An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline.

Background: This document updates previously published Clinical Practice Guidelines for the management of patients with acute respiratory distress syndrome (ARDS), incorporating new evidence addressing the use of corticosteroids, venovenous extracorporeal membrane oxygenation, neuromuscular blocking agents, and positive end-expiratory pressure (PEEP). Methods: We summarized evidence addressing four "PICO questions" (patient, intervention, comparison, and outcome). A multidisciplinary panel with expertise in ARDS used the Grading of Recommendations, Assessment, Development, and Evaluation framework to develop clinical recommendations. Results: We suggest the use of: 1) corticosteroids for patients with ARDS (conditional recommendation, moderate certainty of evidence), 2) venovenous extracorporeal membrane oxygenation in selected patients with severe ARDS (conditional recommendation, low certainty of evidence), 3) neuromuscular blockers in patients with early severe ARDS (conditional recommendation, low certainty of evidence), and 4) higher PEEP without lung recruitment maneuvers as opposed to lower PEEP in patients with moderate to severe ARDS (conditional recommendation, low to moderate certainty), and 5) we recommend against using prolonged lung recruitment maneuvers in patients with moderate to severe ARDS (strong recommendation, moderate certainty). Conclusions: We provide updated evidence-based recommendations for the management of ARDS. Individual patient and illness characteristics should be factored into clinical decision making and implementation of these recommendations while additional evidence is generated from much-needed clinical trials.

Outcomes Among Mechanically Ventilated Patients With Severe Pneumonia and Acute Hypoxemic Respiratory Failure From SARS-CoV-2 and Other Etiologies.

Importance: Early observations suggested that COVID-19 pneumonia had a higher mortality rate than other causes of pneumonia. Objective: To compare outcomes between mechanically ventilated patients with pneumonia due to COVID-19 (March 2020 to June 2021) and other etiologies (July 2016 to December 2019). Design, Setting, and Participants: This retrospective cohort study was conducted at the Johns Hopkins Healthcare System among adult patients (aged ≥18 years) with pneumonia who required mechanical ventilation in the first 2 weeks of hospitalization. Clinical, laboratory, and mechanical ventilation data were extracted from admission to hospital discharge or death. Exposures: Pneumonia due to COVID-19. Main Outcomes and Measures: The primary outcome was 90-day in-hospital mortality. Secondary outcomes were time to liberation from mechanical ventilation, hospital length of stay, static respiratory system compliance, and ventilatory ratio. Unadjusted and multivariable-adjusted logistic regression, proportional hazards regression, and doubly robust regression were used in propensity score-matched sets to compare clinical outcomes. Results: Overall, 719 patients (mean [SD] age, 61.8 [15.3] years; 442 [61.5%] were male; 460 [64.0%] belonged to a minoritized racial group and 253 [35.2%] were White) with severe COVID-19 pneumonia and 1127 patients (mean [SD] age, 60.9 [15.8] years; 586 [52.0%] were male; 459 [40.7%] belonged to a minoritized racial group and 655 [58.1%] were White) with severe non-COVID-19 pneumonia. In unadjusted analyses, patients with COVID-19 pneumonia had higher 90-day mortality (odds ratio, 1.21, 95% CI 1.04-1.41), longer time on mechanical ventilation (subdistribution hazard ratio 0.72, 95% CI 0.63-0.81), and lower compliance (32.0 vs 28.4 mL/kg PBW/cm H2O; P < .001) when compared with those with non-COVID-19 pneumonia. In propensity score-matched analyses, patients with COVID-19 pneumonia were equally likely to die within 90 days as those with non-COVID-19 pneumonia (odds ratio, 1.04; 95% CI, 0.81 to 1.35; P = .85), had similar respiratory system compliance (mean difference, 1.82 mL/cm H2O; 95% CI, -1.53 to 5.17 mL/cm H2O; P = .28) and ventilatory ratio (mean difference, -0.05; 95% CI, -0.22 to 0.11; P = .52), but had lower rates of liberation from mechanical ventilation (subdistribution hazard ratio, 0.81; 95% CI, 0.65 to 1.00) when compared with those with non-COVID-19 pneumonia. Patients with COVID-19 pneumonia had somewhat lower rates of being discharged from the hospital alive at 90 days (subdistribution hazard ratio, 0.83; 95% CI, 0.68 to 1.01) than those with non-COVID-19 pneumonia; however, this was not statistically significant. Conclusions and Relevance: In this study, mechanically ventilated patients with severe COVID-19 pneumonia had similar mortality rates as patients with other causes of severe pneumonia but longer times to liberation from mechanical ventilation. Mechanical ventilation use in COVID-19 pneumonia should follow the same evidence-based guidelines as for any pneumonia.

Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension.

BACKGROUND: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited. METHODS: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed. RESULTS: A total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups. CONCLUSIONS: Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028.).

Oxygen Toxicity in Critically Ill Adults.

Oxygen supplementation is one of the most common interventions in critically ill patients. Despite over a century of data suggesting both beneficial and detrimental effects of supplemental oxygen, optimal arterial oxygenation targets in adult patients remain unclear. Laboratory animal studies have consistently showed that exposure to a high FiO2 causes respiratory failure and early death. Human autopsy studies from the 1960s purported to provide histologic evidence of pulmonary oxygen toxicity in the form of diffuse alveolar damage. However, concomitant ventilator-induced lung injury and/or other causes of acute lung injury may explain these findings. Although some observational studies in general populations of critically adults showed higher mortality in association with higher oxygen exposures, this finding has not been consistent. For some specific populations, such as those with cardiac arrest, studies have suggested harm from targeting supraphysiologic PaO2 levels. More recently, randomized clinical trials of arterial oxygenation targets in narrower physiologic ranges were conducted in critically ill adult patients. Although two smaller trials came to opposite conclusions, the two largest of these trials showed no differences in clinical outcomes in study groups that received conservative versus liberal oxygen targets, suggesting that either strategy is reasonable. It is possible that some strategies are of benefit in some subpopulations, and this remains an important ongoing area of research. Because of the ubiquity of oxygen supplementation in critically ill adults, even small treatment effects could have a large impact on a global scale.

Effect of Lowering Vt on Mortality in Acute Respiratory Distress Syndrome Varies with Respiratory System Elastance.

Rationale: If the risk of ventilator-induced lung injury in acute respiratory distress syndrome (ARDS) is causally determined by driving pressure rather than by Vt, then the effect of ventilation with lower Vt on mortality would be predicted to vary according to respiratory system elastance (Ers). Objectives: To determine whether the mortality benefit of ventilation with lower Vt varies according to Ers. Methods: In a secondary analysis of patients from five randomized trials of lower- versus higher-Vt ventilation strategies in ARDS and acute hypoxemic respiratory failure, the posterior probability of an interaction between the randomized Vt strategy and Ers on 60-day mortality was computed using Bayesian multivariable logistic regression. Measurements and Main Results: Of 1,096 patients available for analysis, 416 (38%) died by Day 60. The posterior probability that the mortality benefit from lower-Vt ventilation strategies varied with Ers was 93% (posterior median interaction odds ratio, 0.80 per cm H2O/[ml/kg]; 90% credible interval, 0.63-1.02). Ers was classified as low (<2 cm H2O/[ml/kg], n = 321, 32%), intermediate (2-3 cm H2O/[ml/kg], n = 475, 46%), and high (>3 cm H2O/[ml/kg], n = 224, 22%). In these groups, the posterior probabilities of an absolute risk reduction in mortality ≥ 1% were 55%, 82%, and 92%, respectively. The posterior probabilities of an absolute risk reduction ≥ 5% were 29%, 58%, and 82%, respectively. Conclusions: The mortality benefit of ventilation with lower Vt in ARDS varies according to elastance, suggesting that lung-protective ventilation strategies should primarily target driving pressure rather than Vt.

Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial.

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.

Rationale and Design of ORCHID: A Randomized Placebo-controlled Clinical Trial of Hydroxychloroquine for Adults Hospitalized with COVID-19.

The ORCHID (Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease) trial is a multicenter, blinded, randomized trial of hydroxychloroquine versus placebo for the treatment of adults hospitalized with coronavirus disease (COVID-19). This document provides the rationale and background for the trial and highlights key design features. We discuss five novel challenges to the design and conduct of a large, multicenter, randomized trial during a pandemic, including 1) widespread, off-label use of the study drug before the availability of safety and efficacy data; 2) the need to adapt traditional procedures for documentation of informed consent during an infectious pandemic; 3) developing a flexible and robust Bayesian analysis incorporating significant uncertainty about the disease, outcomes, and treatment; 4) obtaining indistinguishable drug and placebo without delaying enrollment; and 5) rapidly obtaining administrative and regulatory approvals. Our goals in describing how the ORCHID trial progressed from study conception to enrollment of the first patient in 15 days are to inform the development of other high-quality, multicenter trials targeting COVID-19. We describe lessons learned to improve the efficiency of future clinical trials, particularly in the setting of pandemics. The ORCHID trial will provide high-quality, clinically relevant data on the safety and efficacy of hydroxychloroquine for the treatment of COVID-19 among hospitalized adults.Clinical trial registered with www.clinicaltrials.gov (NCT04332991).

Identifying Clinical Research Priorities in Adult Pulmonary and Critical Care. NHLBI Working Group Report.

Preventing, treating, and promoting recovery from critical illness due to pulmonary disease are foundational goals of the critical care community and the NHLBI. 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 preclinical 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, preclinical disease modeling, and understanding of recovery from acute illness promise to transform the methods of pulmonary and critical care clinical research. To assess the current state of, research priorities for, and future directions in 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 preclinical models by incorporating comorbidities, cointerventions, and organ support; 3) developing and applying novel clinical trial designs; and 4) advancing mechanistic understanding of injury and recovery 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.

Mean Airway Pressure As a Predictor of 90-Day Mortality in Mechanically Ventilated Patients.

OBJECTIVES: To determine the association between mean airway pressure and 90-day mortality in patients with acute respiratory failure requiring mechanical ventilation and to compare the predictive ability of mean airway pressure compared with inspiratory plateau pressure and driving pressure. DESIGN: Prospective observational cohort. SETTING: Five ICUs in Lima, Peru. SUBJECTS: Adults requiring invasive mechanical ventilation via endotracheal tube for acute respiratory failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of potentially eligible participants (n = 1,500), 65 (4%) were missing baseline mean airway pressure, while 352 (23.5%) were missing baseline plateau pressure and driving pressure. Ultimately, 1,429 participants were included in the analysis with an average age of 59 ± 19 years, 45% female, and a mean PaO2/FIO2 ratio of 248 ± 147 mm Hg at baseline. Overall, 90-day mortality was 50.4%. Median baseline mean airway pressure was 13 cm H2O (interquartile range, 10-16 cm H2O) in participants who died compared to a median mean airway pressure of 12 cm H2O (interquartile range, 10-14 cm H2O) in participants who survived greater than 90 days (p < 0.001). Mean airway pressure was independently associated with 90-day mortality (odds ratio, 1.38 for difference comparing the 75th to the 25th percentile for mean airway pressure; 95% CI, 1.10-1.74) after adjusting for age, sex, baseline Acute Physiology and Chronic Health Evaluation III, baseline PaO2/FIO2 (modeled with restricted cubic spline), baseline positive end-expiratory pressure, baseline tidal volume, and hospital site. In predicting 90-day mortality, baseline mean airway pressure demonstrated similar discriminative ability (adjusted area under the curve = 0.69) and calibration characteristics as baseline plateau pressure and driving pressure. CONCLUSIONS: In a multicenter prospective cohort, baseline mean airway pressure was independently associated with 90-day mortality in mechanically ventilated participants and predicts mortality similarly to plateau pressure and driving pressure. Because mean airway pressure is readily available on all mechanically ventilated patients and all ventilator modes, it is a potentially more useful predictor of mortality in acute respiratory failure.

Premature, Opportune, and Delayed Weaning in Mechanically Ventilated Patients: A Call for Implementation of Weaning Protocols in Low- and Middle-Income Countries.

OBJECTIVES: Weaning protocols establish readiness-to-wean criteria to determine the opportune moment to conduct a spontaneous breathing trial. Weaning protocols have not been widely adopted or evaluated in ICUs in low- and middle-income countries. We sought to compare clinical outcomes between participants whose weaning trials were retrospectively determined to have been premature, opportune, or delayed based on when they met readiness-to-wean criteria. DESIGN: Prospective, multicenter observational study. SETTING: Five medical ICUs in four public hospitals in Lima, Perú. SUBJECTS: Adults with acute respiratory failure and at least 24 hours of invasive mechanical ventilation (n = 1,657). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We established six readiness-to-wean criteria and retrospectively categorized our sample into three weaning groups: 1) premature: if the weaning trial took place before fulfilling all criteria, 2) opportune: if the weaning trial took place within 24 hours after fulfilling the criteria, and 3) delayed: if the weaning trial took place over 24 hours after fulfilling criteria. We compared 90-day mortality, ventilator-free days, ICU-free days, and hospital-free days between premature, opportune, and delayed weaning groups. In our sample, 761 participants (60.8%) were classified as having a premature weaning trial, 196 underwent opportune weaning (15.7%), and 295 experienced delayed weaning (23.6%). There was no significant difference in 90-day mortality between the groups. Both the premature and delayed weaning groups had poorer clinical outcomes with fewer ventilator-free days (-2.18, p = 0.008) and (-3.49, p < 0.001), ICU-free days (-2.25, p = 0.001) and (-3.72, p < 0.001), and hospital-free days (-2.76, p = 0.044) and (-4.53, p = 0.004), respectively, compared with the opportune weaning group. CONCLUSIONS: Better clinical outcomes occur with opportune weaning compared with premature and delayed weaning. If readiness-to-wean criteria can be applied in resource-limited settings, it may improve ICU outcomes associated with opportune weaning.

PEEP Titration to Minimize Driving Pressure in Subjects With ARDS: A Prospective Physiological Study.

BACKGROUND: Observational studies report that lower driving pressure (ie, the difference between plateau pressure and PEEP) is associated with improved survival in patients with ARDS and may be a key mediator of lung-protective ventilation strategies. The primary objective of this study was to characterize reductions in driving pressure that could be achieved through changes in PEEP. METHODS: In this prospective physiological pilot study, 10 subjects with ARDS were placed on PEEP according to the ARDS Network Lower PEEP/FIO2 Table. PEEP was adjusted in small increments and decrements above and below this initial PEEP, and driving pressure was measured at each PEEP level. Subsequently, PEEP was set at the level resulting in the lowest driving pressure, and driving pressure was measured after 1, 5, 15, and 30 min to assess stability over time at constant PEEP. RESULTS: All subjects had ARDS with a median (interquartile range [IQR]) PaO2 /FIO2 of 116 (98-132) at enrollment. Median (IQR) driving pressure at baseline was 14 (13-17) cm H2O. After PEEP titration, median driving pressure decreased to 13 (12-14) cm H2O. The largest reduction in driving pressure was 4 cm H2O. Two subjects had no change in driving pressure at multiple PEEP levels. To achieve the lowest driving pressure, final PEEP was increased in 6 subjects and decreased in 4 subjects from the baseline PEEP prescribed by the ARDS Network Lower PEEP/FIO2 Table. Driving pressure reached equilibrium within 1-5 min and remained stable for 30 min following PEEP titration. CONCLUSIONS: PEEP titration had a variable effect in changing driving pressure across this small sample of ARDS subjects. In some subjects, PEEP was decreased from values given in the ARDS Network Lower PEEP/FIO2 Table to minimize driving pressure. Changes in driving pressure stabilized within a few minutes of PEEP titration.

Risk factors for the development of acute respiratory distress syndrome in mechanically ventilated adults in Peru: a multicenter observational study.

BACKGROUND: Clinical and epidemiological differences between acute respiratory distress syndrome (ARDS) that presents at the initiation of mechanical ventilation [MV] (ARDS at MV onset) and that which develops during the course of MV (ARDS after MV onset) are not well understood. We conducted an observational study in five Peruvian ICUs to characterize differences between ARDS at MV onset and after MV onset and identify risk factors for the development of ARDS after MV onset. METHODS: We consecutively enrolled critically ill patients with acute respiratory failure requiring at least 24 h of mechanical ventilation and followed them prospectively during the first 28 days and compared baseline characteristics and clinical outcomes by ARDS status. RESULTS: We enrolled 1657 participants on MV (mean age 60.0 years, 55% males) of whom 334 (20.2%) had ARDS at MV onset and 180 (10.9%) developed ARDS after MV onset. Average tidal volume at the initiation of MV was 8.7 mL/kg of predicted body weight (PBW) for participants with ARDS at MV onset, 8.6 mL/kg PBW for those who developed ARDS after MV onset, and 8.5 mL/kg PBW for those who never developed ARDS (p = 0.23). Overall, 90-day mortality was 56% and 55% for ARDS after MV onset and ARDS at MV onset, respectively, as compared to 46% among those who never developed ARDS (p < 0.01). Adults with ARDS had a higher body mass index (BMI) than those without ARDS (27.3 vs 26.5 kg/m2, p < 0.01). Higher peak pressure (adjusted interquartile OR = 1.51, 95% CI 1.21-1.88), higher mean airway pressure (adjusted interquartile OR = 1.41, 95% CI 1.13-1.76), and higher positive end-expiratory pressure (adjusted interquartile OR = 1.29, 95% CI 1.10-1.50) at MV onset were associated with a higher odds of developing ARDS after MV onset. CONCLUSIONS: In this study of mechanically ventilated patients, 31% of study participants had ARDS at some point during their ICU stay. Optimal lung-protective ventilation was not used in a majority of patients. Patients with ARDS after MV onset had a similar 90-day mortality as those with ARDS at MV onset. Higher airway pressures at MV onset, higher PEEP, and higher BMI were associated with the development of ARDS after MV onset.

Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients.

BACKGROUND: Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality. RESULTS: A total of 1360 patients were found to be vitamin D-deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population. The mean day 3 level of 25-hydroxyvitamin D was 46.9±23.2 ng per milliliter (117±58 nmol per liter) in the vitamin D group and 11.4±5.6 ng per milliliter (28±14 nmol per liter) in the placebo group (difference, 35.5 ng per milliliter; 95% confidence interval [CI], 31.5 to 39.6). The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, -2.1 to 7.9; P = 0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality. CONCLUSIONS: Early administration of high-dose enteral vitamin D3 did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D-deficient patients. (Funded by the National Heart, Lung, and Blood Institute; VIOLET ClinicalTrials.gov number, NCT03096314.).

Association between hospital mortality and inspiratory airway pressures in mechanically ventilated patients without acute respiratory distress syndrome: a prospective cohort study.

BACKGROUND: Higher inspiratory airway pressures are associated with worse outcomes in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS). This relationship, however, has not been well investigated in patients without ARDS. We hypothesized that higher driving pressures (ΔP) and plateau pressures (Pplat) are associated with worse patient-centered outcomes in mechanically ventilated patients without ARDS as well as those with ARDS. METHODS: Using data collected during a prospective, observational cohort study of 6179 critically ill participants enrolled in 59 ICUs across the USA, we used multivariable logistic regression to determine whether ΔP and Pplat at enrollment were associated with hospital mortality among 1132 mechanically ventilated participants. We stratified analyses by ARDS status. RESULTS: Participants without ARDS (n = 822) had lower average severity of illness scores and lower hospital mortality (27.3% vs. 38.7%; p <  0.001) than those with ARDS (n = 310). Average Pplat (20.6 vs. 23.9 cm H2O; p <  0.001), ΔP (14.3 vs. 16.0 cm H2O; p <  0.001), and positive end-expiratory pressure (6.3 vs. 7.9 cm H2O; p <  0.001) were lower in participants without ARDS, whereas average tidal volumes (7.2 vs. 6.8 mL/kg PBW; p <  0.001) were higher. Among those without ARDS, higher ΔP (adjusted OR = 1.36 per 7 cm H2O, 95% CI 1.14-1.62) and Pplat (adjusted OR = 1.42 per 8 cm H2O, 95% CI 1.17-1.73) were associated with higher mortality. We found similar relationships with mortality among those participants with ARDS. CONCLUSIONS: Higher ΔP and Pplat are associated with increased mortality for participants without ARDS. ΔP may be a viable target for lung-protective ventilation in all mechanically ventilated patients.

Use and costs of inhaled nitric oxide and inhaled epoprostenol in adult critically ill patients: A quality improvement project.

PURPOSE: Inhaled epoprostenol and inhaled nitric oxide are pulmonary vasodilators commonly used in the management of acute respiratory distress syndrome and right ventricular failure; however, they have vastly different cost profiles. The purpose of the project was to transition from nitric oxide to epoprostenol as the inhaled pulmonary vasodilator (IPV) of choice in adult critically ill patients and evaluate the effect of the transition on associated usage and costs. METHODS: A single-center, prospective, before and after quality improvement project including adult patients receiving inhaled nitric oxide, inhaled epoprostenol, or both was conducted in 7 adult intensive care units, operating rooms, and postanesthesia care units of a tertiary care academic medical center. The total number of patients, hours of therapy, and costs for each agent were compared between stages of protocol implementation and annually. RESULTS: Seven hundred twenty-nine patients received inhaled nitric oxide, inhaled epoprostenol, or both during the study period. The monthly inhaled nitric oxide use in number of patients, hours, and cost decreased during all stages of the project (p < 0.01). The monthly inhaled epoprostenol use in number of patients, hours, and cost increased during all stages (p < 0.01). Overall, total IPV use increased during the study. However, despite this increase in usage, there was a 47% reduction in total IPV cost. CONCLUSION: Implementation of a staged protocol to introduce and expand inhaled epoprostenol use in adult critically ill patients resulted in decreased use and cost of inhaled nitric oxide. The total cost of all IPV was decreased by 47% despite increased IPV use.

Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome.

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

Sedation practices and clinical outcomes in mechanically ventilated patients in a prospective multicenter cohort.

OBJECTIVES: We sought to study the association between sedation status, medications (benzodiazepines, opioids, and antipsychotics), and clinical outcomes in a resource-limited setting. DESIGN: A longitudinal study of critically ill participants on mechanical ventilation. SETTING: Five intensive care units (ICUs) in four public hospitals in Lima, Peru. PATIENTS: One thousand six hundred fifty-seven critically ill participants were assessed daily for sedation status during 28 days and vital status by day 90. RESULTS: After excluding data of participants without a Richmond Agitation Sedation Scale score and without sedation, we followed 1338 (81%) participants longitudinally for 18,645 ICU days. Deep sedation was present in 98% of participants at some point of the study and in 12,942 ICU days. Deep sedation was associated with higher mortality (interquartile odds ratio (OR) = 5.42, 4.23-6.95; p < 0.001) and a significant decrease in ventilator (- 7.27; p < 0.001), ICU (- 4.38; p < 0.001), and hospital (- 7.00; p < 0.001) free days. Agitation was also associated with higher mortality (OR = 39.9, 6.53-243, p < 0.001). The most commonly used sedatives were opioids and benzodiazepines (9259 and 8453 patient days respectively), and the latter were associated with a 41% higher mortality in participants with a higher cumulative dose (75th vs 25th percentile, interquartile OR = 1.41, 1.12-1.77; p < 0.01). The overall cumulative dose of benzodiazepines and opioids was high, 774.5 mg and 16.8 g, respectively, by day 7 and by day 28; these doses approximately doubled. Haloperidol was only used in 3% of ICU days; however, the use of it was associated with a 70% lower mortality (interquartile OR = 0.3, 0.22-0.44, p < 0.001). CONCLUSIONS: Deep sedation, agitation, and cumulative dose of benzodiazepines were all independently associated with higher 90-day mortality. Additionally, deep sedation was associated with less ventilator-, ICU-, and hospital-free days. In contrast, haloperidol was associated with lower mortality in our study.