals, and 20.1% with an immunocompromising condition), 1983 were case patients with COVID-19 and 2530 were controls without COVID-19. Unvaccinated patients accounted for 84.2% (1669/1983) of COVID-19 hospitalizations. Hospitalization for COVID-19 was significantly associated with decreased likelihood of vaccination (cases, 15.8%; controls, 54.8%; adjusted OR, 0.15; 95% CI, 0.13-0.18), including for sequenced SARS-CoV-2 Alpha (8.7% vs 51.7%; aOR, 0.10; 95% CI, 0.06-0.16) and Delta variants (21.9% vs 61.8%; aOR, 0.14; 95% CI, 0.10-0.21). This association was stronger for immunocompetent patients (11.2% vs 53.5%; aOR, 0.10; 95% CI, 0.09-0.13) than immunocompromised patients (40.1% vs 58.8%; aOR, 0.49; 95% CI, 0.35-0.69) (P

To measure the impact of staged implementation of full versus partial ABCDE bundle on mechanical ventilation duration, ICU and hospital lengths of stay, and cost.Prospective cohort study.Two medical ICUs within Montefiore Healthcare Center (Bronx, NY).One thousand eight hundred fifty-five mechanically ventilated patients admitted to ICUs between July 2011 and July 2014.At baseline, spontaneous (B)reathing trials (B) were ongoing in both ICUs; in period 1, (A)wakening and (D)elirium (AD) were implemented in both full and partial bundle ICUs; in period 2, (E)arly mobilization and structured bundle (C)oordination (EC) were implemented in the full bundle (B-AD-EC) but not the partial bundle ICU (B-AD).In the full bundle ICU, 95% patient days were spent in bed before EC (period 1). After EC was implemented (period 2), 65% of patients stood, 54% walked at least once during their ICU stay, and ICU-acquired pressure ulcers and physical restraint use decreased (period 1 vs 2: 39% vs 23% of patients; 30% vs 26% patient days, respectively; p0.001 for both). After adjustment for patient-level covariates, implementation of the full (B-AD-EC) versus partial (B-AD) bundle was associated with reduced mechanical ventilation duration (-22.3%; 95% CI, -22.5% to -22.0%; p0.001), ICU length of stay (-10.3%; 95% CI, -15.6% to -4.7%; p = 0.028), and hospital length of stay (-7.8%; 95% CI, -8.7% to -6.9%; p = 0.006). Total ICU and hospital cost were also reduced by 24.2% (95% CI, -41.4% to -2.0%; p = 0.03) and 30.2% (95% CI, -46.1% to -9.5%; p = 0.007), respectively.In a clinical practice setting, the addition of (E)arly mobilization and structured (C)oordination of ABCDE bundle components to a spontaneous (B)reathing, (A)wakening, and (D) elirium management background led to substantial reductions in the duration of mechanical ventilation, length of stay, and cost.

Background While specific interventions have previously demonstrated benefit in patients with the Acute Respiratory Distress Syndrome (ARDS), use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown. Research Question What is the impact of treatment variability on mortality in patients with moderate-to-severe ARDS in the United States (US)? Study Design and Methods We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and PaO2/FiO2< 150 on positive end expiratory pressure (PEEP) > 5 cm H2O, who were admitted to 29 US centers between October 1, 2016 and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality were also assessed. Results A total of 2,466 patients were enrolled. Median baseline PaO2/FiO2 was 105 (IQR 78.0, 129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (tidal volume < 6.5 ml/kg predicted body weight, plateau pressure and/or peak inspiratory pressure < 30mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), types of modalities used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early lung protective ventilation (LPV) was correlated with SMR. Interpretation Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT03021824

Adults aged ≥65 years are at increased risk for severe outcomes from COVID-19 and were identified as a priority group to receive the first COVID-19 vaccines approved for use under an Emergency Use Authorization (EUA) in the United States (1-3). In an evaluation at 24 hospitals in 14 states,* the effectiveness of partial or full vaccination† with Pfizer-BioNTech or Moderna vaccines against COVID-19-associated hospitalization was assessed among adults aged ≥65 years. Among 417 hospitalized adults aged ≥65 years (including 187 case-patients and 230 controls), the median age was 73 years, 48% were female, 73% were non-Hispanic White, 17% were non-Hispanic Black, 6% were Hispanic, and 4% lived in a long-term care facility. Adjusted vaccine effectiveness (VE) against COVID-19-associated hospitalization among adults aged ≥65 years was estimated to be 94% (95% confidence interval [CI] = 49%-99%) for full vaccination and 64% (95% CI = 28%-82%) for partial vaccination. These findings are consistent with efficacy determined from clinical trials in the subgroup of adults aged ≥65 years (4,5). This multisite U.S. evaluation under real-world conditions suggests that vaccination provided protection against COVID-19-associated hospitalization among adults aged ≥65 years. Vaccination is a critical tool for reducing severe COVID-19 in groups at high risk.

Importance Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis. Objective To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis. Design, setting, and participants Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020. Interventions Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone. Main outcomes and measures The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality. Results Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group. Conclusions and relevance Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference. Trial registration ClinicalTrials.gov Identifier: NCT03509350.

Background Long-term cognitive impairment frequently occurs after critical illness; no treatments are known to improve long-term cognition. Research Question Does a single high-dose (540,000 International Units) enteral treatment of vitamin D3 given shortly after hospital admission in critically ill patients who are vitamin D deficient improve long-term global cognition or executive function? Study Design and Methods This study evaluated long-term cognitive outcomes among patients enrolled in a multicenter, blinded, randomized clinical trial comparing vitamin D3 treatment vs placebo in critically ill adults with vitamin D deficiency. Global cognition was measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Executive function was measured with a composite score derived from three Delis-Kaplan Executive Function System subscales. Outcomes were assessed at a median of 443 days (interquartile range, 390-482 days) after randomization and were compared using multivariate proportional odds regression. Adjusted ORs of > 1.0 would indicate better outcomes in the vitamin D3 group compared with the placebo group. Results Ninety-five patients were enrolled, including 47 patients randomized to vitamin D3 treatment and 48 patients randomized to placebo. The adjusted median RBANS score at follow-up was 79.6 (95% CI, 73.0-84.0) in the vitamin D3 group and 82.1 (95% CI, 74.7-84.6) in the placebo group (adjusted OR, 0.83; 95% CI, 0.50-1.38). The adjusted median executive function composite scores were 8.1 (95% CI, 6.8-9.0) and 8.7 (95% CI, 7.4-9.3), respectively (adjusted OR, 0.72; 95% CI, 0.36-1.42). Interpretation In vitamin D-deficient, critically-ill adults, a large dose of enteral vitamin D3 did not improve long-term global cognition or executive function. Trial Registry ClinicalTrials.gov; No.: NCT03733418; URL: www.clinicaltrials.gov

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

Health care personnel (HCP) caring for patients with coronavirus disease 2019 (COVID-19) might be at high risk for contracting SARS-CoV-2, the virus that causes COVID-19. Understanding the prevalence of and factors associated with SARS-CoV-2 infection among frontline HCP who care for COVID-19 patients are important for protecting both HCP and their patients. During April 3-June 19, 2020, serum specimens were collected from a convenience sample of frontline HCP who worked with COVID-19 patients at 13 geographically diverse academic medical centers in the United States, and specimens were tested for antibodies to SARS-CoV-2. Participants were asked about potential symptoms of COVID-19 experienced since February 1, 2020, previous testing for acute SARS-CoV-2 infection, and their use of personal protective equipment (PPE) in the past week. Among 3,248 participants, 194 (6.0%) had positive test results for SARS-CoV-2 antibodies. Seroprevalence by hospital ranged from 0.8% to 31.2% (median = 3.6%). Among the 194 seropositive participants, 56 (29%) reported no symptoms since February 1, 2020, 86 (44%) did not believe that they previously had COVID-19, and 133 (69%) did not report a previous COVID-19 diagnosis. Seroprevalence was lower among personnel who reported always wearing a face covering (defined in this study as a surgical mask, N95 respirator, or powered air purifying respirator [PAPR]) while caring for patients (5.6%), compared with that among those who did not (9.0%) (p = 0.012). Consistent with persons in the general population with SARS-CoV-2 infection, many frontline HCP with SARS-CoV-2 infection might be asymptomatic or minimally symptomatic during infection, and infection might be unrecognized. Enhanced screening, including frequent testing of frontline HCP, and universal use of face coverings in hospitals are two strategies that could reduce SARS-CoV-2 transmission.

ObjectiveSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is protean in its manifestations, affecting nearly every organ system. However, nervous system involvement and its effect on disease outcome are poorly characterized. The objective of this study was to determine whether neurologic syndromes are associated with increased risk of inpatient mortality.MethodsA total of 581 hospitalized patients with confirmed SARS-CoV-2 infection, neurologic involvement, and brain imaging were compared to hospitalized non-neurologic patients with coronavirus disease 2019 (COVID-19). Four patterns of neurologic manifestations were identified: acute stroke, new or recrudescent seizures, altered mentation with normal imaging, and neuro-COVID-19 complex. Factors present on admission were analyzed as potential predictors of in-hospital mortality, including sociodemographic variables, preexisting comorbidities, vital signs, laboratory values, and pattern of neurologic manifestations. Significant predictors were incorporated into a disease severity score. Patients with neurologic manifestations were matched with patients of the same age and disease severity to assess the risk of death.ResultsA total of 4,711 patients with confirmed SARS-CoV-2 infection were admitted to one medical system in New York City during a 6-week period. Of these, 581 (12%) had neurologic issues of sufficient concern to warrant neuroimaging. These patients were compared to 1,743 non-neurologic patients with COVID-19 matched for age and disease severity admitted during the same period. Patients with altered mentation (n = 258, p = 0.04, odds ratio [OR] 1.39, confidence interval [CI] 1.04–1.86) or radiologically confirmed stroke (n = 55, p = 0.001, OR 3.1, CI 1.65–5.92) had a higher risk of mortality than age- and severity-matched controls.ConclusionsThe incidence of altered mentation or stroke on admission predicts a modest but significantly higher risk of in-hospital mortality independent of disease severity. While other biomarker factors also predict mortality, measures to identify and treat such patients may be important in reducing overall mortality of COVID-19.

Prolonged symptom duration and disability are common in adults hospitalized with severe coronavirus disease 2019 (COVID-19). Characterizing return to baseline health among outpatients with milder COVID-19 illness is important for understanding the full spectrum of COVID-19-associated illness and tailoring public health messaging, interventions, and policy. During April 15-June 25, 2020, telephone interviews were conducted with a random sample of adults aged ≥18 years who had a first positive reverse transcription-polymerase chain reaction (RT-PCR) test for SARS-CoV-2, the virus that causes COVID-19, at an outpatient visit at one of 14 U.S. academic health care systems in 13 states. Interviews were conducted 14-21 days after the test date. Respondents were asked about demographic characteristics, baseline chronic medical conditions, symptoms present at the time of testing, whether those symptoms had resolved by the interview date, and whether they had returned to their usual state of health at the time of interview. Among 292 respondents, 94% (274) reported experiencing one or more symptoms at the time of testing; 35% of these symptomatic respondents reported not having returned to their usual state of health by the date of the interview (median = 16 days from testing date), including 26% among those aged 18-34 years, 32% among those aged 35-49 years, and 47% among those aged ≥50 years. Among respondents reporting cough, fatigue, or shortness of breath at the time of testing, 43%, 35%, and 29%, respectively, continued to experience these symptoms at the time of the interview. These findings indicate that COVID-19 can result in prolonged illness even among persons with milder outpatient illness, including young adults. Effective public health messaging targeting these groups is warranted. Preventative measures, including social distancing, frequent handwashing, and the consistent and correct use of face coverings in public, should be strongly encouraged to slow the spread of SARS-CoV-2.

Objectives To characterize the association between the use of physiologic assessment (central venous pressure, pulmonary artery occlusion pressure, stroke volume variation, pulse pressure variation, passive leg raise test, and critical care ultrasound) with fluid and vasopressor administration 24 hours after shock onset and with in-hospital mortality. Design Multicenter prospective cohort study between September 2017 and February 2018. Settings Thirty-four hospitals in the United States and Jordan. Patients Consecutive adult patients requiring admission to the ICU with systolic blood pressure less than or equal to 90 mm Hg, mean arterial blood pressure less than or equal to 65 mm Hg, or need for vasopressor. Interventions None. Measurement and main results Of 1,639 patients enrolled, 39% had physiologic assessments. Use of physiologic assessment was not associated with cumulative fluid administered within 24 hours of shock onset, after accounting for baseline characteristics, etiology and location of shock, ICU types, Acute Physiology and Chronic Health Evaluation III, and hospital (beta coefficient, 0.04; 95% CI, -0.07 to 0.15). In multivariate analysis, the use of physiologic assessment was associated with a higher likelihood of vasopressor use (adjusted odds ratio, 1.98; 95% CI, 1.45-2.71) and higher 24-hour cumulative vasopressor dosing as norepinephrine equivalent (beta coefficient, 0.37; 95% CI, 0.19-0.55). The use of vasopressor was associated with increased odds of in-hospital mortality (adjusted odds ratio, 1.88; 95% CI, 1.27-2.78). In-hospital mortality was not associated with the use of physiologic assessment (adjusted odds ratio, 0.86; 95% CI, 0.63-1.18). Conclusions The use of physiologic assessment in the 24 hours after shock onset is associated with increased use of vasopressor but not with fluid administration.

Objective: To understand the impact of adding a medical step-down unit (SDU) on patient outcomes and throughput in a medical intensive care unit (ICU). Design: Retrospective cohort study. Setting: Two academic tertiary care hospitals within the same health-care system. Patients: Adults admitted to the medical ICU at either the control or intervention hospital from October 2013 to March 2014 (preintervention) and October 2014 to March 2015 (postintervention). Interventions: Opening a 4-bed medical SDU at the intervention hospital on April 1, 2014. Measurements and Main Results: Using standard summary statistics, we compared patients across hospitals. Using a difference-in-differences approach, we quantified the association of opening an SDU and outcomes (hospital mortality, hospital and ICU length of stay [LOS], and time to transfer to the ICU) after adjustment for secular trends in patient case-mix and patient-level covariates which might impact outcome. We analyzed 500 (245 pre- and 255 postintervention) patients in the intervention hospital and 678 (323 pre- and 355 postintervention) in the control hospital. Patients at the control hospital were younger (60.5-60.6 vs 64.0-65.4 years, P < .001) with a higher severity of acute illness at the time of evaluation for ICU admission (Sequential Organ Failure Assessment score: 4.9-4.0 vs 3.9-3.9, P < .001). Using the difference-in-differences methodology, we identified no association of hospital mortality (odds ratio [95% confidence interval]: 0.81 [0.42 to 1.55], P = .52) or hospital LOS (% change [95% confidence interval]: −8.7% [−28.6% to 11.2%], P = .39) with admission to the intervention hospital after SDU opening. The ICU LOS overall was not associated with admission to the intervention hospital in the postintervention period (−23.7% [−47.9% to 0.5%], P = .06); ICU LOS among survivors was significantly reduced (−27.5% [−50.5% to −4.6%], P = .019). Time to transfer to ICU was also significantly reduced (−26.7% [−44.7% to −8.8%], P = .004). Conclusions: Opening our medical SDU improved medical ICU throughput but did not affect more patient-centered outcomes of hospital mortality and LOS.

Rationale: Intensive care unit (ICU) patients who receive mechanical ventilation are at high risk for early rehospitalization. Given their medical complexity, a lack of continuity of care may adversely affect outcomes during rehospitalization. Objective: To determine whether outcomes differ for patients who are rehospitalized at a different hospital versus the hospital of the index ICU stay. Methods: Retrospective cohort study of mechanically ventilated ICU patients rehospitalized within 30 days in New York State hospitals from 2008-2013. Measurements: Frequency of rehospitalization at a different hospital; mortality, length of stay and costs during rehospitalization. Main Results: Of 26,947 mechanically ventilated ICU patients rehospitalized within 30 days of discharge, 8,443 (31.3%) were rehospitalized at a different hospital than that of the index ICU stay. For patients at a different hospital, 13.7% died during rehospitalization versus 11.1% at the index hospital (adjusted rate ratio (aRR) 1.11 [1.03 -1.20], p=0.009). Patients who died at a different hospital had shorter length of stay (aRR 0.80 [0.70-0.92], p=0.001) and decreased costs (adjusted mean difference (aMD) -$9,632.73 [-$16,387.60 to -$-2,877.88], p=0.005), while survivors of rehospitalization at a different hospital had a modest increase in length of stay (aRR 1.06 [1.01-1.11], p=0.009) and increased costs of care (aMD $1,665.34 [$602.12 to $2,728.56], p=0.002). Conclusions: Almost one-third of mechanically ventilated critically ill patients were rehospitalized at a different hospital than that of the index ICU stay. This care discontinuity was associated with increased mortality. Further investigation should aim to elucidate reasons for differing patterns of care on rehospitalization and strengthen the causal relationship between care discontinuity and subsequent harm.

Rationale: No previous studies have examined the role of prehospital vulnerability in acute respiratory distress syndrome (ARDS) development and mortality in an acutely ill adult population. Objectives: To describe the association between prehospital vulnerability and 1) the development of ARDS, 2) 28-day mortality, and 3) 1-year mortality. Methods: This was a longitudinal prospective cohort study nested within the multicenter LIPS-A (Lung Injury Prevention Study-Aspirin) trial. We analyzed 301 participants who completed Vulnerable Elders Survey (VES) at baseline. Multivariable logistic regression and Cox regression analyses were used to describe the association between vulnerability and short-term outcomes (ARDS and 28-day mortality) and long-term outcomes (1-year mortality), respectively. Results: The VES score ranged from 0 to 10 (median [interquartile range], 2.0 [0–6]); 143 (47.5%) fit criteria for prehospital vulnerability (VES ≥ 3). Vulnerability was not significantly associated with ARDS development (10 [7.0%] vulnerable patients developed ARDS as per LIPS-A study criteria vs. 20 [12.7%] without vulnerability; P = 0.10; adjusted odds ratio [95% confidence interval (CI)], 0.54 [0.24–1.24]; P = 0.15). Nor was vulnerability associated with 28-day mortality (15 [10.5%] vulnerable patients were dead by Day 28 vs. 11 [7.0%] nonvulnerable patients; P = 0.28; adjusted odds ratio [95% CI], 0.95 [0.39–2.26]; P = 0.90). Vulnerability was significantly associated with 1-year mortality in hospital survivors (35 [26.9%] vs. 13 [9.3%]; adjusted hazard ratio [95% CI], 2.20 [1.10–4.37]; P = 0.02). Conclusions: In a population of adults recruited for their high risk of ARDS, prehospital vulnerability, measured by VES, was highly prevalent and strongly associated with 1-year mortality.

Background Prehospital frailty has been associated with adverse hospital outcomes in critically ill adults. Although frailty assessment in intensive care units depends on patients’ surrogates, frailty assessments by surrogates and researchers have not been compared. Objectives To compare agreement and validity between surrogates’ and researchers’ assessments of frailty in critically ill older adults. Methods An observational cohort study of adults (aged ≥ 50 years) admitted to a medical/surgical intensive care unit was conducted. On admission, patients’ surrogates quantified prehospital frailty by using the Clinical Frailty Scale (range, 1–9; scores > 4 defined as frail). Researchers blinded to surrogates’ assessments also quantified frailty. Agreement was described with κ scores, McNemar tests, and Bland-Altman plots; validity was compared by using χ2 tests and logistic regression. Results For 298 patients (mean [SD] age, 67.2 [10.5] years), both surrogates’ and researchers’ frailty assessment scores ranged from 1 to 9, with moderate to substantial agreement between scores (g ≥ 0.40). Surrogates’ frailty assessment scores were significantly lower than researchers’ (mean difference, −0.62; 95% CI, −0.77 to −0.48; P < .001). Surrogates were less likely than researchers to identify as frail those patients who experienced adverse hospital outcomes (death, prolonged stay, or disability newly identified at discharge). Conclusions Surrogates identified fewer patients as frail than did researchers. Factors involved in surrogates’ assessments of patients’ prehospital frailty status should be studied to see if the Clinical Frailty Scale can be modified to facilitate more accurate surrogate assessments.

Although results from clinical trials have advanced the treatment of acute respiratory distress syndrome (ARDS), mortality remains high. More recently, focus has shifted from treatment of ARDS to early identification and prevention in at-risk populations.There have been 30 published and registered clinical trials with either the primary or secondary goal of reducing ARDS.With this change in paradigm, come additional challenges and consideration in study design that depends not only on the intervention but also whether the intervention aims for a primary, secondary, or tertiary prevention of ARDS that targets a patient population for universal, selective, or indicated prevention. These epidemiologic concepts of prevention in public health also apply to ARDS and are relevant to the study population to target, the timing of the intervention relative to critical illness, the study design and outcomes to measure in an ARDS prevention study. This shift in focus is reflected by the new National Heart Lung Blood Institute Prevention and Early Treatment of Acute Lung Injury network, and signifies an overall movement away from reacting to and supporting acute organ failure after it is established to early detection and prevention in acute critical illness wherever and whenever it may occur.

To identify stable and specific biomarkers/biomarker combinations for fatigue assessment and establish a discriminant model.Saliva was collected and electroencephalogram analysis was performed for 47 emergency physicians while awake and after continuoutas duty for 18-24 h. Physicians were divided into the fatigue and non-fatigue groups. Protein spectra of completely quantified saliva specimens were identified before and after long working hours using mass spectrometry. Data were analyzed through Proteome Discoverer software combined with SEQUEST to search protein databases. Proteins were characterized by collision-induced dissociation spectra. A global internal standard (GIS) was added to each group of samples and labeled by tandem mass tags m/z 131.1. All data were compared with GIS, and data between groups were further compared. Qualitative and quantitative data on proteins were exported for fatigue-related proteomic analysis, and a fatigue assessment model was established.We identified 767 salivary proteins in the fatigue group. The correct rates of the discriminant function of the non-fatigue and fatigue groups were 97.1% and 91.7%, respectively (the total correct rate was 95.7%).We identified 30 fatigue-related protein markers from saliva. We also established a fatigue assessment model for emergency physicians using salivary biomarkers.

BackgroundThere are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU).MethodsIn 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.ResultsWritten 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.ConclusionsThe 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 .).

RationaleLow-tidal volume ventilation (LTVV; 6 ml/kg) benefits patients with acute respiratory distress syndrome and may aid those with other causes of respiratory failure. Current early ventilation practices are poorly defined.ObjectivesWe observed patients with acute respiratory failure to assess the feasibility of a pragmatic trial of LTVV and to guide experimental design.MethodsWe prospectively enrolled consecutive patients with acute respiratory failure admitted to intensive care units expected to participate in the proposed trial. We collected clinical data as well as information on initial and daily ventilator settings and inpatient mortality. We estimated the benefit of LTVV using predictive linear and nonlinear models. We simulated models to estimate power and feasibility of a cluster-randomized trial of LTVV versus usual care in acute respiratory failure.ResultsWe included 2,484 newly mechanically ventilated patients (31% with acute respiratory distress syndrome) from 49 hospitals. Hospital mortality was 28%. Mean initial tidal volume was 7.1 ml/kg predicted body weight (95% confidence interval, 7.1-7.2), with 78% of patients receiving tidal volumes less than or equal to 8 ml/kg. Our models estimated a mortality benefit of 0-2% from LTVV compared with usual care. Simulation of a stepped-wedged cluster-randomized trial suggested that enrollment of 106,361 patients would be necessary to achieve greater than 90% power.ConclusionsUse of initial tidal volumes less than 8 ml/kg predicted body weight was common at hospitals participating in the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury (PETAL) Network. After considering the size and budgetary requirement for a cluster-randomized trial of LTVV versus usual care in acute respiratory failure, the PETAL Network deemed the proposed trial infeasible. A rapid observational study and simulations to model anticipated power may help better design trials.

Objectives Mechanical ventilation with low tidal volumes is recommended for all patients with acute respiratory distress syndrome and may be beneficial to other intubated patients, yet consistent implementation remains difficult to obtain. Using detailed electronic health record data, we examined patterns of tidal volume administration, the effect on clinical outcomes, and alternate metrics for evaluating low tidal volume compliance in clinical practice. Design Observational cohort study. Setting Six ICUs in a single hospital system. Patients Adult patients who received invasive mechanical ventilation more than 12 hours. Interventions None. Measurements and main results Tidal volumes were analyzed across 1,905 hospitalizations. Although mean tidal volume was 6.8 mL/kg predicted body weight, 40% of patients were exposed to tidal volumes greater than 8 mL/kg predicted body weight, with 11% for more than 24 hours. At a patient level, exposure to 24 total hours of tidal volumes greater than 8 mL/kg predicted body weight was associated with increased mortality (odds ratio, 1.82; 95% CI, 1.20-2.78), whereas mean tidal volume exposure was not (odds ratio, 0.87/1 mL/kg increase; 95% CI, 0.74-1.02). Initial tidal volume settings strongly predicted exposure to volumes greater than 8 mL/kg for 24 hours; the adjusted rate was 21.5% when initial volumes were greater than 8 mL/kg predicted body weight and 7.1% when initial volumes were less than 8 mL/kg predicted body weight. Across ICUs, correlation of mean tidal volume with alternative measures of low tidal volume delivery ranged from 0.38 to 0.66. Conclusions Despite low mean tidal volume in the cohort, a significant percentage of patients were exposed to a prolonged duration of high tidal volumes which was correlated with higher mortality. Detailed ventilator records in the electronic health record provide a unique window for evaluating low tidal volume delivery and targets for improvement.

Background Acute respiratory failure occurs frequently in hospitalized patients and often starts before ICU admission. A risk stratification tool to predict mortality and risk for mechanical ventilation (MV) may allow for earlier evaluation and intervention. We developed and validated an automated electronic health record (EHR)-based model—Accurate Prediction of Prolonged Ventilation (APPROVE)—to identify patients at risk of death or respiratory failure requiring >= 48 h of MV. Methods This was an observational study of adults admitted to four hospitals in 2013 or a fifth hospital in 2017. Clinical data were extracted from the EHRs. The 2013 patients were randomly split 50:50 into a derivation/validation cohort. The qualifying event was death or intubation leading to MV >= 48 h. Random forest method was used in model derivation. APPROVE was calculated retrospectively whenever data were available in 2013, and prospectively every 4 h after hospital admission in 2017. The Modified Early Warning Score (MEWS) and National Early Warning Score (NEWS) were calculated at the same times as APPROVE. Clinicians were not alerted except for APPROVE in 2017cohort. Results There were 68,775 admissions in 2013 and 2258 in 2017. APPROVE had an area under the receiver operator curve of 0.87 (95% CI 0.85–0.88) in 2013 and 0.90 (95% CI 0.84–0.95) in 2017, which is significantly better than the MEWS and NEWS in 2013 but similar to the MEWS and NEWS in 2017. At a threshold of > 0.25, APPROVE had similar sensitivity and positive predictive value (PPV) (sensitivity 63% and PPV 21% in 2013 vs 64% and 16%, respectively, in 2017). Compared to APPROVE in 2013, at a threshold to achieve comparable PPV (19% at MEWS > 4 and 22% at NEWS > 6), the MEWS and NEWS had lower sensitivity (16% for MEWS and NEWS). Similarly in 2017, at a comparable sensitivity threshold (64% for APPROVE > 0.25 and 67% for MEWS and NEWS > 4), more patients who triggered an alert developed the event with APPROVE (PPV 16%) while achieving a lower false positive rate (FPR 5%) compared to the MEWS (PPV 7%, FPR 14%) and NEWS (PPV 4%, FPR 25%). Conclusions An automated EHR model to identify patients at high risk of MV or death was validated retrospectively and prospectively, and was determined to be feasible for real-time risk identification. Trial registration ClinicalTrials.gov, NCT02488174. Registered on 18 March 2015. Electronic supplementary material The online version of this article (10.1186/s13054-018-2194-7) contains supplementary material, which is available to authorized users.

To estimate the effect of pre-intensive care unit (ICU) health categories on mortality during and after critical illness, focusing specifically on the effect of pre-ICU frailty on short- and long-term mortality.Retrospective cohort study.Medicare claims data from 2004 to 2008.A nationally representative sample of elderly Medicare beneficiaries admitted to an ICU in 2005.Participants were classified into four pre-ICU health categories (robust, cancer, chronic organ failure, frailty) using claims data from the year before admission, allowing for assignment to multiple categories. The association between pre-ICU health category and hospital and 3-year mortality was assessed using multivariable logistic regression and Cox proportional hazards models.Of 47,427 elderly individuals in the ICU, 18.8% were robust, 28.6% had cancer, 68.1% had chronic organ failure, and 34.0% were frail; 41.3% qualified for multiple categories. Overall hospital mortality was 12.6%, with the lowest mortality for robust participants (9.7%). Participants with pre-ICU frailty had higher hospital mortality than those with the same pre-ICU health categories without frailty. (Adjusted odds ratios ranged from 1.27 (95% confidence interval (CI) 1.10-1.47) to 1.52 (95% CI = 1.35-1.63).) Robust hospital survivors had the lowest 3-year mortality (24.6%). Pre-ICU frailty conferred higher 3-year mortality than pre-ICU categories without frailty. (Adjusted hazard ratios ranged from 1.54 (95% CI = 1.45-1.64) to 1.84 (95% CI = 1.70-1.99).)Critically ill elderly adults can be categorized according to pre-ICU health categories. These categories, particularly pre-ICU frailty, may be important for understanding risk of death during and after critical illness.

Context Previous research has identified a large unmet need in provision of specialist-level palliative care services in the hospital. How much of this gap is filled by primary palliative care provided by generalists or nonpalliative specialists has not been quantified. Estimates of racial and ethnic disparities have been inconsistent. Objectives The objective of this study was to 1) estimate primary and specialty palliative care delivery and to measure unmet needs in the inpatient setting and 2) explore racial and ethnic disparities in palliative care delivery. Methods This was a cross-sectional, retrospective study of 55,658 adult admissions to two acute care hospitals in the Bronx in 2013. Patients with palliative care needs were identified by criteria adapted from the literature. The primary outcomes were delivery of primary and specialist-level palliative care. Results In all, 18.5% of admissions met criteria for needing palliative care. Of those, 18% received specialist-level palliative care, an estimated 30% received primary palliative care, and 37% had no evidence of palliative care or advance care planning. Black and Hispanic patients were not less likely to receive specialist-level palliative care (adjusted odds ratio [OR] black patients = 1.18, 95% CI 0.98, 1.42; adjusted OR Hispanic patients = 1.24, 95% CI 1.04, 1.48), but they were less likely to receive primary palliative care (adjusted OR black patients = 0.41, 95% CI 0.20, 0.84; adjusted OR Hispanic patients = 0.48, 95% CI 0.25, 0.94). Conclusion Even when considering primary and specialty palliative care, hospitalized patients have a high prevalence of unmet palliative care need. Further research is needed understand racial and ethnic disparities in palliative care delivery.

PURPOSE: We aimed to estimate the independent effect of pre-hospital frailty (PHF) on hospital mortality and prolonged hospital length of stay (pLOS) while adjusting for other patient level factors. METHODS: This is a cohort study of hospitalized adults with acute respiratory failure (ARF) who required invasive mechanical ventilation for ≥ 24 hours in 2013. We used inpatient/outpatient claims from a list of diagnoses from the year before index hospital admission to define PHF. Differences in characteristics/outcomes by PHF were explored using descriptive statistics; multivariable logistic regression was used to estimate association between PHF and hospital outcomes. RESULTS: Among 1157 patients (mean age (standard deviation) 67.1 [16.4]), 53.2 % had PHF. PHF was independently associated with higher hospital mortality (44.2% in PHF patients vs. 34.6% in those without, adjusted Odds Ratio (aOR) (95% Confidence Interval [CI] 1.56 (1.19 -2.05), p

Identifying frailty by the presence of a critical number of frailty markers has been difficult to operationalize in the intensive care unit (ICU), where patients often cannot complete performance measures or answer complex questions.To assess the construct and predictive validity of a questionnaire-based approach to identifying frailty in adult ICU patients.We conducted an observational cohort study of adults admitted to a medical or surgical ICU at one of two hospitals in New York. We asked patients or surrogates about demographic information, frailty markers, and prehospital disability status. ICU physicians completed the Clinical Frailty Scale (CFS), a judgment-based frailty assessment tool. We examined the relationship between individual frailty markers, CFS, and demographic correlates of frailty such as age, prehospital living arrangement, and prehospital disability. We assessed the predictive validity of possible frailty phenotypes, using hospital and 6-month outcomes.Among 95 study participants (mean age [SD], 57.1 [17.5] yr), 80% reported one or more of seven frailty markers (median [interquartile range], 3 [1-4]). The most common frailty markers were impaired mobility (60%), impaired physical activity (60%), and decreased strength (44.2%). Patients with more frailty markers were older (mean age [SD] of those with at least three frailty markers: 62.3 [17.7] vs. 51.6 [15.8] yr; P 0.001) compared with those with fewer than three markers, and were more likely to be judged frail by CFS (57.0 vs. 19.6%; P = 0.001), although of the 49 patients with three or more frailty markers, CFS identified 36.7% as not frail. Malnutrition and fatigue or low energy were not significantly associated with other frailty correlates. Survivors with more frailty markers were more likely to die or report increased disability at follow-up. In multivariate models, a frailty phenotype defined as at least three of the seven frailty markers performed similarly to CFS in predicting death or increased disability at 6 months (adjusted odds ratio [95% confidence interval], 3.3 [1.2-9.0] vs. 3.8 [1.2-11.7]) for CFS.Asking patients or surrogates about frailty markers may be a valid approach to identifying critically ill adults with a frailty phenotype associated with increased risk of adverse outcomes. Larger studies measuring frailty markers may provide insight into factors that impact short- and long-term outcomes after ICU admission.

BACKGROUND Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. METHODS We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 mu g of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. RESULTS A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P

Context Terminally ill hospitalized patients and their families consistently rank effective communication and shared decision-making among their top priorities. Advance practice providers such as physician assistants (PAs) are increasingly providing care in the hospital setting and are often called to communicate with patients and families. A first step to improving PA communication is to better understand PAs' current experiences in their daily practices. Objectives This study aimed to explore roles PAs serve in communicating with terminally ill patients/families; PAs' attitudes and opinions about communication roles; and perceived barriers and facilitators of communication with patients/families in the hospital setting. Methods Five focus groups were conducted with PAs practicing on adult medical services at three acute care hospitals of an academic medical center in Bronx, New York. An open-ended question guide was used. An inductive thematic analysis strategy was used to examine the data from transcribed audiotapes of focus group sessions to identify emergent concepts and themes. Results The overarching theme that emerged was being stuck in the middle. PAs experienced ambiguity around their roles and responsibilities in communications between the medical team as well as patients and families; gaps in knowledge and skills; and organizational or structural deficits in the patient care systems that placed them in uncomfortable situations. Conclusion Interventions aimed at improving PA communication with terminally ill patients and their families should target institutional structures, systems, and culture around roles and responsibilities in addition to skill and knowledge gaps to be most effective.

Objective: The primary objective was to conduct a meta-analysis on published observational cohort data describing the association between acetyl-salicylic acid (aspirin) use prior to the onset of sepsis and mortality in hospitalized patients. Study Selection: Studies that reported mortality in patients on aspirin with sepsis with a comparison group of patients with sepsis not on prior aspirin therapy were included. Data Sources: Fifteen studies described hospital-based cohorts (n = 17,065), whereas one was a large insurance-based database (n = 683,421). Individual-level patient data were incorporated from all selected studies. Data Extraction: Propensity analyses with 1:1 propensity score matching at the study level were performed, using the most consistently available covariates judged to be associated with aspirin. Meta-analyses were performed to estimate the pooled average treatment effect of aspirin on sepsis-related mortality. Data Synthesis: Use of aspirin was associated with a 7% (95% CI, 2-12%; p = 0.005) reduction in the risk of death as shown by meta-analysis with considerable statistical heterogeneity (I-2 = 61.6%). Conclusions: These results are consistent with effects ranging from a 2% to 12% reduction in mortality risk in patients taking aspirin prior to sepsis onset. This association anticipates results of definitive studies of the use of low-dose aspirin as a strategy for reduction of deaths in patients with sepsis

Background Health workers' awareness and knowledge of transplantation medicine can improve people's sensitivity and reduce their degree of opposition to donations. The medical literature contains numerous examples of attitudes toward organ transplantation and donation aimed at university students or medical staff members, but rarely for transplantation nurses. Objective The purposes of the study were to investigate the attitudes toward organ transplantation and donation among transplantation nurses and to explore the impact factors. Methods The study was conducted in 37 transplantation surgery wards in 22 hospitals using cross-sectional approach. SPSS (International Business Machines Corporation, Armonk, New York, USA) 7.0 software was used to analysis descriptive and inferential statistics for data. Results Five hundred thirty-six effective questionnaires were received and the effective rate was 89.33%. Nurses' mean age was 28.40 years with a mean service length of 6.54 years. Among these nurses, 66.6% and 78.0% were willing to accept organ transplantation surgery for themselves and their relatives, respectively. Of these nurses, 33.4% would donate their organs after death; whereas 39.9% were uncertain. Only 38.2% were willing to register in the national organ donation system. Of these nurses, 28.2% were willing to sign the organ donation consent forms when their relatives became potential organ donors, and 45.7% were uncertain. Eight independent variables that affected nurses' attitudes toward donating their organs from most to least significant were: ratio of nurse to bed, title, employment form, age, length of service, position, monthly income, and the highest educational degree earned. Pearson correlation analysis showed a significant correlation among nurses' attitudes toward organ transplantation, organ donation, and online registration. Conclusion The attitude toward donation and transplantation in the hospitals was not too optimistic, and an improvement in the training regarding transplantation and donation among nurses in China is necessary. Nurses are an important group who generate opinion in the patient population, and their negative attitudes can have a significant negative impact on society's attitudes toward organ donation.

Introduction Acute respiratory failure (ARF) often presents and progresses outside of the intensive care unit. However, recognition and treatment of acute critical illness is often delayed with inconsistent adherence to evidence-based care known to decrease the duration of mechanical ventilation (MV) and complications of critical illness. The goal of this trial is to determine whether the implementation of an electronic medical record-based early alert for progressive respiratory failure coupled with a checklist to promote early compliance to best practice in respiratory failure can improve the outcomes of patients at risk for prolonged respiratory failure and death. Methods and analysis A pragmatic stepped-wedged cluster clinical trial involving 6 hospitals is planned. The study will include adult hospitalised patients identified as high risk for MV >48 hours or death because they were mechanically ventilated outside of the operating room or they were identified as high risk for ARF on the Accurate Prediction of PROlonged VEntilation (APPROVE) score. Patients with advanced directives limiting intubation will be excluded. The intervention will consist of (1) automated identification and notification of clinician of high-risk patients by APPROVE or by invasive MV and (2) checklist of evidence-based practices in ARF (Prevention of Organ Failure Checklist—PROOFCheck). APPROVE and PROOFCheck will be developed in the pretrial period. Primary outcome is hospital mortality. Secondary outcomes include length of stay, ventilator and organ failure-free days and 6-month and 12-month mortality. Predefined subgroup analysis of patients with limitation of aggressive care after study entry is planned. Generalised estimating equations will be used to compare patients in the intervention phase with the control phase, adjusting for clustering within hospitals and time. Ethics and dissemination The study was approved by the institutional review boards. Results will be published in peer-reviewed journals and presented at international meetings. Trial registration number NCT02488174.

Understanding ICU workflow and how it is impacted by ICU strain is necessary for implementing effective improvements. This study aimed to quantify how ICU physicians spend time and to examine the impact of ICU strain on workflow.Prospective, observational time-motion study.Five ICUs in two hospitals at an academic medical center.Thirty attending and resident physicians.None.In 137 hours of field observations, the most time-84 hours (62% of total observation time)-was spent on professional communication. Reviewing patient data and documentation occupied a combined 52 hours (38%), whereas direct patient care and education occupied 24 hours (17%) and 13 hours (9%), respectively. The most frequently used tool was the computer, used in tasks that occupied 51 hours (37%). Severity of illness of the ICU on day of observation was the only strain factor that significantly impacted work patterns. In a linear regression model, increase in average ICU Sequential Organ Failure Assessment was associated with more time spent on direct patient care (β = 4.3; 95% CI, 0.9-7.7) and education (β = 3.2; 95% CI, 0.7-5.8), and less time spent on documentation (β = -7.4; 95% CI, -11.6 to -3.2) and on tasks using the computer (β = -7.8; 95% CI, -14.1 to -1.6). These results were more pronounced with a combined strain score that took into account unit census and Sequential Organ Failure Assessment score. After accounting for ICU type (medical vs surgical) and staffing structure (resident staffed vs physician assistant staffed), results changed minimally.Clinicians spend the bulk of their time in the ICU on professional communication and tasks involving computers. With the strain of high severity of illness and a full unit, clinicians reallocate time from documentation to patient care and education. Further efforts are needed to examine system-related aspects of care to understand the impact of workflow and strain on patient care.

Background The role of genetics in the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) from direct or indirect lung injury has not been specifically investigated. The aim of this study was to identify genetic variants contributing to ALI/ARDS from pulmonary or extrapulmonary causes. Methods We conducted a multistage genetic association study. We first performed a large-scale genotyping (50K ITMAT-Broad_CARe Chip) in 1717 critically ill Caucasian patients with either pulmonary or extrapulmonary injury, to identify single nucleotide polymorphisms (SNPs) associated with the development of ARDS from direct or indirect insults to the lung. Identified SNPs (p≤0.0005) were validated in two separated populations (Stage II), with trauma (Population I; n=765) and pneumonia/pulmonary sepsis (Population II; n=838), as causes for ALI/ARDS. Genetic variants replicating their association with trauma related-ALI in Stage II were validated in a second trauma-associated ALI population (n=224, Stage III). Results In Stage I, non-overlapping SNPs were significantly associated with ARDS from direct/indirect lung injury, respectively. The association between rs1190286 ( POPDC3 ) and reduced risk of ARDS from pulmonary injury was validated in Stage II (p

Objective:Acute kidney injury frequently complicates septic shock and independently predicts mortality in this population. Clinical factors alone do not entirely account for differences in risk of acute kidney injury between patients. Genetic variants are likely to explain this differential suscepti

OBJECTIVE The pleiotropic effects of statins, 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitor, have been shown to modify inflammatory cell signaling on the immune response to infection. It was postulated that statins may be a good candidate as novel therapeutic agents for the treatment of sepsis. We investigated whether ongoing statin therapy is associated with mortality in patients with bloodstream infection. DESIGN A retrospective cohort study. SETTING Two tertiary hospitals in Bronx, NY. PATIENTS Adult patients in the hospital with bloodstream infection and categorized according to statin therapy as an outpatient or inpatient before bacteremia. INTERVENTIONS None. MEASUREMENT AND MAIN RESULTS Of 2,139 bacteremic hospitalized patients, 592 (28%) received statins before blood cultures and 677 (32%) died within 90 days. On multivariate adjustment, the association between statin therapy and 90-day all-cause mortality was statistically significant (hazard ratio, 0.78; 95% confidence interval [CI] 0.65-0.94), but statin users and nonusers differed significantly on many baseline clinical factors. Using the propensity score matched analysis to balance the differences between groups, the association was no longer significant (hazard ratio 0.99; 95% CI 0.77-1.25). Multivariate analysis after stratifying by decile in propensity score for statin use demonstrated similar results (hazard ratio 0.86; 95% CI 0.70-1.06). Statin use was not associated with reduced intensive care unit admission (odds ratio [OR], 0.86; 95% CI 0.59-1.26), hospital length of stay (β = -0.8 days; 95% CI -2.2 to 1.7 days), intensive care unit length of stay (β = -0.1 days; 95% CI -3.7 to 3.8 days), or need for mechanical or noninvasive ventilation (OR 1.03; 95% CI 0.70-1.51). CONCLUSION After adjusting for the propensity to receive statin therapy, no statistically significant association between statin therapy before bloodstream infection and survival was identified.

Background Pre-B-cell colony-enhancing factor (PBEF) is a potential biomarker for acute lung injury (ALI) in sepsis. We aimed to determine the clinical correlates for elevated plasma PBEF upon ICU admission for severe sepsis and the usefulness of PBEF to predict ALI development and sepsis mortality. Methods This is a prospective cohort of patients admitted to the medical ICU with severe sepsis. Patients without available blood samples or who were not enrolled within 24 h of admission were excluded. Plasma collected within 24 h of ICU admission was measured for PBEF concentrations by enzyme-linked immunosorbent assay. Patients were followed for ALI development as defined by the American-European Consensus Conference and for all-cause hospital mortality. Results Between September 30, 2008, and March 10, 2009, 113 patients were enrolled, and 50 (44%) developed ALI. Elevated PBEF levels significantly correlated with higher APACHE (Acute Physiology and Chronic Health Evaluation) III scores ( R 2 = 0.08, P = .003) and failure to reach early sepsis goals within 6 h of severe sepsis ( P = .003). PBEF did not differ by ALI status ( P = .58). The mortality rate was 46%. Nonsurvivors had higher PBEF levels than survivors (2.53 ng/mL; interquartile range [IQR], 1.07-8.16 vs 1.44 ng/mL; IQR, 0.84-2.81; P = .02). After adjusting for severity of illness, PBEF levels were no longer significantly associated with mortality (OR, 1.44 per 10-fold increase; 95% CI, 0.69-3.03, P = .34). Conclusions In this study, elevated PBEF did not correlate with lung injury in sepsis. However, it was associated with sepsis mortality mainly due to its association with greater severity of illness on ICU admission.

In the United States, the Belmont Report identified three ethical principles that underlie the Common Rule and guide Institutional Review Boards (IRBs) in their efforts to protect human subjects in research: respect for persons, beneficence, and justice (1). Respect for persons requires that informed consent be obtained for research participation and that special protections are given to protect persons with diminished autonomy. It is now recognized that many older adults with acute illnesses may be incapacitated and unable to consent to research. During acute illness, 26% to 67% of elderly patients, 32% of patients with acute myocardial infarction, and 14% of patients with diabetes have impaired cognition (2–7). Delirium and dementia, common contributors to decisional impairment among hospitalized patients, are more common among the elderly (8–11). As the population ages, the number of U.S. adults with dementia is expected to increase to 13.2 million by 2050 (12), and the number of potentially incapacitated adult patients in the hospital will likely increase. In the intensive care unit (ICU), most of the patients are impaired in their decision-making and unable to consent to research. Yet, the issue of how IRBs should best guide research that involves incapacitated adults is unclear. The Common Rule allows for informed consent for research from the subject or the subject’s legally authorized representative, but it leaves the definition of surrogate to applicable state laws (13, 14). Unfortunately, most states have no laws regarding surrogate consent for research, and reliance on health care proxies is problematic because most elderly individuals do not have a legally authorized representative for medical decision-making (15–17). Federal regulations also dictate that in research involving decisionally impaired adults, “additional safeguards” should be included to protect this vulnerable population (18). However, the regulations are silent about the nature of these safeguards. A number of national, state, and international bodies, including the National Institutes of Health (NIH) and the National Bioethics Advisory Commission, have proposed guidelines for research involving incapacitated individuals. These guidelines describe six possible safeguards: assessment for competence to consent, demonstration that research cannot be performed without enrolling incapacitated adults, use of surrogate decision-makers with evidence of the patient’s previous preferences depending on research risk, institutional assessment of the research risk and benefit to ensure that they are appropriate, a requirement for assent or dissent from participants, and a requirement for independent consent and participation monitors to ensure that research participation is consistent with the patient’s preferences (19). However, there is debate about the specifics, necessity, and implementation of these safeguards. The resulting confusion has led to a working group convened by the Office of Human Research Protection to make recommendations with regard to research involving decisionally impaired adults (Subcommittee for the Inclusion of Individuals with Impaired Decision-Making in Research) (20). Consequently, it is not clear how IRBs handle research involving incapacitated adults. In this study, we examined the variability of IRB practices with regard to surrogate consent and other safeguards implemented to protect incapacitated adults, including ICU patients, in research. Understanding the scope of IRB practices with this population is especially timely and important given the increasing age of the population and the current discussions of how best to protect this group of vulnerable individuals.

Infection is the most frequent cause of acute respiratory distress syndrome (ARDS). However, little is known about the influence of infection sites on ARDS. This study aimed to assess the associations of infection sites with ARDS development and mortality in critically ill infected patients.Prospective observational study.Adult intensive care units (ICUs) of an academic medical center.Study population included 1,973 consecutive patients admitted to ICUs with bacteremia, pneumonia or sepsis. During follow-up, 549 patients developed ARDS and 212 of them died within 60 days.The distribution of infection sites in ARDS patients was: lung (77.2%), abdomen (19.3%), skin/soft tissues (6.0%), urinary tract (4.7%), unknown (2.6%), and multiple sites (17.7%). On multivariate analysis, lung was the only infection site associated with increased ARDS risk [adjusted odds ratio (OR) 3.49]. Urinary tract (adjusted OR 0.43), skin/soft tissue (adjusted OR 0.64), and unknown-site infections (adjusted OR 0.38) were associated with decreased risk. No association was found between individual infection site and ARDS mortality. However, unknown-site [adjusted hazard ratio (HR) 3.08] and multiple-site infections (adjusted HR 1.63) were associated with increased ARDS mortality. When grouping patients into pulmonary, nonpulmonary, and combined infections, nonpulmonary infection was associated with decreased ARDS risk (adjusted OR 0.28) and combined infections was associated with increased ARDS mortality (adjusted HR 1.69), compared with pulmonary infection.In critically ill infected patients, pulmonary infection is associated with higher risk of ARDS development than are infections at other sites. Pulmonary versus nonpulmonary infection significantly affects ARDS development but not mortality.

Objective: To determine whether polymorphisms of the surfactant protein B gene may be associated with increased mortality in patients with the acute respiratory distress syndrome. Design: A prospective cohort study. Setting: Four adult intensive care units at a tertiary academic medical center. Patients: Two hundred fourteen white patients who had met criteria for acute respiratory distress syndrome. Interventions: None. Measurements and Main Results: Patients were genotyped for a variable nuclear tandem repeat polymorphism in intron 4 of the surfactant protein B gene and the surfactant protein B gene 1580 polymorphism. For the variable nuclear tandem repeat surfactant protein B gene polymorphism, patients were found to have either a homozygous wild-type genotype or a variant genotype consisting of either a heterozygous insertion or deletion polymorphism. Logistic regression was performed to analyze the relationship of the polymorphisms to mortality in patients with acute respiratory distress syndrome. In multivariate analysis, the presence of variable nuclear tandem repeat surfactant protein B gene polymorphism was associated with a 3.51 greater odds of death at 60 days in patients with acute respiratory distress syndrome as compared to those patients with the wild-type genotype (95% confidence interval 1.39‐8.88, p 0.008). There was no association found between the 1580 variant and outcome (p 0.15). Conclusions: In this study, the variable nuclear tandem repeat surfactant protein B gene polymorphism in intron 4 is associated with an increased 60 day mortality in acute respiratory distress syndrome after adjusting for age, severity of illness, and other potential confounders. Additional studies in other populations are needed to confirm this finding. (Crit Care Med 2008; 36: 2511‐2516)

Patients with acute respiratory distress syndrome suffer from profound cardiac and pulmonary derangement, including right ventricular strain and noncardiogenic pulmonary edema, which may potentially alter concentrations of cardiac natriuretic peptides. We sought to determine whether N-terminal probrain natriuretic peptide (NT-proBNP) levels are elevated in acute respiratory distress syndrome and whether they can serve as a marker of prognosis in this setting.Prospective study.Tertiary-care academic medical center.One hundred seventy-seven acute respiratory distress syndrome subjects enrolled in a prospective intensive care unit cohort.None.NT-proBNP was measured from blood taken within 48 hrs of acute respiratory distress syndrome onset. Patients were followed for the primary outcome of 60-day mortality and secondary outcomes of organ dysfunction and ventilator-free days. Seventy patients died (40%). Median NT-proBNP level was 3181 ng/L (interquartile range 723-9246 ng/L). NT-proBNP levels were significantly higher among nonsurvivors (p.0001). Receiver operating curve analysis revealed an optimal NT-proBNP cut-point of 6813 ng/L for predicting death. Patients with levels above the cut-point had significantly higher odds of mortality on multivariable analysis (odds ratio 2.36, 95% confidence interval 1.11-4.99, p = .02) than those with levels below the cut-point. Kaplan-Meier survival analysis showed that this difference emerged early and was sustained (p.0001). Patients with elevated NT-proBNP also had higher organ dysfunction scores (p.0001) and fewer ventilator free days (p = .03) than those with lower NT-proBNP levels.NT-proBNP levels are elevated among acute respiratory distress syndrome patients and parallel the severity of the syndrome and likelihood for morbidity and mortality. This demonstrates the potential utility of this biomarker for prognosis in this disease.

OBJECTIVE The nuclear factor (NF)-kappaB regulates inflammatory responses and plays important roles in the pathogenesis of acute respiratory distress syndrome (ARDS). Inhibitor kappaB-alpha (NFKBIA) inhibits NF-kappaB and controls its activities. The objective was to determine whether polymorphisms in NFKBIA gene would be associated with ARDS development. DESIGN Prospective cohort of adults with clinical risk factors for ARDS. SETTING Hospital system. PATIENTS Patients were 1,210 critically ill Caucasian patients meeting study criteria for a defined risk factor for ARDS who were enrolled and prospectively followed for 60 days; 382 had ARDS, and 828 were controls. INTERVENTIONS Genetic polymorphisms in the NFKBIA promoter (-881A/G, -826C/T, -297C/T) were determined using TaqMan techniques. MEASUREMENTS AND MAIN RESULTS The three polymorphisms were in Hardy-Weinberg equilibrium. No individual genotype was significantly associated with ARDS development. In contrast, haplotypes of NFKBIA were globally associated with ARDS development (p = .02, degree of freedom = 2). The frequency of haplotype GTC (-881G/-826T/-297C) was significantly higher among ARDS patients (7.4%) than that among controls (5.2%) (p = .03). Crude analysis showed that the haplotype GTC was significantly associated with higher risks of ARDS in the whole cohort compared with the common haplotype ACC (-881A/-826C/-297C) (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.03-2.09; p = .03), especially among male subjects (OR, 1.90; 95% CI, 1.20-2.97; p < .01). After adjustment for covariates, the haplotype GTC remained significantly associated with increased risk of ARDS in the whole cohort (OR, 1.66; 95% CI, 1.09-2.53; p = .02), particularly among male patients (OR, 1.98; 95% CI, 1.16-3.40; p = .02) and among subjects with direct pulmonary injury (OR, 1.75; 95% CI, 1.04-2.95; p = .04). CONCLUSIONS The haplotype GTC of NFKBIA gene is associated with higher risk of ARDS in Caucasians, particularly in male patients and in patients with direct lung injury.