Trial Oversight

The investigator-initiated LOCO 2 trial was conducted in 13 ICUs in France from June 2016 through September 2018. The trial, which was designed and overseen by a steering committee, was funded by a grant from the French Ministry of Health, with additional oversight by the University Hospital of Besançon. The funder had no influence on the trial design, the collection or analysis of the data, or the writing of the manuscript; no commercial support was provided for this trial.

The trial protocol and the statistical analysis plan, available with the full text of this article at NEJM.org, were approved for all centers by the ethics committee of Besançon-Est II (Comité de Protection des Personnes Est II) according to French law. The trial was monitored by an independent data and safety monitoring board that planned to meet at the beginning of the trial and after the enrollment of 50 patients, 200 patients, and then every 200 patients or at the sponsor’s request. The data and safety monitoring board was informed of all serious adverse events, and data were provided by the safety monitoring team. The steering committee vouches for the completeness and accuracy of the data and for the fidelity of the trial to the protocol.

Patients

Patients were eligible for enrollment if they had undergone intubation and had been receiving mechanical ventilation for less than 12 hours for ARDS (defined according to the Berlin definition),1 with a ratio of Pao 2 to Fio 2 (Pao 2 :Fio 2 ) of 300 mm Hg or less, at a positive end-expiratory pressure (PEEP) of 5 cm of water or more, less than 7 days between a known clinical insult (i.e., lung damage) and new or worsening respiratory symptoms, and if they had bilateral opacities on chest imaging and respiratory failure that was not fully explained by heart failure or fluid overload. The main exclusion criteria were the use of long-term oxygen therapy or noninvasive ventilation at home and cardiac arrest, traumatic brain injury, or cranial hypertension as the reason for hospitalization in the ICU. Further details are available in Section 2a in the Supplementary Appendix, available at NEJM.org.

If patients were unable to provide written informed consent, information was given to their next of kin and patients were included with the use of emergency consent procedures. A definitive post hoc consent was obtained from all the patients. This procedure was accepted by the ethics committee because of the short time window between intubation and inclusion.

Trial Procedures

Randomization was stratified according to center, age (<45 years, 45 to 65 years, or >65 years), and severity of respiratory failure evaluated according to the Pao 2 :Fio 2 (≤150 mm Hg or >150 mm Hg), with a PEEP of 5 cm of water and a Fio 2 of 60 to 100%. Computer randomization was performed in blocks of four. This was an open-label trial because of the impossibility of masking treatment assignments with the use of Spo 2 and Pao 2 monitoring in the ICU.

Patients were assigned to either the liberal-oxygen group (Pao 2 target between 90 and 105 mm Hg) or the conservative-oxygen group (Pao 2 target between 55 and 70 mm Hg) over the first 7 days of invasive mechanical ventilation or until extubation, if the latter was performed earlier. During the 6-hour interval between the two measurements of levels of arterial blood gases, the Spo 2 was maintained at a level of at least 96% in the liberal-oxygen group and between 88 and 92% in the conservative-oxygen group. If the Pao 2 was not within the predefined range according to the levels of arterial blood gases, the Fio 2 was modified by 0.05 (absolute value) if the difference from the assigned target was less than 5 mm Hg and by 0.10 if the difference was greater. When the level of arterial blood gases was measured, the pulse oximetry was compared with the arterial oxygen saturation (Sao 2 ) to adapt Spo 2 monitoring. During the 6-hour interval between the two measurements of levels of arterial blood gases, the Fio 2 was modified by 0.05 (absolute value) every 5 minutes until the desired Spo 2 target was reached.

In the case of an intervention such as fibroscopy or patient transport for imaging or to the operating room, oxygenation was managed at the discretion of the clinician. We recommended following the protocol as far as possible and returning to the protocol as soon as possible. No transient elevation in the Fio 2 was systematically performed during tracheal suctioning.

Ventilation and Weaning Protocol

The volume assist–control mode of ventilation was recommended, with a tidal volume of 6 ml per kilogram of predicted body weight (Section 2b in the Supplementary Appendix). The PEEP was adjusted according to the Pao 2 :Fio 2 . If the Pao 2 :Fio 2 was between 200 and 300 mm Hg, the PEEP was set to between 5 and 10 cm of water. If the Pao 2 :Fio 2 was less than 200 mm Hg, the PEEP was set at the maximal value to reach a plateau pressure of 28 to 30 cm of water after setting a tidal volume at 6 ml per kilogram of predicted body weight. The PEEP was adjusted to between 5 and 10 cm of water if the Pao 2 :FiO 2 remained at 200 mm Hg or higher for 12 hours.6

Neuromuscular blocking agents were recommended for 48 hours in patients with a Pao 2 :Fio 2 of less than 150 mm Hg.7 Prone positioning was recommended in patients with a Pao 2 :Fio 2 of less than 150 mm Hg.8

Trial Outcomes

The primary outcome was death from any cause at 28 days after randomization among the patients, including those for whom care was limited or withdrawn. Secondary outcomes were death in the ICU and at day 90; the Sequential Organ Failure Assessment score (which ranges from 0 to 20, with higher scores indicating more severe organ failure) calculated without the respiratory component at days 0, 3, and 7 (Section 2c in the Supplementary Appendix); ventilator-associated pneumonia during the first 28 days; and septicemia during the first 28 days.

Additional secondary outcomes were cardiovascular complications, defined as new-onset arrhythmia or a cardiac ischemic event and the use of vasopressors (recorded every morning) over the first 7 days. In addition, respiratory weaning success was determined at days 28 and 90, and neurologic status was measured according to the daily Richmond Agitation and Sedation Scale (scores range from 4 [combative] to −5 [unresponsive], with a score of 0 indicating that the patient is alert and calm). Other secondary outcomes were seizures, new cerebral stroke on imaging, administration of neuroleptics, and delirium.

Statistical Analysis

We performed a power calculation with the published results of two available prospective trials on oxygen targets in ICU populations.9,10 The estimated percentage difference was derived from the odds ratio of 0.62 in the reduction in the risk of death observed with a conservative-oxygenation strategy in the CLOSE (Conservative versus Liberal Oxygenation Targets for Mechanically Ventilated Patients) trial9 and the OXYGEN-ICU (Effect of Conservative versus Conventional Oxygen Therapy on Mortality among Patients in an Intensive Care Unit) trial.10 We determined that the inclusion of 850 patients would provide a power of 90% to show an absolute between-group difference of 9 percentage points in the primary outcome, assuming a death rate of 30% at day 28 in the liberal-oxygen group, a one-sided test, and a significance level of 0.05.

A total of 833 days after the enrollment of the first patient, when 205 patients had been enrolled, the data and safety monitoring board decided to stop the trial because of the potential increased risk of serious adverse events and futility. Follow-up by the research team was completed for 149 patients and external auditing of the data by independent reviewers was completed for 56 patients at that time. Contrary to the initial plan to perform an interim analysis after 425 patients had been enrolled, no interim analysis was conducted because the trial was stopped prematurely, and two-sided tests were performed in the final statistical analysis.

Categorical variables are reported as numbers and percentages, and quantitative variables as means and standard deviations or medians and interquartile ranges. Results in the two groups and the differences between the two groups with respect to the primary and secondary outcomes are presented with 95% confidence intervals that have not been adjusted for multiple comparisons. For explanatory purposes, multilevel linear or logistic models were designed to investigate the relationship between the treatment groups and repeated measurements of biologic, physiological, and ventilation variables. A two-level hierarchical structure (patients and measurements [longitudinal approach]) was considered for analysis. This allowed us to estimate a time-adjusted difference or time-adjusted odds ratio between the two groups on repeated measurements. A complementary analysis regarding mortality was conducted at 28 days, 90 days, and in the ICU with the use of a Cox model. Both models were adjusted for age, Pao 2 :Fio 2 , and Simplified Acute Physiology Score (SAPS) III.

Analyses were performed in the intention-to-treat population, defined as all patients who underwent randomization except those who did not provide consent, those for whom the family declined inclusion, and those who did not meet the inclusion criteria as defined in the protocol. All analyses were performed with the use of SAS software, version 9.3 (SAS Institute), and MLwiN software, version 3.02 (Centre for Multilevel Modeling, University of Bristol, United Kingdom).