Study Oversight

For the pilot phase of the study, we enrolled patients at 11 centers in Canada and 1 in Saudi Arabia from July 2007 through June 2008; for the main trial, we enrolled patients at the same centers and at an additional 27 centers in Canada, the United States, Saudi Arabia, Chile, and India from July 2009 through August 2012 (see the Supplementary Appendix, available with the full text of this article at NEJM.org). The trial protocol, which is available at NEJM.org, was approved by the research ethics board at each participating site. The first and last author vouch for the accuracy and completeness of the reported data and for the fidelity of this report to the study protocol. For HFOV, we used the SensorMedics 3100B High-Frequency Oscillatory Ventilator (CareFusion); the manufacturer loaned nine ventilators and provided technical support but had no role in the design of the study, the collection or analysis of the data, or the preparation of the manuscript.

Patients

Patients were eligible for inclusion if they had had an onset of pulmonary symptoms within the previous 2 weeks, had undergone tracheal intubation, had hypoxemia (defined as a ratio of the partial pressure of arterial oxygen [PaO 2 ] to the fraction of inspired oxygen [FiO 2 ] of ≤200, with an FiO 2 of ≥0.5), and had bilateral air-space opacities on chest radiography. Patients were excluded if they had hypoxemia primarily related to left atrial hypertension, suspected vasculitic pulmonary hemorrhage, neuromuscular disorders that are known to prolong the need for mechanical ventilation, severe chronic respiratory disease, or preexisting conditions with an expected 6-month mortality exceeding 50%; if they were at risk for intracranial hypertension; if there was a lack of commitment to life support; if the expected duration of mechanical ventilation was less than 48 hours; if they were younger than 16 years of age or older than 85 years of age; or if their weight was less than 35 kg or more than 1 kg per centimeter of height. We did not enroll patients who had already met the eligibility criteria for more than 72 hours, those who were already receiving HFOV, or those whose physicians declined to enroll them.

After enrollment, standardized ventilator settings were used for all the patients: pressure-control mode, a tidal volume of 6 ml per kilogram, and an FiO 2 of 0.60 with a PEEP level of 10 cm of water or higher if needed for oxygenation. After 30 minutes, if the PaO 2 :FiO 2 ratio remained at 200 or lower, patients underwent randomization; otherwise the standardized ventilator settings were maintained, and the patients were reassessed at least once daily for up to 72 hours. Eligible patients were randomly assigned in a 1:1 ratio to the HFOV group or to the conventional-ventilation group. Randomization was performed in undisclosed block sizes of 2 and 4 with the use of a central Web-based randomization system, stratified according to center. All patients or their legal surrogates provided written informed consent for participation in the study.

HFOV Protocol

Table 1. Table 1. Ventilator Protocols.

Table 2. Table 2. Usual Combinations of the Fraction of Inspired Oxygen (FiO 2 ) and Positive End-Expiratory Pressure (PEEP) or Mean Airway Pressure Used to Adjust Ventilators.

The HFOV protocol was designed on the basis of the results of pilot testing and consensus guidelines.24,27 We first conducted a recruitment maneuver, by applying 40 cm of water pressure for 40 seconds to the airway opening in an effort to reopen closed lung units. We then initiated HFOV with a mean airway pressure of 30 cm of water, adjusting the pressure thereafter according to the protocol, targeting a PaO 2 of 55 to 80 mm Hg (Table 1 and Table 2). We minimized HFOV tidal volumes by using the highest possible frequency that would maintain arterial blood pH above 7.25.13,28

After 24 hours of HFOV, conventional ventilation could be resumed if the mean airway pressure was 24 cm of water or less for 12 hours. This transition was mandatory when airway pressures reached 20 cm of water. Thereafter, mechanical ventilation followed the control protocol. Over the next 48 hours, if an FiO 2 of more than 0.4 or a PEEP level of more than 14 cm of water was required for more than 1 hour to achieve oxygenation targets, HFOV was resumed.

Control Ventilation Protocol

The control ventilation protocol, which was adapted from an earlier trial,9 called for a target tidal volume of 6 ml per kilogram, with plateau airway pressure of 35 cm of water or less and high levels of PEEP. After an initial recruitment maneuver (the same as that used for the HFOV group), clinicians applied ventilation using pressure-control mode with a PEEP level of 20 cm of water and then adjusted the PEEP level and the FiO 2 according to the protocol (Table 1 and Table 2). The protocol permitted the use of volume-assist control mode or pressure-support mode with the same limits for tidal volumes and airway pressures. For patients receiving pressure support with PEEP levels of 10 cm of water or less and an FiO 2 of 0.4 or less, there were no limits on tidal volume or airway pressures. The weaning protocol, which has been published previously, included daily trials of spontaneous breathing.9,29

Procedures in Both Groups

When hypoxemia persisted despite increases in PEEP or mean airway pressure, or when, on the basis of radiographic or clinical evidence, physicians judged that the lungs were over-distended, they could reduce PEEP or mean airway pressure to a level below that indicated in the assigned protocol (Table 2).

For patients with hypoxemia who required an FiO 2 of 0.9 or greater, clinicians could institute therapies for hypoxemia (e.g., prone positioning or inhaled nitric oxide) that did not interfere with the assigned ventilator protocols. Physicians could institute any alternative therapy (including HFOV in the control group) for patients who met any one of the following criteria: refractory hypoxemia (PaO 2 <60 mm Hg for 1 hour with an FiO 2 of 1.0 and neuromuscular blockade), refractory barotrauma (persistent pneumothorax or increasing subcutaneous emphysema despite two thoracostomy tubes on the involved side), or refractory acidosis (pH of ≤7.05 despite neuromuscular blockade).

Physicians prescribed fluids, sedatives, and neuromuscular blockers at their discretion. We recorded cardiorespiratory variables daily as well as data on cointerventions applied while patients were undergoing mechanical ventilation for up to 60 days. Intensivists reviewed chest radiographs for evidence of new barotrauma. Patients were followed until their discharge from the hospital.

Statistical Analysis

We anticipated that mortality in the control group would be 45%. Assuming a two-sided alpha level of 0.05, we calculated that enrollment of 1200 patients would provide at least 80% power to detect a relative-risk reduction with HFOV of 20%, even if mortality in the control group was as low as 37%.

Investigators reviewed feasibility data from the pilot phase, which involved 94 patients, but remained unaware of the clinical outcomes. The independent data monitoring committee reviewed the clinical outcomes from the pilot phase and recommended that the trial continue to the next phase. As originally planned, data from the patients involved in the pilot phase were included in the current analyses. In addition to an interim analysis after 800 patients had undergone randomization, safety analyses of physiological data at the initiation of the study were planned after 300, 500, and 700 patients had undergone randomization. After reviewing these safety data, the data monitoring committee could request analyses of in-hospital mortality, which they did after both the 300-patient and 500-patient safety analyses. With plans to stop the study early only in response to a strong signal of harm in association with the use of HFOV, we used the O'Brien–Fleming method to calculate alpha spending and generated one-sided P values for considering early stopping after random assignment of 300 patients (P≤0.00001), 500 patients (P≤0.0001), and 700 patients (P≤0.0064).

We used SAS software, version 9.2, for the statistical analyses. We summarized data using means with standard deviations, medians and interquartile ranges, or proportions. Normally distributed data were compared with the use of Student's t-test, nonnormally distributed data with the use of the Wilcoxon rank-sum test, and proportions with the use of the Mantel–Haenszel chi-square test, with stratification according to center. We analyzed data from all patients according to their assigned group.

The primary outcome was in-hospital mortality, with the outcome compared between the two groups stratified according to center. Other than recording whether death occurred as a result of withdrawal of life support, we did not record specific causes of death. As a sensitivity analysis, we used logistic regression to adjust the treatment effect for prespecified baseline variables: age, the Acute Physiology Score component of the Acute Physiology and Chronic Health Evaluation (APACHE) II score,30 the presence or absence of sepsis, and the duration of hospitalization before randomization.9 To compare the two groups with respect to the time to death, we used a survival analysis, in which patients who were discharged alive from the hospital were assumed to be alive at day 60.