High-Frequency Oscillatory Ventilation for Acute Respiratory Distress Syndrome in Adults A Randomized, Controlled Trial Stephen Derdak, Sangeeta Mehta, Thomas E. Stewart, Terry Smith, Mark Rogers, Timothy G. Buchman, Brian Carlin, Stuart Lowson, John Granton, and the Multicenter Oscillatory Ventilation for Acute Respiratory Distress Syndrome Trial (MOAT) Study Investigators Pulmonary/Critical Care Medicine, Wilford Hall Medical Center, San Antonio, Texas; Departments of Medicine, Anaesthesia, Critical Care Medicine, and Trauma, Mt. Sinai Hospital, Sunnybrook and Women’s College Health Sciences Center, and University Health Network, University of Toronto, Toronto, Ontario, Canada; Departments of Critical Care Medicine and Respiratory Care, Loma Linda University Medical Center, Loma Linda, California; Division of Surgery, Barnes Jewish Hospital, St. Louis, Missouri; Department of Pulmonary/Critical Care Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania; and Departments of Anesthesia and Critical Care Medicine, University of Virginia Medical Center, Charlottesville, Virginia Observational studies of high-frequency oscillatory ventilation in tients with the acute respiratory distress syndrome (ARDS) adults with the acute respiratory distress syndrome have demon- (1–3). To avoid ventilator-induced lung injury, current recom- strated improvements in oxygenation. We designed a multicenter, mendations focus on the avoidance of both alveolar overdis- randomized, controlled trial comparing the safety and effective- tension and cyclic alveolar collapse and re-expansion, as well ness of high-frequency oscillatory ventilation with conventional as achieving and maintaining alveolar recruitment (4–6). A re- ventilation in adults with acute respiratory distress syndrome; 148 cently published trial by the National Institutes of Health adults with acute respiratory distress syndrome (Pa /fraction of O2 ARDS Network comparing a “lung protective” strategy of р inspired oxygen 200 mm Hg on 10 or more cm H2O positive lower tidal volumes (6 ml/kg) and plateau pressures (less than end-expiratory pressure) were randomized to high-frequency os- 30 cm H O) with a higher tidal volume strategy found an abso- cillatory ventilation (n ϭ 75) or conventional ventilation (n ϭ 73). 2 lute mortality reduction of 9% (7). This trial primarily tar- Applied mean airway pressure was significantly higher in the high- geted the avoidance of lung overdistension. frequency oscillation group compared with the conventional ven- tilation group throughout the first 72 hours (p ϭ 0.0001). The High-frequency oscillatory ventilation (HFOV) is a method high-frequency oscillation group showed early (less than 16 of ventilation that theoretically achieves all of the goals of lung protective ventilation (6, 8). HFOV oscillates the lung hours) improvement in PaO2/fraction of inspired oxygen com- pared with the conventional ventilation group (p ϭ 0.008); how- around a constant mean airway pressure (mPaw) that is higher ever, this difference did not persist beyond 24 hours. Oxygenation than that usually applied during conventional ventilation (CV). index decreased similarly over the first 72 hours in both groups. Although the oscillations may cause significant pressure swings Thirty-day mortality was 37% in the high-frequency oscillation in the endotracheal tube, the pressure fluctuations are signifi- group and was 52% in the conventional ventilation group (p ϭ cantly attenuated at the alveolar level (9–12). Distal attenua- 0.102). The percentage of patients alive without mechanical venti- tion of pressure swings depends on multiple variables, includ- lation at Day 30 was 36% and 31% in the high-frequency oscilla- ing endotracheal tube diameter, respiratory frequency, inspiratory tion and conventional ventilation groups, respectively (p ϭ 0.686). time, lung compliance, and lung region (e.g., middle versus up- There were no significant differences in hemodynamic variables, per lobe). Application of a constant mPaw during HFOV al- oxygenation failure, ventilation failure, barotraumas, or mucus lows maintenance of alveolar recruitment while avoiding low plugging between treatment groups. We conclude that high-fre- end-expiratory pressure and high peak pressures. The mecha- quency oscillation is a safe and effective mode of ventilation for nisms of gas exchange during HFOV have previously been de- the treatment of acute respiratory distress syndrome in adults. scribed (13, 14). Keywords: acute respiratory distress syndrome; high-frequency ventila- In premature primates and surfactant-deficient adult rab- tion; high-frequency oscillation; mechanical ventilation; oxygenation index bits, the use of HFOV is associated with improved gas ex- change, more uniform lung inflation, and reduced histopatho- Mechanical ventilation may lead to further lung injury and logic evidence of ventilator-induced lung injury (15–17). may contribute to the systemic inflammatory response in pa- Additionally, HFOV has been demonstrated to reduce levels of inflammatory mediators when compared with CV tech- niques applying similar mPaw values (18–20). In view of the encouraging findings with HFOV in animal models, numerous (Received in original form August 13, 2001; accepted in final form May 9, 2002) randomized clinical trials have been undertaken in neonatal Supported in part by SensorMedics Corporation, which also provided use of the and pediatric patients (21–24). None of these trials have 3100B high-frequency oscillatory ventilators, and the Zachary and Elizabeth Fisher Foundation Joint Chiefs of Staff Grant Award (S.D.). shown a significant improvement in mortality. However, some The views expressed in this article are those of the authors and do not represent of these studies have shown that HFOV, using a volume re- the official policy of the United States Department of Defense or other Depart- cruitment strategy, results in significant improvements in oxy- ments of the United States Government. None of the study investigators have a genation without increasing barotrauma. financial interest in SensorMedics Corporation. Published experience with HFOV in adults is limited to ob- Correspondence and requests for reprints should be addressed to Stephen Der- servational studies and case reports evaluating its use in pa- dak, D.O., Col. U.S.A.F. M.C., Wilford Hall Medical Center, Pulmonary/Critical tients failing CV (25–30). These studies report significant im- Care Medicine (MCCP), Lackland AFB, TX 78236. E-mail: [email protected] provements in oxygenation using an open lung strategy, and a Am J Respir Crit Care Med Vol 166. pp 801–808, 2002 DOI: 10.1164/rccm.2108052 suggestion of better outcome when HFOV is applied early in Internet address: www.atsjournals.org the course of ARDS. 802 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 166 2002 TABLE 1. SUMMARY OF VENTILATOR STRATEGIES CV HFOV Initial VT (ml/kg)* 6–10 – Initial RR (breaths/min or Hz) Adjust for pH Ͼ 7.15 (max 35) 5 Hz † у Initial PEEP (cm H2O) 10 – ϩ Initial mPaw (cm H2O) – CV 5 Initial ⌬P – Adequate chest wall vibration Initial percentage inspiratory time 33% 33% Ventilation ↑ RR (max 35) ↑ ⌬P ↑ VT (max 10 ml/kg) ↓ Hz (min 3) Cuff leak ↑ ↑ Oxygenation PEEP (18 cm H2O) mPaw (max 45 cm H2O) ↑ FI ↑ FI O2 O2 ↑ % I time (max 66%) Weaning ↓ FI р 0.50 ↓ FI р 0.50 O2 O2 ↓ ↓ р I:E ratio mPaw 24 cm H2O ↓ PEEP Switch to CV Convert to PS wean Breathing trials Definition of abbreviations: CV ϭ conventional ventilation; FI ϭ fraction of inspired oxygen; HFOV ϭ high-frequency oscillatory ventila- O2 tion; I:E ϭ inspiratory:expiratory; mPaw ϭ mean airway pressure; ⌬P ϭ proximal airway pressure amplitude of oscillation; PEEP ϭ positive end-expiratory pressure; PS ϭ pressure support ventilation; RR ϭ respiratory rate in breaths/min or in Hz; VT ϭ tidal volume. * The tidal volume is based on actual body weight. † A minimum PEEP of 18 cm H2O was required before increasing the inspiratory time. We designed a randomized, controlled trial comparing (or if available, pulmonary artery occlusion pressure of 18 mm Hg or HFOV with a CV strategy in adult patients with early-phase less). Patients were excluded if they weighed less than 35 kg, had se- ARDS. The specific aim of this trial was to demonstrate the vere chronic obstructive pulmonary disease or asthma, intractable shock, safety and effectiveness of high-frequency oscillatory ventila- severe airleak (i.e., more than one chest tube per hemithorax with a tion and to determine whether it was comparable to CV for persistent airleak of more than 120 hours), a nonpulmonary terminal diagnosis with an estimated 6-month mortality of more than 50%, and the treatment of ARDS in an adult population. an FIO2 of more than 0.80 for more than 48 hours, or had participated in other investigational trials for ARDS or septic shock within 30 days. METHODS Ventilator Strategies Patients Ventilator strategies used are summarized in Table 1. The physiologic Patients were recruited from October 1997 through December 2000 in targets for the two ventilator treatment arms were similar. The oxy- 13 university-affiliated medical centers (APPENDIX). The institutional genation goal was an O saturation of 88% or more on FI р 0.60 review board at each hospital approved the protocol. Surrogate in- 2 O2 with maintenance of mPaw in the HFOV group or PEEP in the CV formed consent was obtained for all patients. group until FI could be reduced to 0.60 or less. The target Pa was Patients 16 years of age or more who were mechanically ventilated O2 CO2 between 40–70 mm Hg, although a higher Pa was tolerated, provid- were eligible if they met the following criteria for ARDS: Pa /fraction CO2 O2 ing that the pH was more than 7.15. Bicarbonate therapy could be em- of inspired oxygen (FI ) ratio р 200 mm Hg while on positive end- O2 ployed for severe respiratory acidosis (pH less than 7.15). Attending expiratory pressure (PEEP) у 10 cm H O, bilateral radiographic pul- 2 physicians oversaw ventilator management and were consulted about monary infiltrates, and no clinical evidence of left atrial hypertension major decisions on a 24-hour basis.