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Background Although specific interventions previously demonstrated benefit in patients with 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? Study Design and Methods We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and Pa o 2 to F io 2 ratio of ≤ 150 with positive end-expiratory pressure of ≥ 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 also were assessed. Results A total of 2,466 patients were enrolled. Median baseline Pa o 2 to F io 2 ratio was 105 (interquartile range, 78.0-129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (LPV; tidal volume, ≤ 6.5 mL/kg predicted body weight; plateau pressure, or when unavailable, peak inspiratory pressure, ≤ 30 mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), methods 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 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. Trial Registry ClinicalTrials.gov; No.: NCT03021824; URL: www.clinicaltrials.gov

Purpose To measure the rate of recall of study participation and study attrition in survivors of acute respiratory distress syndrome(ARDS). Materials/Methods In this ancillary study of the Re-evaluation of Systemic Early neuromuscular blockade(ROSE) trial, we measured the rate of study participation recall 3 months following discharge and subsequent study attrition at 6 months. We compared patient and hospital characteristics, and long-term outcomes by recall. As surrogate decision-makers provided initial consent, we measured the rate of patient reconsent and its association with study recall. Results Of 487 patients evaluated, recall status was determined in 386(82.7%). Among these, 287(74.4%) patients recalled participation in the ROSE trial, while 99(25.6%) did not. There was no significant difference in 6-month attrition among patients who recalled study participation (9.1%) and those who did not (12.1%) (p = 0.38). Patient characteristics were similar between groups, except SOFA scores, ventilator-free days, and length of stay. 330(68%) were reconsented. Compared to those not reconsented, significantly more patients who were reconsented recalled study participation(78% vs. 66%;p = 0.01). Conclusions One in 4 ARDS survivors do not recall their participation in a clinical trial during hospitalization 3 months following hospital discharge, which did not influence 6-month attrition. However, more patients recall study participation if reconsent is obtained.

Objectives: To measure the impact of full versus partial ABCDE bundle implementation on specific cost centers and related resource utilization. Design: Retrospective cohort study. Setting: Two medical ICUs within Montefiore Health System (Bronx, NY). Patients: Four hundred and seventy-two mechanically ventilated patients admitted to the medical ICUs during a hospitalization which began and ended between January 1, 2013 and December 31, 2013. Interventions: The full (A)wakening, (B)reathing, (C)oordination, (D)elirium Monitoring/Management and (E)arly Mobilization bundle was implemented in the intervention ICU while a portion of the bundle (A, B, and D components) was implemented in the comparison ICU. Measurements and Main Results: Relative to the comparison ICU, implementation of the entire bundle in the intervention ICU was associated with a 27.3% (95% CI: 9.9%, 41.3%; P = 0.004) decrease in total hospital laboratory costs and a 2,888.6% (95% CI: 77.9%, 50,113.2%; P = 0.018) increase in total hospital physical therapy costs. Cost of total hospital medications, diagnostic radiology and respiratory therapy were unchanged. Relative to the comparison ICU, total hospital resource use decreased in the intervention ICU (incidence rate ratio [95% CI], laboratory: 0.68 [0.54, 0.87], P = 0.002; diagnostic radiology: 0.75 [0.59, 0.96], P = 0.020). Conclusions: Full ABCDE bundle implementation resulted in a decrease in total hospital laboratory costs and total hospital laboratory and diagnostic resource utilization while leading to an increase in physical therapy costs.

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.

Preventing, treating, and promoting recovery from critical illness due to pulmonary disease are foundational goals of the critical care community and the National Heart, Lung, and Blood Institute. Decades of clinical research in acute respiratory distress syndrome, acute respiratory failure, pneumonia, and sepsis have yielded improvements in supportive care, which have translated into improved patient outcomes. Novel therapeutics have largely failed to translate from promising pre-clinical findings into improved patient outcomes in late-phase clinical trials. Recent advances in personalized medicine, "big data", causal inference using observational data, novel clinical trial designs, pre-clinical disease modeling, and understanding recovery from acute illness promise to transform the methods of pulmonary and critical care clinical research. To assess the current state, research priorities, and future directions for adult pulmonary and critical care research, the NHLBI assembled a multidisciplinary working group of investigators. This working group identified recommendations for future research, including: (1) focusing on understanding the clinical, physiological, and biological underpinnings of heterogeneity in syndromes, diseases, and treatment-response with the goal of developing targeted, personalized interventions; (2) optimizing pre-clinical models by incorporating comorbidities, co-interventions, and organ support; (3) developing and applying novel clinical trial designs; and (4) advancing mechanistic understanding of injury and recovery in order to develop and test interventions targeted at achieving long-term improvements in the lives of patients and families. Specific areas of research are highlighted as especially promising for making advances in pneumonia, acute hypoxemic respiratory failure, and acute respiratory distress syndrome.

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.

Background The recent pandemic highlights the essential nature of optimizing the use of invasive mechanical ventilation (IMV) in complex critical care settings. This review of reviews maps evidence-based practices (EBPs) that are associated with better outcomes among adult patients with acute respiratory failure or ARDS on the continuum of care, from intubation to liberation. Research Question What EPBs are recommended to reduce the duration of IMV and mortality rate among patients with acute respiratory failure/ARDS? Study Design and Methods We identified an initial set of reports that links EBPs to mortality rates and/or duration of IMV. We conducted a review of reviews, focusing on preappraised guidelines, meta-analyses, and systematic reviews. We searched Scopus, CINAHL, and PubMed from January 2016 to January 2019 for additional evidence that has not yet been incorporated into current guidelines. Results Our initial search produced 61 publications that contained 42 EBPs. We excluded 42 manuscripts during the data extraction process, primarily because they were not associated with improved patient outcomes. The remaining 19 preappraised guidelines, meta-analyses, and systematic reviews met our full inclusion criteria and spanned the continuum of IMV care from intubation to liberation. These contained 20 EBPs, a majority of which were supported with moderate levels of evidence. Of these, six EBPs focused on intubation and escalation of care, such as ventilator management and synchrony; ten EBPs reduced complications associated with IMV, which included spontaneous awakening and breathing trials and early mobility protocols; and four EBPs promoted timely extubation and postextubation recovery. Interpretation This review describes EBPs that are associated with fewer ventilator days and/or lower mortality rates among patients who received IMV for acute respiratory failure/ARDS. Many of these EBPs are connected across the care continuum, which indicates the need to promote and assess effective implementation jointly, rather than individually.

Mortality historically has been the primary outcome of choice for acute and critical care clinical trials. However, undue reliance on mortality can limit the scope of trials that can be performed. Large sample sizes are usually needed for trials powered for a mortality outcome, and focusing solely on mortality fails to recognize the importance that reducing morbidity can have on patients' lives. The COVID-19 pandemic has highlighted the need for rapid, efficient trials to rigorously evaluate new therapies for hospitalized patients with acute lung injury. Oxygen-free days (OFDs) is a novel outcome for clinical trials that is a composite of mortality and duration of new supplemental oxygen use. It is designed to characterize recovery from acute lung injury in populations with a high prevalence of new hypoxemia and supplemental oxygen use. In these populations, OFDs captures two patient-centered consequences of acute lung injury: mortality and hypoxemic lung dysfunction. Power to detect differences in OFDs typically is greater than that for other clinical trial outcomes, such as mortality and ventilator-free days. OFDs is the primary outcome for the Fourth Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4) Host Tissue platform, which evaluates novel therapies targeting the host response to COVID-19 among adults hospitalized with COVID-19 and new hypoxemia. This article outlines the rationale for use of OFDs as an outcome for clinical trials, proposes a standardized method for defining and analyzing OFDs, and provides a framework for sample size calculations using the OFD outcome.

Purpose: We aimed to describe the association between prehospital frailty (PHF), acute organ dysfunction (AOD), and posthospital disability (PHD) outcome in older adults admitted to the intensive care unit (ICU). Methods: In a prospective observational cohort study, we assessed PHF using the Clinical Frailty Scale (CFS) and assessed the level of AOD using Sequential Organ Failure Assessment (SOFA) scores on ICU day 1. We assessed Activities of Daily Living disability levels through to 6 months after discharge and used generalized estimating equations (log link and negative binomial family) to determine the independent association of PHF and AOD with PHD. Results: Of the 302 patients enrolled, 221 (73.1%) survived the hospitalization. Prehospital frailty was associated with PHD (adjusted incident rate ratio [aIRR] 95% confidence interval [95% CI] per unit increase in CFS 1.38 [1.15-1.67], P = .001). Total day 1 SOFA score was weakly associated with PHD, (aIRR [95% CI] 1.05 [1.00-1.10], P = .037) while day 1 SOFA neurologic score was strongly associated with PHD (aIRR [95% CI] 1.42 [1.24-1.62] per unit increase in SOFA neurologic score, P < .001), and these effects were independent of PHF and other premorbid factors. Conclusions: Both PHF and early acute brain dysfunction are important factors associated with increasing PHD in older adults who survive critical illness.

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.

Acute respiratory distress syndrome (ARDS) remains an important clinical entity in the intensive care unit with a significant impact on morbidity and mortality. Effective therapeutic interventions are limited; thus current research focus has shifted from treatment to the prevention of this pulmonary syndrome. In recent decades, a decrease in the incidence of ARDS has been observed and this reduction is largely due to preventive strategies including safe lung ventilation practices, avoidance of iatrogenic exposures, and improvement in care of predisposing conditions such as sepsis and pneumonia. Early identification of at-risk patients, prompt treatment of predisposing conditions, and adoption of evidence-based best practice including restrictive transfusion strategies, conservative fluid management, avoidance of large tidal volume ventilation, and aspiration precaution practices are key preventive strategies with demonstrated benefits. There are currently no effective pharmacological preventive strategies for ARDS.

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

BACKGROUND: The coronavirus disease 2019 pandemic continues to affect millions worldwide. Given the rapidly growing evidence base, we implemented a living guideline model to provide guidance on the management of patients with severe or critical coronavirus disease 2019 in the ICU. METHODS: The Surviving Sepsis Campaign Coronavirus Disease 2019 panel has expanded to include 43 experts from 14 countries; all panel members completed an electronic conflict-of-interest disclosure form. In this update, the panel addressed nine questions relevant to managing severe or critical coronavirus disease 2019 in the ICU. We used the World Health Organization's definition of severe and critical coronavirus disease 2019. The systematic reviews team searched the literature for relevant evidence, aiming to identify systematic reviews and clinical trials. When appropriate, we performed a random-effects meta-analysis to summarize treatment effects. We assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach, then used the evidence-to-decision framework to generate recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. RESULTS: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued nine statements (three new and six updated) related to ICU patients with severe or critical coronavirus disease 2019. For severe or critical coronavirus disease 2019, the panel strongly recommends using systemic corticosteroids and venous thromboprophylaxis but strongly recommends against using hydroxychloroquine. In addition, the panel suggests using dexamethasone (compared with other corticosteroids) and suggests against using convalescent plasma and therapeutic anticoagulation outside clinical trials. The Surviving Sepsis Campaign Coronavirus Diease 2019 panel suggests using remdesivir in nonventilated patients with severe coronavirus disease 2019 and suggests against starting remdesivir in patients with critical coronavirus disease 2019 outside clinical trials. Because of insufficient evidence, the panel did not issue a recommendation on the use of awake prone positioning. CONCLUSION: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued several recommendations to guide healthcare professionals caring for adults with critical or severe coronavirus disease 2019 in the ICU. Based on a living guideline model the recommendations will be updated as new evidence becomes available.

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.

Background Conducting research in critically-ill patient populations is challenging, and most randomized trials of critically-ill patients have not achieved pre-specified statistical thresholds to conclude that the intervention being investigated was beneficial. Methods In 2019, a diverse group of patient representatives, regulators from the USA and European Union, federal grant managers, industry representatives, clinical trialists, epidemiologists, and clinicians convened the First Critical Care Clinical Trialists (3CT) Workshop to discuss challenges and opportunities in conducting and assessing critical care trials. Herein, we present the advantages and disadvantages of available methodologies for clinical trial design, conduct, and analysis, and a series of recommendations to potentially improve future trials in critical care. Conclusion The 3CT Workshop participants identified opportunities to improve critical care trials using strategies to optimize sample size calculations, account for patient and disease heterogeneity, increase the efficiency of trial conduct, maximize the use of trial data, and to refine and standardize the collection of patient-centered and patient-informed outcome measures beyond mortality. Electronic supplementary material The online version of this article (10.1007/s00134-020-05934-6) contains supplementary material, which is available to authorized users.

Background Early clinical data showed that some patients with vasodilatory shock are responsive to low doses of angiotensin II. The objective of this analysis was to compare clinical outcomes in patients requiring ≤ 5 ng kg−1 min−1 angiotensin II at 30 min (≤ 5 ng kg−1 min−1 subgroup) to maintain mean arterial pressure (MAP) ≥ 75 mmHg versus patients receiving > 5 ng kg−1 min−1 angiotensin II at 30 min (> 5 ng kg−1 min−1 subgroup). Data from angiotensin II-treated patients enrolled in the ATHOS-3 trial were used. Results The subgroup of patients whose angiotensin II dose was down-titrated from 20 ng kg−1 min−1 at treatment initiation to ≤ 5 ng kg−1 min−1 at 30 min (79/163) had significantly lower endogenous serum angiotensin II levels and norepinephrine-equivalent doses and significantly higher MAP versus the > 5 ng kg−1 min−1 subgroup (84/163). Patients in the ≤ 5 ng kg−1 min−1 subgroup were more likely to have a MAP response at 3 h versus those in the > 5 ng kg−1 min−1 subgroup (90% vs. 51%, respectively; odds ratio, 8.46 [95% CI 3.63–19.7], P 5 ng kg−1 min−1 subgroup (59% vs. 33%, respectively; hazard ratio, 0.48 [95% CI 0.28–0.72], P = 0.0007); multivariate analyses supported the survival benefit in patients with lower angiotensin II levels. The ≤ 5 ng kg−1 min−1 subgroup had a more favorable safety profile and lower treatment discontinuation rate than the > 5 ng kg−1 min−1 subgroup. Conclusions This prespecified analysis showed that down-titration to ≤ 5 ng kg−1 min−1 angiotensin II at 30 min is an early predictor of favorable clinical outcomes which may be related to relative angiotensin II insufficiency. Electronic supplementary material The online version of this article (10.1186/s13613-019-0536-5) contains supplementary material, which is available to authorized users.

Supplemental Digital Content is available in the text., Objectives: To determine the association between prone positioning in nonintubated patients with coronavirus disease 2019 and frequency of invasive mechanical ventilation or inhospital mortality. Design: A nested case-matched control analysis. Setting: Three hospital sites in Bronx, NY. Patients: Adult coronavirus disease 2019 patients admitted between March 1, 2020, and April 1, 2020. We excluded patients with do-not-intubate orders. Cases were defined by invasive mechanical ventilation or inhospital mortality. Each case was matched with two controls based on age, gender, admission date, and hospital length of stay greater than index time of matched case via risk-set sampling. The presence of nonintubated proning was identified from provider documentation. Intervention: Nonintubated proning documented prior to invasive mechanical ventilation or inhospital mortality for cases or prior to corresponding index time for matched controls. Measurements and Main Results: We included 600 patients, 41 (6.8%) underwent nonintubated proning. Cases had lower Spo2/Fio2 ratios prior to invasive mechanical ventilation or inhospital mortality compared with controls (case median, 97 [interquartile range, 90–290] vs control median, 404 [interquartile range, 296–452]). Although most providers (58.5%) documented immediate improvement in oxygenation status after initiating nonintubated proning, there was no difference in worst Spo2/Fio2 ratios before and after nonintubated proning in both case and control (case median Spo2/Fio2 ratio difference, 3 [interquartile range, –3 to 8] vs control median Spo2/Fio2 ratio difference, 0 [interquartile range, –3 to 50]). In the univariate analysis, patients who underwent nonintubated proning were 2.57 times more likely to require invasive mechanical ventilation or experience inhospital mortality (hazard ratio, 2.57; 95% CI, 1.17–5.64; p = 0.02). Following adjustment for patient level differences, we found no association between nonintubated proning and invasive mechanical ventilation or inhospital mortality (adjusted hazard ratio, 0.92; 95% CI, 0.34–2.45; p = 0.86). Conclusions: There was no significant association with reduced risk of invasive mechanical ventilation or inhospital mortality after adjusting for baseline severity of illness and oxygenation status.

Background An update of evidence-based guidelines concerning liberation from mechanical ventilation is needed as new evidence has become available. The American College of Chest Physicians (CHEST) and the American Thoracic Society (ATS) have collaborated to provide recommendations to clinicians concerning liberation from the ventilator. Methods Comprehensive evidence syntheses, including meta-analyses, were performed to summarize all available evidence relevant to the guideline panel's questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, and the results were summarized in evidence profiles. The evidence syntheses were discussed and recommendations developed and approved by a multidisciplinary committee of experts in mechanical ventilation. Results Recommendations for three population, intervention, comparator, outcome (PICO) questions concerning ventilator liberation are presented in this document. The guideline panel considered the balance of desirable (benefits) and undesirable (burdens, adverse effects, costs) consequences, quality of evidence, feasibility, and acceptability of various interventions with respect to the selected questions. Conditional (weak) recommendations were made to use inspiratory pressure augmentation in the initial spontaneous breathing trial (SBT) and to use protocols to minimize sedation for patients ventilated for more than 24 h. A strong recommendation was made to use preventive noninvasive ventilation (NIV) for high-risk patients ventilated for more than 24 h immediately after extubation to improve selected outcomes. The recommendations were limited by the quality of the available evidence. Conclusions The guideline panel provided recommendations for inspiratory pressure augmentation during an initial SBT, protocols minimizing sedation, and preventative NIV, in relation to ventilator liberation.

Background This clinical practice guideline addresses six questions related to liberation from mechanical ventilation in critically ill adults. It is the result of a collaborative effort between the American Thoracic Society (ATS) and the American College of Chest Physicians (CHEST). Methods A multidisciplinary panel posed six clinical questions in a population, intervention, comparator, outcomes (PICO) format. A comprehensive literature search and evidence synthesis was performed for each question, which included appraising the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The Evidence-to-Decision framework was applied to each question, requiring the panel to evaluate and weigh the importance of the problem, confidence in the evidence, certainty about how much the public values the main outcomes, magnitude and balance of desirable and undesirable outcomes, resources and costs associated with the intervention, impact on health disparities, and acceptability and feasibility of the intervention. Results Evidence-based recommendations were formulated and graded initially by subcommittees and then modified following full panel discussions. The recommendations were confirmed by confidential electronic voting; approval required that at least 80% of the panel members agree with the recommendation. Conclusions The panel provides recommendations regarding liberation from mechanical ventilation. The details regarding the evidence and rationale for each recommendation are presented in the American Journal of Respiratory and Critical Care Medicine and CHEST.

Objective:The Lung Injury Prediction Score identifies patients at risk for acute respiratory distress syndrome in the emergency department, but it has not been validated in non-emergency department hospitalized patients. We aimed to evaluate whether Lung Injury Prediction Score identifies non-emerge

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.

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.

Patient handoffs are highly variable and error prone. They have been recognized as a major health care challenge. Patients in the intensive care unit are particularly vulnerable due to their complex clinical history and the critical nature of their condition. Given a general movement from traditional long call to shift schedules, the number of patient handoffs will likely continue to increase. Optimization of the handoff process has become even more critical to ensure patient safety. In this review, we reflect on the importance of the handoff process, review common errors, identify barriers and challenges, and propose different methods to improving the handoff process. The purpose of this article is to examine the overall scope of the problem; provide the most up-to-date evidence on the handoff process; and identify ways to perform handoffs in an accurate, safe, and efficient manner to provide high-quality patient care. The direction of future research is also proposed.

Rationale: Both acute respiratory distress syndrome (ARDS) and intensive care unit (ICU) delirium are associated with significant morbidity and mortality. However, the risk of delirium and its impact on mortality in ARDS patients is unknown.Objectives: To determine if ARDS is associated with a higher risk for delirium compared with respiratory failure without ARDS, and to determine the association between ARDS and in-hospital mortality after adjusting for delirium.Methods: Prospective observational cohort study of adult ICU patients admitted to two urban academic hospitals.Measurements and Main Results: Delirium was assessed daily using the Confusion Assessment Method for the ICU and Richmond Agitation and Sedation Scale. Of the 564 patients in our cohort, 48 had ARDS (9%). Intubated patients with ARDS had the highest prevalence of delirium compared with intubated patients without ARDS and nonintubated patients (73% vs. 52% vs. 21%, respectively; P

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

To summarize the current literature on racial and gender disparities in critical care and the mechanisms underlying these disparities in the course of acute critical illness.MEDLINE search on the published literature addressing racial, ethnic, or gender disparities in acute critical illness, such as sepsis, acute lung injury, pneumonia, venous thromboembolism, and cardiac arrest.Clinical studies that evaluated general critically ill patient populations in the United States as well as specific critical care conditions were reviewed with a focus on studies evaluating factors and contributors to health disparities.Study findings are presented according to their association with the prevalence, clinical presentation, management, and outcomes in acute critical illness.This review presents potential contributors for racial and gender disparities related to genetic susceptibility, comorbidities, preventive health services, socioeconomic factors, cultural differences, and access to care. The data are organized along the course of acute critical illness.The literature to date shows that disparities in critical care are most likely multifactorial involving individual, community, and hospital-level factors at several points in the continuum of acute critical illness. The data presented identify potential targets as interventions to reduce disparities in critical care and future avenues for research.

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

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.

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.

Acute lung injury affects a subset of hospitalized patients but is not universal. This syndrome can substantially delay ventilator liberation, prolong intensive care unit (ICU) stay, and increase mortality. As with many critical illness syndromes, the available treatment options are limited in number and impact. Once a patient develops lung injury, the best known strategy is supportive care. Observational studies have identified potential risk factors and have suggested that the use and timing of certain critical care interventions may influence the likelihood of developing lung injury. These findings suggest that a well designed screening tool and the systematic application of best practices in critical care may limit the risk of lung injury. An effective prediction score may also facilitate enrollment in pharmacopreventive trials. Development of such tools is accelerated by multicenter collaboration.

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)