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Figure 1.
Flow of Patients in the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial
Flow of Patients in the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial

ARDS indicates acute respiratory distress syndrome; Fio2, fraction of inspired oxygen; MAP, mean arterial pressure; Pao2, partial pressure of arterial oxygen; PEEP, positive end-expiratory pressure.

aPatients could have more than 1 reason for exclusion.

Figure 2.
28-Day Mortality in the Lung Recruitment Maneuver With Titrated PEEP Group vs the Low-PEEP Group
28-Day Mortality in the Lung Recruitment Maneuver With Titrated PEEP Group vs the Low-PEEP Group

PEEP indicates positive end-expiratory pressure.

Figure 3.
Effects of the Lung Recruitment Maneuver With Titrated PEEP vs the Low-PEEP Group on Mortality According to Subgroups
Effects of the Lung Recruitment Maneuver With Titrated PEEP vs the Low-PEEP Group on Mortality According to Subgroups

The size of data markers is proportional to the inverse of variance. Protocol modification indicates the modification in the experimental group strategy after the 556th patient, with decreases in the pressures and duration of the recruitment maneuver.

ARDS indicates acute respiratory distress syndrome; Fio2,fraction of inspired oxygen; Pao2, partial pressure of arterial oxygen; PEEP, positive end-expiratory pressure.

Table 1.  
Baseline Characteristics of the Patients
Baseline Characteristics of the Patients
Table 2.  
Outcomes Among Patients Treated With Lung Recruitment Maneuver With Positive End-Expiratory Pressure (PEEP) vs Low-PEEP Strategy
Outcomes Among Patients Treated With Lung Recruitment Maneuver With Positive End-Expiratory Pressure (PEEP) vs Low-PEEP Strategy
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Original Investigation
Caring for the Critically Ill Patient
October 10, 2017

Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial

Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators
JAMA. 2017;318(14):1335-1345. doi:10.1001/jama.2017.14171
Key Points

Question  Does use of a lung recruitment maneuver associated with positive end-expiratory pressure (PEEP) titration according to the best respiratory-system compliance reduce 28-day mortality of patients with moderate to severe acute respiratory distress syndrome (ARDS) compared with a conventional low-PEEP strategy?

Findings  In this randomized trial of 1010 patients, 28-day mortality was significantly higher among patients treated with a strategy of lung recruitment and PEEP titration (55.3%) than those treated with a conventional low-PEEP strategy (49.3%).

Meaning  A strategy using a lung recruitment maneuver and titrated PEEP, in association with volume-assist control ventilation, increased mortality of patients with moderate to severe ARDS.

Abstract

Importance  The effects of recruitment maneuvers and positive end-expiratory pressure (PEEP) titration on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remain uncertain.

Objective  To determine if lung recruitment associated with PEEP titration according to the best respiratory-system compliance decreases 28-day mortality of patients with moderate to severe ARDS compared with a conventional low-PEEP strategy.

Design, Setting, and Participants  Multicenter, randomized trial conducted at 120 intensive care units (ICUs) from 9 countries from November 17, 2011, through April 25, 2017, enrolling adults with moderate to severe ARDS.

Interventions  An experimental strategy with a lung recruitment maneuver and PEEP titration according to the best respiratory–system compliance (n = 501; experimental group) or a control strategy of low PEEP (n = 509). All patients received volume-assist control mode until weaning.

Main Outcomes and Measures  The primary outcome was all-cause mortality until 28 days. Secondary outcomes were length of ICU and hospital stay; ventilator-free days through day 28; pneumothorax requiring drainage within 7 days; barotrauma within 7 days; and ICU, in-hospital, and 6-month mortality.

Results  A total of 1010 patients (37.5% female; mean [SD] age, 50.9 [17.4] years) were enrolled and followed up. At 28 days, 277 of 501 patients (55.3%) in the experimental group and 251 of 509 patients (49.3%) in the control group had died (hazard ratio [HR], 1.20; 95% CI, 1.01 to 1.42; P = .041). Compared with the control group, the experimental group strategy increased 6-month mortality (65.3% vs 59.9%; HR, 1.18; 95% CI, 1.01 to 1.38; P = .04), decreased the number of mean ventilator-free days (5.3 vs 6.4; difference, −1.1; 95% CI, −2.1 to −0.1; P = .03), increased the risk of pneumothorax requiring drainage (3.2% vs 1.2%; difference, 2.0%; 95% CI, 0.0% to 4.0%; P = .03), and the risk of barotrauma (5.6% vs 1.6%; difference, 4.0%; 95% CI, 1.5% to 6.5%; P = .001). There were no significant differences in the length of ICU stay, length of hospital stay, ICU mortality, and in-hospital mortality.

Conclusions and Relevance  In patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality. These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients.

Trial Registration  clinicaltrials.gov Identifier: NCT01374022

Introduction

Quiz Ref IDAcute respiratory distress syndrome (ARDS) is a common clinical problem among critically ill patients and is associated with high mortality and limited long-term quality of life.1,2 The functional lung size is decreased in ARDS, since many lung units become poorly or nonaerated due to collapse, flooding, or consolidation.3 This places patients at increased risk of ventilator-induced lung injury due both to overdistention of aerated lung units and cyclic opening and closing of small airways and alveoli (atelectrauma).4-6

Quiz Ref IDThe aim of recruitment maneuvers and positive end-expiratory pressure (PEEP) titration is to open collapsed lung units and keep them opened, potentially decreasing the risk of atelectrauma. Prospective noncontrolled trials have shown that a lung recruitment maneuver with stepwise increases in PEEP, achieving inspiratory pressures up to 60 cm H2O, is able to open most of the collapsed lung tissue in patients with ARDS.7,8 Two randomized trials9,10 comparing similar recruitment maneuvers followed by decremental PEEP titration vs a well-established low-PEEP strategy6 suggested beneficial effects on oxygenation, respiratory-system compliance, and biomarkers of systemic inflammation, without increasing barotrauma or other adverse events. Additionally, systematic reviews evaluating recruitment maneuvers suggested a reduction in mortality, also without increase in barotrauma.11,12 However, quality of evidence is limited by high risk of bias in most trials and variable use of cointerventions. Thus, the Alveolar Recruitment for ARDS Trial (ART) was conducted to assess whether a strategy of lung recruitment maneuver associated with PEEP titrated according to the best respiratory-system compliance vs a well-established low-PEEP strategy6 improves clinical outcomes of patients with moderate to severe ARDS.

Methods
Study Design and Oversight

We conducted a randomized clinical trial in 120 intensive care units (ICUs) from 9 countries (Brazil, Argentina, Colombia, Italy, Poland, Portugal, Malaysia, Spain, and Uruguay). The protocol and statistical analysis plan (in Supplement 1) were published previously.13,14 Data analysis started after the statistical analysis plan was accepted for publication (see eAppendix in Supplement 2 for details). Ethics committees of all institutions approved the study. Informed consent was obtained from all patients’ representatives. An independent data monitoring committee oversaw efficacy and safety data.

Patients

We enrolled patients receiving invasive mechanical ventilation with moderate to severe ARDS of less than 72 hours of duration. Eligibility was evaluated in 2 phases, a screening and a confirmatory phase. In the screening phase, patients were considered for inclusion in the study if they met the American-European Consensus Conference criteria15 for ARDS. The exclusion criteria were age younger than 18 years; use of vasoconstrictor drugs in increasing doses over the past 2 hours or mean arterial pressure (MAP) less than 65 mm Hg; contraindications to hypercapnia, such as intracranial hypertension or acute coronary syndrome; pneumothorax, subcutaneous emphysema, pneumomediastinum or pneumatocele; patients in palliative care only; or previously enrolled patients.

Before confirming eligibility, patients received at least 3 hours of mechanical ventilation using a low-PEEP and low-tidal volume strategy proposed by the Acute Respiratory Distress Syndrome Network (ARDSNet).6 After that, the fraction of inspired oxygen (Fio2) was set at 100% and the PEEP at 10 cm H2O or more for 30 minutes and arterial blood gases were collected. Eligibility was confirmed if the ratio of the partial pressure (Pao2) of oxygen to the Fio2 (Pao2:Fio2) was 200 or lower and less than 72 hours had passed since the first time a Pao2:Fio2 ratio of 200 or less was determined.

Randomization and Masking

Patients were randomized in a 1:1 ratio to a strategy of lung recruitment associated with PEEP adjusted according to the respiratory-system compliance or to a low-PEEP strategy. The random allocation list was generated by a statistician with no clinical involvement in the trial using a computer-generated random number list. Randomization was conducted with blocks of 4 and stratification by site, age (≤55 years or >55 years) and Pao2:Fio2 ratio (≤100 or >100). Allocation concealment was ensured via a central web-based system. The treatment to which a patient was allocated was disclosed only after the patient was enrolled in the study.

Participant, clinicians, and outcome assessors were aware of the assigned treatment.

Interventions

Patients assigned to the control group continued to receive the low-PEEP strategy.6 Immediately after randomization, patients assigned to the experimental strategy received a bolus of neuromuscular blocker and hemodynamic status was maintained by administering intravenous fluids when there were signs of fluid responsiveness. Then, we conducted a lung recruitment maneuver with incremental PEEP levels, followed by a decremental PEEP titration according to the best respiratory-system static compliance and by a second recruitment maneuver. The lung recruitment maneuver and PEEP titration technique were based on those used in previous noncontrolled studies.7,8 After recruitment and PEEP titration, patients were ventilated under volume-assist control mode with PEEP set at the titrated value (the PEEP associated with highest respiratory-system compliance plus 2 cm H2O). If Pao2:Fio2 levels were stable or increasing for 24 hours or more after recruitment, weaning of PEEP was started with decreases of 2 cm H2O every 8 hours. Apart from the lung recruitment maneuver and PEEP titration scheme, other aspects of care were similar for both groups. The experimental and control group procedures are detailed in the protocol and the manual of operations (Supplements 1 and 3).

Quiz Ref IDInitially, we applied a recruitment maneuver using pressure-controlled ventilation and driving pressure of 15 cm H2O. We started with a PEEP of 25 cm H2O for 1 minute, then a PEEP of 35 cm H2O for 1 minute, and then 45 cm H2O for 2 minutes. After recruitment, decremental PEEP titration was started with a PEEP of 23 cm H2O in volume-controlled mode. PEEP levels were decreased in steps of 3 cm H2O down to a minimum of 11 cm H2O. After 4 minutes in each step, we measured respiratory-system static compliance. The PEEP associated with the best compliance plus 2 cm H2O was considered the optimal PEEP. After PEEP titration, a new recruitment in pressure-controlled ventilation was conducted in 1 step using PEEP of 45 cm H2O for 2 minutes.

In June 2015, starting with the 556th patient, the steering committee, in consultation with the data monitoring committee, decided to modify the recruitment maneuver and PEEP titration strategy after 3 cases of resuscitated cardiac arrest possibly associated with the experimental group treatment were observed. During the recruitment maneuver, PEEP was increased to 25 cm H2O, 30 cm H2O, and then 35 cm H2O, in steps of 1 minute. Maximum plateau pressure was 50 cm H2O. Decremental PEEP trial was shorter, with each PEEP step lasting 3 minutes, followed by a new recruitment maneuver with PEEP of 35 cm H2O.

Outcomes

Our primary outcome was mortality until 28 days. Secondary outcomes were length of ICU and hospital stay; ventilator-free days from day 1 until day 28; pneumothorax requiring drainage within 7 days; barotrauma within 7 days; and ICU, in-hospital, and 6-month mortality. We defined as pneumothorax requiring drainage for any case that was possibly due to barotrauma; that is, we did not consider cases judged to be clearly caused by invasive procedures such as central venous punction or thoracocentesis. We defined as barotrauma within 7 days any pneumothorax, pneumomediastinum, subcutaneous emphysema, or pneumatocele of more than 2 cm detected on image examinations between randomization and 7 days, except those judged to be clearly caused by invasive procedures.

Other exploratory outcomes were death with refractory hypoxemia within 7 days; death with refractory acidosis within 7 days; death with barotrauma within 7 days; cardiorespiratory arrest on day 1; need of commencement or increase of vasopressors or hypotension (MAP<65 mm Hg) within 1 hour after randomization; refractory hypoxemia (Pao2<55 mm Hg) within 1 hour after randomization; and severe acidosis (pH<7.10) within 1 hour after randomization.

Length of ICU stay (secondary outcome) and all other exploratory outcomes were included in our statistical analysis plan14 and ClinicalTrials.gov, although they were not originally in our study protocol (see eAppendix in Supplement 2 for details).

Statistical Analysis

ART was an event-driven study designed to continue until 520 events (28-day deaths) had accrued. This number of events was estimated to provide 90% power, assuming a hazard ratio of 0.75 and type I error of 5%. This hazard ratio is similar to the size of effect used to estimate sample size in other trials in the field.16,17

All analyses followed the intention-to-treat principle, considering all patients in the treatment groups to which they were randomly assigned, except for cases lost to follow-up. We carried out complete-case analysis for all outcomes. We planned to conduct sensitivity analysis for the primary outcome using multiple imputation techniques only if follow-up data of 1% or more of the patients was lost. Baseline characteristics were reported as counts and percentages, mean and standard deviation (SD), or median and interquartile range (IQR), whenever appropriate. Hypothesis tests were 2-sided. Two interim analyses were performed after recruitment of one-third and two-thirds of the planned sample size to assess effects on clinical outcomes. The data monitoring committee would consider stopping the trial early if there was evidence of harm with 1-sided P value <.01. The significance level for the primary outcome final analysis was .042, to maintain overall α at .05. For all other outcomes, the significance level was .05, without adjustment for multiple comparisons. Because of this, all secondary outcomes and analyses should be interpreted as exploratory.

We assessed the effect of the trial treatments on the primary outcome using Kaplan-Meier curves and calculated the hazard ratio with 95% CI using the Cox proportional hazard model. We conducted 2 sensitivity analyses. The first was a prespecified Cox proportional hazards model adjusted for age, Simplified Acute Physiology Score 3 (SAPS 3) score, and Pao2:Fio2 ratio. The second was a post hoc frailty Cox model with stratification variables (site, age, and Pao2:Fio2) as random effects.

We used Kaplan-Meier curves and the Cox proportional hazard model to assess the effect of treatment on 6-month survival. We assessed the effects of the intervention on categorical variables with risk ratios and 95% CIs, and we used the χ2 test to compare between-group differences. For continuous outcomes, we estimated the effects of the intervention with generalized linear models using gamma distributions (for lengths of ICU and hospital stay) or a truncated Poisson distribution (for ventilator-free days).

We used Cox proportional hazards to assess interactions between treatment effect and the following prespecified subgroups: Pao2:Fio2 (≤100 vs >100 mm Hg); SAPS 3 score (<50 vs ≥50); pulmonary vs extrapulmonary ARDS; duration of ARDS (≤36 hours vs >36 to <72 hours); mechanical ventilation (≤2 days, 3-4 days, ≥5 days); and prone position. As an exploratory analysis, we tested whether treatment effects were similar before and after the protocol amendment of June 2015. We also tested in a post hoc analysis whether treatment effects per quartiles according to order of enrollment in the trial (earlier vs later) were homogeneous. All analyses were performed using the R (R Core Team, 2016) software.

Results
Patients

Quiz Ref IDFrom November 17, 2011, through April 25, 2017, we screened 2077 patients with moderate to severe ARDS. A total of 1064 were not enrolled, of whom 863 (81.1%) met exclusion criteria and 201 (18.9%) were eligible but were not enrolled for other reasons. We randomized 1013 patients, 501 to the lung recruitment strategy and 512 to the low-PEEP strategy. Representatives of 3 patients assigned to the control group withdrew consent to use study data. We obtained 28-day and 6-month follow-up data of all remaining patients, except for 23 who were followed up and censored between 2 and 6 months. Thus, data of 1010 patients (501 in the experimental group and 509 in the control groups) were considered for the final analysis. The data monitoring committee evaluated 2 interim analyses and recommended the trial to be continued. (Figure 1)

Baseline characteristics were well balanced between the study groups (Table 1). Two-thirds of the patients had septic shock. The mean number of nonpulmonary organ failures was more than 2. Most ARDS cases were of pulmonary (62.0%) rather than extrapulmonary origin (38.0%). In the experimental and control groups, baseline mean (SD) tidal volume and plateau pressures were 5.8 (1.1) and 5.8 (1.0) mL/Kg of predicted body weight, and 25.8 (4.7) and 26.2 (5.2) cm H2O, respectively.

Lung Recruitment

A total of 480 patients (95.8%) in the experimental group received a lung recruitment maneuver after randomization (eTable 1 in Supplement 2). In 78 cases (15.6%) the maneuver had to be interrupted, most often due to hypotension or a decrease in oxygen saturation. In 21 cases, a recruitment maneuver was not attempted due to uncontrolled hypotension (14 cases), detection of pneumothorax (3 cases) after randomization, or other reasons (4 cases). The mean (SD) titrated PEEP was 16.8 (3.8) cm H2O. Lung recruitment was repeated after PEEP titration in 393 patients (78.4%). After the initial recruitment and PEEP titration, alveolar recruitment was not repeated from day 1 to 7 in most patients (62.7%). Conversely, 28 patients in the control group also received a recruitment maneuver within the first 7 days.

Ventilator Settings and Respiratory Variables

Mean PEEP values from hour 1 through day 7 were higher in the experimental than in the control group (eTable 2 in Supplement 2). Mean values of plateau pressure were also higher in the experimental group, although always below 30 cm H2O in both groups. Mean tidal volumes were below 6 mL/kg of predicted body weight in both groups from hour 1 through day 3. The mean Pao2:Fio2 ratios were higher in the experimental group. Yet decreases in driving pressure from control to experimental group were limited to less than 2 cm H2O from day 1 through day 7. Partial pressure of carbon dioxide was higher and arterial pH was lower in experimental group only at the first hour, with values that were not significantly different after day 1.

Cointerventions

Use of neuromuscular blockers was higher in the experimental than the control group (96.8% vs 73.3%; difference, 23.5%; 95% CI, 19.2%-27.9%; P < .001), reflecting the protocol requirement for their use before the recruitment maneuver (eTable 3 in Supplement 2). The proportion of patients who received sedatives on any day was higher in the experimental group (99.0% vs 97.1%; difference, 1.9%; 95% CI, 0.0%-3.9%; P = .05), although there was no difference between groups in the median number of days receiving sedatives. There were no differences among groups in other cointerventions or on the need of rescue therapies for hypoxemia.

Outcomes

At 28 days, there were 277 deaths (55.3%) among 501 patients in the experimental group and 251 deaths (49.3%) among 509 patients in the control group, with a hazard ratio of 1.20 (95% CI, 1.01-1.42; P = .041) (Figure 2). After adjustment for baseline covariates, age, SAPS 3, and Pao2:Fio2, the hazard ratio for 28-day mortality was 1.22 (95% CI, 1.03-1.45; P = .02). In the post hoc frailty Cox model, the hazard ratio was 1.21 (95% CI, 1.02-1.44; P = .03).

All-cause mortality was also higher within 6 months in the experimental than in the control group (65.3% vs 59.9%; hazard ratio, 1.18; 95% CI, 1.01-1.38; P = .04) (Table 2). Differences in the ICU or in-hospital mortality between groups were not statistically significant. Compared with the control group, mortality in the experimental group was higher during the first 7 days, with increased rates of death with barotrauma (Table 2). There were no significant differences in the rates of death with refractory hypoxemia, death with acidosis, and cardiorespiratory arrest between groups. Lengths of stay in the ICU or hospital were also not significantly different. The experimental group had fewer ventilator-free days during the first 28 days. The rates of pneumothorax requiring drainage and rates of any barotrauma increased in the experimental group. Within 1 hour, commencement or increase in vasopressors or hypotension were more common in the experimental group, but there were no differences in refractory hypoxemia or severe acidosis.

Subgroup and Exploratory Analyses

Effects of experimental vs control strategy on 28-day mortality were not significantly different across subgroups (Figure 3). Treatment effects were also not significantly different in the periods of study before and after the protocol was modified with reduction in the length and in the maximum PEEP and pressure levels of the recruitment maneuver (P = .89). Treatment effects were also not significantly different per quartiles according to order of enrollment in the trial (P = .76).

Discussion

In this trial enrolling adults with moderate to severe ARDS, a strategy of lung recruitment and PEEP titration according to the respiratory-system compliance increased 28-day mortality compared with an established low-PEEP strategy. In addition, the lung recruitment strategy increased 6-month mortality, the risk of any barotrauma and death with barotrauma, and the need for vasopressors or hypotension in the first hour. Conversely, the lung recruitment strategy decreased the number of days free of mechanical ventilation during 28 days.

One potential explanation for the findings of this trial relates to an unfavorable balance between potential positive (reduction in driving pressure)10 and negative (increase in overdistention, hemodynamic impairment)18,19 physiological consequences of lung recruitment and PEEP. Although some studies showed almost full opening of collapsed alveoli after recruitment maneuvers achieving high inspiratory pressures,7,8 only mild responses were observed in this trial as suggested by the small increments in the respiratory-system compliance and reductions in driving pressure. Furthermore, the driving pressure, a strong predictor of survival in ARDS,20,21 decreased by a mean of only less than 2 cm of water. On the contrary, the risk of barotrauma within 7 days and signs of hemodynamic impairment within 1 hour increased in the experimental group, suggesting lung injury and hemodynamic impairment as mechanisms that may have driven increased mortality. Nevertheless, the incidence of barotrauma, even in the experimental group, was lower than in any previous studies using high PEEP levels.22

Another potential explanation for the results observed in this trial lies in the lung protective characteristics of the control group, which may have offset any potential physiological advantages of the lung recruitment and PEEP titration strategy. The control group strategy called for a tidal volume of 6 mL/kg (or less if plateau pressure was >30 cm H2O) and use of lower PEEP levels.6 Adherence to low tidal volume was very strict, with lower mean tidal volumes than the ARDSNet trials.6,23 Conversely, PEEP values were approximately 3 cm H2O higher than that observed in control groups from previous studies.22 The use of strictly low tidal volumes and resulting low driving pressures may have reduced lung injury due to tidal overdistention. Furthermore, intermediate levels of PEEP may have contributed to maximizing homogeneity and preventing atelectrauma.

A third possible explanation for the findings of this trial is the breath stacking phenomenon, which may occur inadvertently in patients receiving protective ventilation, especially in the volume-assist control mode and with low tidal volumes.24,25 It was documented in 1 patient enrolled in the experimental group and routinely monitored with electrical impedance tomography (eFigure 1 in Supplement 2). The patient received 12 mL/kg of effective tidal volume in more than 40% of the breaths, whereas the ventilator displayed 6 mL/kg. Although the incidence of this phenomenon was likely similar in both groups, it may have caused more lung overstretch with disproportionally higher driving pressures in patients submitted to higher PEEP levels.

The choice of the ARDSNet table of lower instead of higher PEEP values for the control group in this trial might be questioned, since an individual patient data meta-analysis suggested a survival benefit for higher PEEP levels in the subgroup of patients with moderate to severe ARDS.22 Three main reasons supported the option for lower PEEP values. First, the meta-analysis did not show benefit of high PEEP for the overall group of patients with ARDS.22 Second, none of the individual trials showed a significant effect on mortality.17,23,26 Third, the trials included in the meta-analysis used substantially different strategies both in the experimental and control groups, with variable use of recruitment maneuvers. Therefore, it is uncertain whether the potential benefit was due to higher PEEP or to the lung recruitment maneuver itself.

This trial has strengths. Bias was controlled by using concealed allocation, intention-to-treat analysis, and by avoiding losses to follow-up. Analyses were based on a large number of events, which allowed for adequate random error control. Patient eligibility was confirmed only after ventilation with a lung protective low-tidal volume strategy and standardized Fio2 and PEEP settings before collecting arterial blood gases. Except for the lung recruitment maneuvers and PEEP titration scheme, identical mechanical ventilation protocol with low-tidal volume was applied for both groups. In addition, the study involved centers from 9 countries, which contributes to generalizability of its results.

Limitations

This study has several limitations. First, it was not feasible to blind participants, clinicians, and outcome assessors. It is possible that processes of care might have been affected by knowledge of treatment allocation. Conversely, blinding would not affect classification of the primary outcome. Second, it was not possible to classify enrolled patients into ARDS subphenotypes, which may respond differently to therapies such as PEEP.27,28 Determination of subphenotype requires collecting plasma samples to perform analysis of biomarkers; however, this was not conducted due to funding restrictions. Third, it has been suggested that baseline responsiveness to a test of PEEP elevation predicts percentage of potentially recruitable lung and the clinical response to a strategy of lung recruitment associated with high PEEP.29,30 However, since responsiveness to PEEP at baseline was not assessed, it is not possible to analyze whether this characteristic modifies treatment effect. Nevertheless, there was no evidence of heterogeneity of treatment effect in any of the subgroups examined. Fourth, patients were enrolled in the trial over 6 years. The care of patients with ARDS may have changed during this period, which might have affected results. However, an analysis of treatment effects on mortality according to order of enrollment provides no evidence that effects changed over time. Fifth, a strategy involving lung recruitment and PEEP titration (primary interventions) is complex in the sense that not only the primary interventions are part of it, but also cointerventions that need to be aggregated. For example, administering neuromuscular blockers and fluids in preparation for the recruitment maneuver. As a consequence, it is not possible to ascribe observed clinical effects exclusively to the direct effects of lung recruitment maneuver and PEEP.

Conclusions

Quiz Ref IDIn patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality. These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients.

Section Editor: Derek C. Angus, MD, MPH, Associate Editor, JAMA (angusdc@upmc.edu).
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Article Information

Accepted for Publication: September 1, 2017.

Corresponding Author: Alexandre Biasi Cavalcanti, MD, PhD, HCor Research Institute—Hospital do Coração, Rua Abílio Soares 250, 12th Floor, CEP: 04005-000, São Paulo, SP, Brazil (abiasi@hcor.com.br).

Published Online: September 27, 2017. doi:10.1001/jama.2017.14171

Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators: Alexandre Biasi Cavalcanti, MD, PhD; Érica Aranha Suzumura, MSc; Ligia Nasi Laranjeira, RT; Denise de Moraes Paisani, PhD; Lucas Petri Damiani, MSc; Helio Penna Guimarães, MD, PhD; Edson Renato Romano, MD, PhD; Marisa de Moraes Regenga, RT; Luzia Noriko Takahashi Taniguchi, RT; Cassiano Teixeira, MD, PhD; Roselaine Pinheiro de Oliveira, MD, PhD; Flavia Ribeiro Machado, MD, PhD; Fredi Alexander Diaz-Quijano, MD, PhD; Meton Soares de Alencar Filho, MD; Israel Silva Maia, MD; Eliana Bernardete Caser, MD, PhD; Wilson de Oliveira Filho, MD; Marcos de Carvalho Borges, MD, PhD; Priscilla de Aquino Martins, MD; Mirna Matsui, MD, PhD; Gustavo Adolfo Ospina-Tascón, MD, PhD; Thiago Simões Giancursi, MD; Nelson Dario Giraldo-Ramirez, MD, MSc; Silvia Regina Rios Vieira, MD, PhD; Maria da Graça Pasquotto de Lima Assef, MD, PhD; Mohd Shahnaz Hasan, MD, PhD; Wojciech Szczeklik, MD, PhD; Fernando Rios, MD, PhD; Marcelo Britto Passos Amato, MD, PhD; Otávio Berwanger, MD, PhD; Carlos Roberto Ribeiro de Carvalho, MD, PhD.

Affiliations of Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators: HCor Research Institute, São Paulo, Brazil (Cavalcanti, Suzumura, Laranjeira, Paisani, Damiani, Guimarães, Romano, Regenga, Taniguchi, Berwanger); Cardio-Pulmonary Department, Pulmonary Division, Heart Institute (Incor), University of São Paulo, São Paulo, Brazil (Amato, Ribeiro de Carvalho); Hospital Moinhos de Vento, Porto Alegre, Brazil (Teixeira); Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil (Pinheiro de Oliveira); Anesthesiology, Pain, and Intensive Care Department, Federal University of São Paulo–UNIFESP, São Paulo, Brazil (Machado); Epidemiology Department, School of Public Health, University of São Paulo, São Paulo, Brazil (Diaz-Quijano); Hospital Maternidade São Vicente de Paulo, Barbalha, Brazil (M. S. d. Filho); Hospital Nereu Ramos, Florianópolis, Brazil (Maia); Hospital Unimed Vitória, Vitória, Brazil (Caser); Hospital e Pronto-Socorro 28 de Agosto, Manaus, Brazil (W. d. O. Filho); Unidade de Emergência do Hospital das Clínicas da FMRP-USP, Ribeirão Preto, Brazil (Borges); Hospital Estadual Dr Jayme dos Santos Neves, Serra, Brazil (Martins); Hospital Universitário da Universidade Federal da Grande Dourados, Dourados, Brazil (Matsui); Department of Intensive Care Medicine, Fundación Valle del Lili - Universidad ICESI, Cali, Colombia (Ospina-Tascón); Hospital Universitário do Oeste do Paraná, Cascavel, Brazil (Giancursi); Hospital Pablo Tóbon Uribe, Medellín, Colombia (Giraldo-Ramirez); Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (Vieira); Hospital Regional Hans Dieter Schmidt, Joinville, Brazil (Assef); University Malaya Medical Centre, Kuala Lumpur, Malaysia (Hasan); Jagiellonian University Medical College; Department of Intensive Care and Perioperative Medicine, Krakow, Poland (Szczeklik); Hospital Nacional Alejandro Posadas, Moron, Argentina (Rios).

Author Contributions: Dr Cavalcanti had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The writing group vouches for the accuracy and completeness of the data and for the fidelity of the study to the protocol.

Concept and design: Cavalcanti, Suzumura, Amato, Berwanger, Carvalho.

Acquisition, analysis, or interpretation of data: Cavalcanti, Suzumura, Laranjeira, Paisani, Damiani, Guimarães, Romano, Regenga, Taniguchi, Teixeira, Oliveira, Machado, Diaz-Quijano, Alencar Filho, Maia, Caser, Oliveira Filho, Borges, Martins, Matsui, Ospina-Tascón, Giancursi, Giraldo-Ramirez, Vieira, Assef, Hasan, Szczeklik, Rios, Amato, Berwanger, Carvalho.

Drafting of the manuscript: Cavalcanti, Laranjeira, Paisani, Damiani, Amato, Berwanger.

Critical revision of the manuscript for important intellectual content: Suzumura, Guimarães, Romano, Regenga, Taniguchi, Teixeira, Oliveira, Machado, Diaz-Quijano, Alencar Filho, Maia, Caser, Oliveira Filho, Borges, Martins, Matsui, Ospina-Tascón, Giancursi, Giraldo-Ramirez, Vieira, Assef, Hasan, Szczeklik, Rios, Carvalho.

Statistical analysis: Cavalcanti, Paisani, Damiani, Amato, Berwanger.

Obtained funding: Cavalcanti, Berwanger.

Administrative, technical, or material support: Cavalcanti, Suzumura, Laranjeira, Paisani, Diaz-Quijano, Szczeklik, Rios, Amato, Berwanger, Carvalho.

Supervision: Cavalcanti, Laranjeira, Suzumura, Paisani, Machado, Diaz-Quijano, Amato, Berwanger, Carvalho.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. All authors received grant support from Program to Support Institutional Development of Universal System (PROADI) from the Brazilian Ministry of Health to conduct the study. Dr Amato also received grants from Timpel S. A. and Medtronic. No other disclosures are reported.

Site Investigators: Argentina:Hospital Nacional Alejandro Posadas: Fernando Rios, Judith Sagardia, Roger Rodrigues Lamoglie, Juan Manuel Vincenti; Sanatorio Juncal: Marcelo Lareu, Maria Soledad Esteban, Valeria Cerrato, and Rodrigo Fodor; and Sanatorio Las Lomas: Fernando Rios, Pablo E Gomez, and Alejandro Riso Vasquez.

Brazil:AC Camargo Cancer Center: Mauro Roberto Tucci, Lucio Souza dos Santos, Maria Cristina França de Oliveira, Ivan Peres, and Isabel Freitas; Fundação Hospital de Clínicas Gaspar Vianna: Helder Reis, Adriana Veríssimo, Daniel Torres, and Amanda Barroso; Fundação Hospitalar São Sebastião: Wesley Semboloni Bitencourt, Mônica Ribeiro Franco, and Jarbas Oliveira Lage; Hospital Municipal Dr José Soares Hungria: Katia Aparecida Pessoa Conde, Fernando Antonio Charro, and Andrea Naia; Hospital Adventista de Belém: Edgar de Brito Sobrinho, Adriana Lameira Veríssimo, and Milce Ellen Barros de Oliveira; Hospital Alemão Oswaldo Cruz: Fernando Zampieri, José Paulo Ladeira, Ricardo Cordioli, Andrea Diogo Sala, and Dimas Tadahiro Ikeoka; Hospital Bandeirantes: Mario Lucio A. Baptista Filho, Alexandre Ray, Andre Guerra de Almeida, and Claudio Nazareno Conceição; Hospital Barra D'Or: Diamantino Ribeiro Salgado, Juan Carlos Rosso Verdeal, and Glória Adriana Martins; Hospital Cônego Monte Raso: Wesley Semboloni Bitencourt, Lauriane Junqueira Ribeiro, and Helder Vilela Siqueira; Hospital da Luz: Francisco Flávio Costa Filho, Bruno Adler Maccagnan Pinheiro Besen, Eliana Vieira do Nascimento Martins, and Joyce Aparecida Pereira; Hospital das Clinicas da Universidade Federal de Goiás (UFG): Denise Milioli Ferreira, Fernanda Alves Ferreira Gonçalves, Marciano de Souza Nobrega, and Italo Julierme Barros Duarte; Hospital das Clinicas da Universidade Federal de Minas Gerais: Vandack Nobre, Lídia Miranda Barreto Mourão, Cecília Gómez Ravetti, and Anna Carolina Scalzo; Hospital das Clinicas de Botucatu: Laercio Martins De Stefano and Ana Lucia Gut; Hospital das Clínicas Luzia de Pinho Melo: Wilson Nogueira Filho, Ciro Gatti Cirillo, and Shizuo Ishiwaki Jr; Hospital de Base de São José do Rio Preto: Suzana Lobo, Neymar Elias de Oliveira, Luana Fernandes Machado, and Lais Sisconetto; Hospital de Clínicas de Porto Alegre (HCPA): Silvia Regina Rios Vieira, Lea Fialkow, Karen Fontoura Prado, Cristiano Franke, Rafael Barberena Moraes, Iuri Christmann Wawrzeniak, Tatiana Helena Rech, Edino Parolo, and Josué Almeida Victorino; Hospital de Urgências e Emergências de Rio Branco: Claudineia Marques Barroso, Márcia Odilia Marçal de Vasconcelos, Rosicley Souza da Silva, and André Rafael Lesti Esteves; Hospital do Círculo: Ana Paula Camassola, Rodrigo Antoniazzi, Morgana Griebler, and Jean Favretto; Hospital do Coração-HCor: Marcelo Romano, André Franz da Costa, Vinicius Werneck, Mieko Cláudia Miura, Jorge Farran, and Rosianne de Vasconcelos; Hospital do Servidor Público Estadual de São Paulo (IAMSPE-HSPE): Alexandre Isola, Ederlon Resende, Ricardo Goulart, and Sérgio Luzzi; Hospital do Trabalhador: Alvaro Réa-Neto, Mirella Cristine de Oliveira, Mariana Bruinje Cosentino, Bruna Martins Dzivielevski, Fernanda B. Reese, Sabrina Donatti Ferreira da Silva, Esperidião Elias Aquim, and Fabiane Girotto; Hospital e Pronto Socorro Dr Aristóteles Platão Bezerra de Araújo: Riani Helenditi Fernandes Camurça Martins and Altamira Lima de Andrade; Hospital e Pronto-Socorro 28 de Agosto: Wilson de Oliveira Filho, Débora Cristine Breckenfeld Heirel, Rodrigo Ryoji Takatani, Samara Dias de Almeida, Adriano Medina Matos, Tomomi Iwamoto, and Paulo Eugênio do Val Tavares; Hospital Escola Padre Albin-Faculdades Integradas Padre Albino-Medicina: Jorge Luis Valiatti, Francisco Carllos de Lucca, Júlio Cezar Fornazari, and Izabela Dias Brugugnolli; Hospital Especializado Octávio Mangabeira: Marcelo de Araújo Nazaré, Nathan Nascimento Loureiro, Gilmara Vasconcelos de Sousa, and Lucas Staffa Gonzaga da Silva; Hospital Estadual Dr Jayme dos Santos Neves: Priscilla de Aquino Martins, Fernando Cesar dos Anjos Sad, Enrico Miguel Stucchi, Rafael Melo Silva, and Thais Fonseca Silva; Hospital Estadual e Pronto Socorro João Paulo II: Sérgio Paulo Mendes Filho, Thattyane Borba Pereira, and Patrícia Nicoleit da Silva; Hospital Estatual Getúlio Vargas: Giulliana Martines Moralez, Simone Abrantes Saraiva, Alexandre Abrunhosa, and Claudio Eduardo Ranger C. Chagas; Hospital Evangélico de Cachoeiro de Itapemirim: Marlus Muri Thompson, Claudio Henrique Pinto Gonçalves, Renata de Oliveira Dias, and Fernando Schwan Filho; Hospital Evangélico de Londrina: Cintia Magalhães Carvalho Grion, Ana Luzia Mezzaroba, and Josiane Festti; Hospital Evangélico de Vila Velha: Priscilla de Aquino Martins, Thiago Carlos Massariol, and Gedealvares Francisco de Souza Jr; Hospital Geral da Vitória da Conquista: Miquéias Martins Lima Silva, José de Souza Andrade Neto, Graziele Costa, and Mário Souza Ribeiro II; Hospital Geral de Roraima: Marcus Coelho, Roberto Carlos Cruz Carbonell, and Renata de Souza Trindade; Hospital Israelita Albert Einstein: Carmen Silvia Valente Barbas, Thiago Domingos Correa, Ary Serpa Neto, and Murillo Santucci Cesar de Assunção; Hospital Lifecenter: Bruno Vilela Costa Pinto and Priscila Gonçalves Libânio; Hospital Marcelino Champagnat: Alvaro Réa-Neto, Jarbas da Silva Motta Jr, Esperdião Elias Aquim, Gabriela Santa Maria Lucin, and Lorena Macedo Araujo; Hospital Maternidade São Vicente de Paulo: Meton Soares de Alencar Filho, Thales Anibal Leite Barros Agostinho, Kiara Monteiro de Andrade, Moisés Sampaio da Silva, Emerson Pereira da Silva, Rodrigo Luis Mousinho Gomes, Nilma Maria P. Campos, and Jairo Fonseca de Sousa; Hospital Metropolitano de Urgência e Emergência: Leonardo Ramos Nicolau da Costa, Norma Suely de Carvalho Fonseca Assunção, and Gabriela Martins de Lima; Hospital Moinhos de Vento: Cassiano Teixeira, Roselaine Pinheiro de Oliveira, Juçara Gasparetto Maccari, Patrícia de Campos Balzano, and Luciana Tagliari; Hospital Municipal da Vila Santa Catarina: Ana Paula Metran Nascente, Mônica Andrade de Carvalho, Monique Buttignol, and Renata Henn Moura; Hospital Municipal Dr Mario Gatti: Marcus Vinicius Pereira, Gabriel Alberti da Silva, Marina Akemi Higo, and Mariana Morales: Hospital Municipal Dr Moysés Deutsch (M'Boi Mirim): Ana Helena Vicente Andrade, Ana Paula de Paiva, Karina Suzane da Silva Pereira, Priscila Andrioli de Araujo, and Carlos Alberto Cordeiro de Abreu Filho; Hospital Municipal São Francisco de Assis: Guilherme Abdalla, Marcia Loureiro Sebold, and Rene Moreira; Hospital Municipal São José de Joinville: Milton Caldeira Filho, Rodrigo de Brito Cordeiro, and Felipe Pfuetzenreiter; Hospital Naval Marcílio Dias: Luiz Fernando Costa Carvalho, Bruno Leonardo da Silva Guimarães, Hebe de Faria Cordeiro, Sergio Hernando Pimentel Alvim, and José Amalth do Espirito Santo; Hospital Nereu Ramos: Israel Silva Maia, Mariangela Pincelli, Cassio Luis Zandonai, Ana Cristina Burigo Grumann, and Lara Patrícia Kretzer; Hospital Nossa Senhora da Conceição: Wagner Nedel, Márcio Manozzo Boniatti, and José Augusto Santos Pellegrini, and Leonardo da Silva Marques; Hospital Novo Atibaia: Walter Carlos Girardelli Baptista, Rubens Sérgio da Silva Franco, Manoela Moreira de Sousa, and Amauri Francisco de Marchi Benfica; Hospital Primavera: André Luis Veiga de Oliveira, Diego L. Reis, Mirene de O. Morais, and Hericalizandra Santa Rosa Santana; Hospital Regional da Asa Norte (HRAN): Sergio Murilo Domingues Jr, Cassia de Menezes Ferreira, and Livia Amado Rabelo; Hospital Regional de Mato Grosso do Sul Rosa Pedrossian: Claudnei Menezes de Rezende, Paula Riccio, Patrícia Silva de Almeida, and Patrícia Rubini; Hospital Regional Hans Dieter Schmidt: Maria da Graça Pasquotto de Lima Assef, Rafael Nardela, Laise Locks Stahlhöfer, and Carolina Gatelli Noronha; Hospital Samaritano de Governador Valadares: Sérgio de Azevedo Naves and Fabiano Dias da Silva; Hospital Samaritano de São Paulo: Bruno Franco Mazza, Samantha Longhi Simões de Almeida, Rosana Mayumi Higa, and Cristiane Helena Papacídero; Hospital Samur: Miquéias Martins Lima Silva, Livia de Assunção Melo, Manuele Miranda Mafra Oliveira, and Cynthia Matos Brito Coelho; Hospital Santa Casa de Bragança Paulista: Jocimar António Machado, Yara Lucia de Souza Machado, João Vitor Fera, and Nadia Cristina dos Santos Ramos; Hospital Santa Cruz, Santa Cruz do Sul: Rafael Botelho Foernges, Roberto Ritter de Souza, and William Rutzen; Hospital Santa Juliana: Edgar Miguel Villasante Troncoso, Thaiane K. B. Paiva, and Normando Melo Vieira de Lacerda; Hospital Santa Luzia: José Aires de Araújo Neto, Marcelo de Oliveira Maia, Edmilson Bastos de Moura, and Gisele Brocco Magnan; Hospital Santa Rosa: Mara Lílian Soares Nasrala, Rogéria Lobato Campos Tonussi, Eloisa Kohl Pinheiro, and Fabio Simões da Silva; Hospital São José–Criciúma: Felipe Dal-Pizzol, Fernando Schmitz de Figueiredo, and Cristiane Ritter; Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS): Sérgio de Vasconcellos Baldisserotto, Clarissa Blattner, Rafael Saldanha dos Santos, and Fernanda da Silva Bettega; Hospital São Lucas de Governador Valadares: Sérgio de Azevedo Naves and Fabiano Dias da Silva; Hospital São Lucas-FAG: Péricles Almeida Delfino Duarte, Tatiane Cristina Tozo, and Priscila Peliser; Hospital São Luiz—Unidade Anália Franco: Rafaela Deczka Morsch, Érika Guimarães Leal Guadalupe, and Denise Souza Amorim; Hospital Saúde da Mulher: Leila Rezegue de Moraes Rego; Hospital Sirio-Libanês: Luciano Azevedo, Fernando Ramos, Laerte Pastore, and Patricia Nery; Hospital Unimed Araçatuba: Marcelo Spegiorin Moreno, Vinicius Nakad Orsatti, Fabio Yudi Horikawa, and Gabriela Samartino Zavanelli; Hospital Unimed Joinville: Glauco Adrieno Westphal, Geonice Sperotto, and Micheli Dadam; Hospital Unimed Santa Helena: Marcelo Nunes, Sílvio Luis Pantaleão, and Roberto Camargo Narciso; Hospital Unimed Vitória: Eliana Bernadete Caser, Jansen G. Falcão, Gustavo Genelhu, Felipe Lessa Soares, Betania Silva Sales, Karinne Rebello de Jesus, Daniela Correia Santos Bonomo, and Juliano Martins Arruda; Hospital Unimed-Rio: João Carlos de Pinho, Janine Belacho Azeredo Coutinho, Rafaela Braga Hagreaves Ribeiro de Freitas, and Tiego de Souza Oliveira Garcia; Hospital Universitário Cassiano Antonio de Moraes da Universidade Federal do Espirito Santo (UFES): Paula Frizera Vassallo and Maria Helena Buarque Souza de Lima; Hospital Universitário da Universidade Federal da Grande Dourados: Mirna Matsui, Ervin, Eberhart Neto, Alexandre Satoshi Inagaki, Aline Evangelista Oliveira de Paula, Tiago Amador Correia, Silmara Nomoto, Fernando Seiji Ueno Gil, Mario Florizel Almeida de Araújo, and Zildamara Bezerra Lima; Hospital Universitário do Oeste do Paraná: Thiago Simões Giancursi, Cláudia Rejane de Lima, Macedo Costa, Erica Fernanda Osaku, and Amaury Cezar Jorge; Hospital Universitário Pedro Ernesto: Mônica Rodrigues da Cruz, Sergio da Cunha, Katia Silva Cavallaro Torres, and Fernanda Rocha Rodrigues da Silva; Hospital Universitário Polydoro Ernani de São Thiago: Rafael Lisboa de Souza, Fernando Osni Machado, Elizabeth Kristiane Buss, and Kelly Cattelan Bonorino; Hospital Universitário Regional de Maringá: Almir Germano, Sandra Regina Bin da Silva, Andrea Herek, and Sanderland José Tavares Gurgel; Hospital Universitário Regional do Norte do Paraná: Cintia Magalhães Carvalho Grion, Alexandre Sanches Laranjeira, Marcos Toshiyuki Tanita, and Lucienne Tibery Queiroz Cardoso; Hospital Universitário São Francisco de Paula: Márcio Osorio Guerreiro, Marina Peres Bainy, and Luciano de Oliveira Teixeira; Hospital Universitário São Francisco: Giovana Colozza Mecatti, Maria Carolina Salomão, Aline Ribeiro Moreira, and Camila Vantini Capasso Palamim; Hospital Vita Batel: Alvaro Réa-Neto, Esperdião Elias Aquim, Rafael Alexandre O. Deucher, and Francine Castro Escobar Furlan; Instituto de Infectologia—Emílio Ribas: Fabrício Rodrigues Torres de Carvalho, Roberto Muniz Jr, Hélio Penna Guimarães, and Lucia Conceição Andrade; Instituto do Câncer do Estado de São Paulo—ICESP: Ludhmila Abrahão Hajjar, Filomena Regina Barbosa Gomes Galas, and Juliano Pinheiro de Almeida; Irmandade da Santa Casa de Misericórdia de São Paulo: Roberto Marco, Elzo Peixoto, Fabiano Hirata, and Chen Yen Ju; MEDIMIG: Bruno Bonaccorsi Fernandino, Daniel Lage de Assis Rocha, and Nathalia Azzi Barbosa; Santa Casa da Misericórdia de Ouro Preto: Janine Dias Alves, Ludmila Furtado Lamego, and Juliana Maria de Linhares; Santa Casa de Caridade de Diamantina: Marcelo Ferreira Sousa, Marcia Maria Ferreira de Souza, Fernanda Luiza Guimarães de Carvalho, and Monica Aparecida Leite; Santa Casa de Maringá: Paulo Torres, Daniel Bolognese, and Valintin Lacerda; Sociedade Brasileira de Amparo a Saúde (SOBRASA): Giovanni Cisari, Alexandre Souza Marques, Alex Amarante Costa, and Leonardo Bonin Campos; Unidade de Emergência do Hospital das Clínicas da FMRP-USP: Marcos de Carvalho Borges, Wilson José Lovato, Bruno Guimarães Dantas, Débora Ribeiro Campos, Larissa Christina Pires Barrientto, Vivian Rossi Peras Américo, Thatiana Barboza Carnevalli Bueno, Daniela Morales, Tania Mara Gomes, and Rodrigo Barbosa Cerantola; UTI Central da Irmandade Santa Casa de Misericórdia de Porto Alegre: Roselaine Pinheiro de Oliveira, Cassiano Teixeira, and Jorge Höher; UTIs da Anestesiologia, da Emergência Cirúrgica e Gastroenterologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP): Luiz Marcelo Sá Malbouisson, Filipe Matheus Cadamuro, Estevão Bassi, Rafaella Maia, João Alexandre Dias e Santos, Catherine Oliveira, Ana Paula Balzi, Paulo Tierno, and Guilherme Marques Andrade; UTI Clínica do Hospital São Paulo da Universidade Federal de São Paulo (UNIFESP): Renato Delascio Lopes, Marcos Cesar Ramos Mello, Hélio Penna Guimarães, and Leticia Sandre Vendrame; UTI da Disciplina de Anestesiologia, Dor e Terapia Intensiva do Hospital São Paulo da Universidade Federal de São Paulo (UNIFESP): Flávia Ribeiro Machado, Heloisa Baccaro Rossetti Santana, Alessandre de Carvalho Jr, Vanessa Marques Ferreira Mendez, Walkyria de Araujo Macedo Pinto, Renata dos Santos Francisco, Flavio Steponovicius Piedade Cruz, Abigail Silva de Araujo, Alda Paiva de Souza, and Tuanny Teixeira Pinheiro; UTI de Emergências Clínicas do Hospital de Clínicas da Universidade Estadual de Campinas (UNICAMP): Thiago Martins Santos, Carolina Matida Gontijo-Coutinho, Daniel Franci, and Marco Antonio de Carvalho-Filho; UTI de Queimados do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP): Amanda Maria Ribas Rosa de Oliveira and João Manoel Silva Jr; UTI do Hospital Santa Rita—Irmandade Santa Casa de Misericórdia de Porto Alegre: Thiago Costa Lisboa, André Peretti Torelly, Alldren Silva de Souza, and Martha Hadrich; UTI do Pavilhão Pereira Filho da Irmandade Santa Casa de Misericórdia de Porto Alegre: Patricia Schwarz, Paula Berto and José Augusto Santos Pellegrini; UTI do Pronto Socorro do Hospital São Paulo da Universidade Federal de São Paulo (UNIFESP): Aécio Flavio Teixeira de Gois, Moacyr Silva Jr, Paulo Gessolo Lins, and Eulália Priscila Cavalcante Lola Biazzoto; UTI Geral dos Adultos do Hospital de Clínicas da Universidade Estadual de Campinas (UNICAMP): Desanka Dragosavac; UTI Respiratória do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP): Carlos Roberto Ribeiro de Carvalho, Marcelo Britto Passos Amato, Carlos Toufen Jr, Roberta Ribeiro de Santis Santiago, and Adriana S. Hirota; UTI Respiratória do Hospital São Paulo da Universidade Federal de São Paulo (UNIFESP): Milton Rodrigues Jr, Luciana Dias Chiavegato, Paulo César Bastos Vieira, Marcella Marson M. F. de Almeida, and Pedro Gabriel Barbosa; Vila Velha Hospital: José Roberto Pereira Santos and Ludmila Nogueira de Paula; and Vitória Apart Hospital: Claudio Piras, Jonas Giuberti Jr, Albano Siqueira da Silva, and Rodrigo Conti Ramos.

Colombia:Organización Latinoamericana para el Fomento de la Investigación en Salud (OLFIS), Bucaramanga, Colombia. National Coordination of Sites in Colombia: Fredi Alexander Diaz-Quijano; Clinica Chicamocha: Reinaldo Plata Valdivieso, Hugo Hernan Gonzalez, and Myriam Ortiz; Department of Intensive Care Medicine, Fundación Valle del Lili—Universidad ICESI: Gustavo A. Ospina-Tascón, Diego F. Bautista-Rincón, Edgardo Quiñones, Luis Eduardo Calderon, and Monica Vargas; Fundación Cardiovascular de Colombia: Camilo Pizarro, Mauricio Orozco Levi and Angela Maria Espitia Hernández; Hospital Pablo Tóbon Uribe: Carlos Cadavid Gutierrez, Nelson Giraldo Ramirez, Diego Alejandro Gallego, and Santiago Naranjo Sierra; Hospital Santa Clara: Guillermo Ortiz, Maria Esneda Rocha Gaona, and Manuel Garay; and Hospital Universitario del Valle: Elías Vieda, William F. Bermúdez, and Julieth A. Castañeda.

Italy:Policlinico Paolo Giaccone. University of Palermo: Andrea Cortegiani, Vincenzo Russotto, Santi Maurizio Raineri, and Antonino Giarratano.

Malaysia:University Malaya Medical Centre: Mohd Shahnaz Hasan, Vineya Rai Hakumat Rai, Mohamad Fadhil Hadi bin Jamaluddin, and Mohamad Afiq Syahmi Ramli.

Poland:Jagiellonian University Medical College; Department of Intensive Care and Perioperative Medicine: Wojciech Szczeklik, Jacek Gorka, Ilona Nowak, Bozena Seczynska, and Aurelia Sega.

Portugal:Hospital de São Francisco Xavier, Centro Hospitalar de Lisboa Ocidental: Carolina Paulino and Pedro Póvoa.

Spain:Hospital Clinico Universitario. University of Valencia: F. Javier Belda, Carlos Ferrando, Jose A. Carbonell, Jaume Puig, and Marina Soro.

Uruguay:Hospital Español, JJ Crottogini: Nicolas Nin, Javier Hurtado, Ariel Gacel, Agustin Gaudin, and Leonardo Sande.

Data Monitoring Committee: Gordon Guyatt, MD, PhD; Niall Ferguson, MD, PhD; and Stephen Walter, PhD.

Study Coordinating Office:HCor Research Institute, São Paulo, Brazil: Alexandre Biasi Cavalcanti, MD, PhD; Ligia Nasi Laranjeira, RT; Denise de Moraes Paisani, PhD; Lucas Petri Damiani, MSc; Érica Aranha Suzumura, MSc; Samara Pinheiro do Carmo Gomes, BSc; Alessandra Akiko Kodama, MSc; Bruna dos Santos Sampaio, BSc; and Otávio Berwanger, MD, PhD.

Funding/Support: This study was funded by and conducted as part of the Program to Support Institutional Development of Universal System (PROADI) from the Brazilian Ministry of Health. The trial was coordinated by the HCor Research Institute and endorsed by the Brazilian Research in Intensive Care Network (BRICNet).

Role of the Funder/Sponsor: The funding sources had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Reproducible Research Statement: We will share the database containing deidentified individual participant data, data dictionary documentation, statistical analysis plan, and analysis code. Beginning 6 months and ending 24 months following article publication, the trial steering committee will evaluate proposals of studies accompanied by a statistical analysis plan and may grant access to the data for approved proposals. After 24 months, the database and accompanying documents will be publicly available in an institutional data repository (http://www.hcor.com.br).

Additional Contributions: We thank the Brazilian Association of Intensive Care Medicine for assisting with facilitating invitation to Brazilian intensivists. We thank all multidisciplinary teams in participant centers for their enthusiastic support and following the study interventions.

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