By Trushil Shah, MD

Assistant Professor of Medicine, University of Texas Southwestern Medical Center, Dallas

Dr. Shah reports he serves on the speakers bureau for Gilead Sciences.

SYNOPSIS: In this patient-level meta-analysis of four well-known randomized, controlled trials of high-frequency oscillatory ventilation (HFOV) in acute respiratory distress syndrome (ARDS), the authors found that HFOV increases mortality for most patients with ARDS but may improve survival among patients specifically with severe ARDS.

SOURCE: Meade MO, et al. Severity of hypoxemia and effect of high-frequency oscillatory ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 2017;196:727-733.

Theoretically, high-frequency oscillator ventilation (HFOV) is beneficial for lung protection. Meta-analyses of four early randomized, controlled trials (RCTs) comparing HFOV to conventional ventilation showed a survival benefit favoring HFOV.1 However, two large RCTs (OSCAR and OSCILLATE) did not show clear benefit of HFOV over conventional ventilation.2,3 A more recent study-level meta-analysis of 10 RCTs comparing HFOV to conventional ventilation did not show any statistical difference in mortality.4 Moreover, the OSCILLATE trial ended early because of potential harm from HFOV.3 As such, current guidelines recommend against the use of HFOV in the management of ARDS.5 However, this study suggests that HFOV may produce a different effect in a subpopulation of acute respiratory distress syndrome (ARDS) patients.

Meade et al performed an individual patient data meta-analysis to identify subgroups of ARDS patients who are likely to benefit or be harmed from the use of HFOV. They included 1,552 patients from four RCTs (MOAT, EMOAT, OSCAR, and OSCILLATE). Effects of PaO2/FiO2, respiratory system compliance, and body mass index (BMI) were studied in the association of HFOV and 30-day mortality. Out of 1,552 patients, complete data were available for 1,327 patients. The two groups (HFOV vs. conventional ventilation) demonstrated similar baseline characteristics. Lung injury was relatively severe, with a mean PaO2/FiO2 of 114 ± 39 mmHg and an average positive end-expiratory pressure (PEEP) of 12 ± 3 cm H2O. Thirty-day mortality was 40.9% for HFOV vs. 37.6% for conventional ventilation (P = 0.16).

The authors found a statistically significant interaction between baseline PaO2/FiO2 and the effect of HFOV (P = 0.0003), with increasing harm from HFOV at higher values of PaO2/FiO2 and suggestion of possible benefit at lower PaO2/FiO2 levels. The line of best fit crossed an odds ratio (OR) of 1.0 at a PaO2/FiO2 value close to 100 mmHg (95% confidence interval [CI], 64-117), suggesting a benefit of HFOV over conventional ventilation below PaO2/FiO2 of 64 and harm above PaO2/FiO2 of 117. Interaction between respiratory system compliance and BMI and the effect of HFOV on 30-day mortality was not statistically significant. There was weak interaction between the treatment effect and degree of low tidal volume ventilation. For the lowest quartile of tidal volume (< 6.29 mL/kg predicted body weight), the OR for HFOV vs. conventional ventilation was 1.92 (95% CI, 1.18-3.13; P = 0.01), consistent with harm with HFOV over low tidal volume ventilation. The overall rate of barotrauma was 98 in 1,458 patients, and the odds of barotrauma was higher with HFOV (adjusted OR, 1.87; 95% CI, 1.06-3.28; P = 0.03). Contrary to conventional wisdom, survival was better among earlier quartiles of HFOV patients enrolled in each hospital when compared with later patients (P < 0.02), with a clear dose-response relationship. This association was consistent in the three largest trials and was preserved after adjusting for the total number of patients at each hospital and when the analysis was restricted to hospitals enrolling more than 10 patients.

COMMENTARY

Conventional study-level meta-analyses so far have suggested no net benefit and perhaps even harm from HFOV. This meta-analysis suggests that adults with ARDS may be harmed or helped with HFOV, depending on the severity of lung injury as measured by PaO2/FiO2. It shows definite harm of HFOV over conventional mechanical ventilation, especially when low tidal volume ventilation is adhered to in patients with moderate ARDS (PaO2/FiO2 > 117).

This review suggests barotrauma from HFOV as one of the potential reasons for increased harm. Interestingly, this analysis also found increasing harm associated with HFOV as more patients were enrolled in any given hospital. Although it is difficult to draw conclusions, it does refute the role of lack of experience as a cause of increased mortality in HFOV. The meta-analysis shows a possible benefit of HFOV in patients with very severe ARDS (PaO2/FiO2 < 64). However, unmeasured confounding factors could alter this threshold. Notably, the study was underpowered to detect a benefit in severe ARDS, as only 140 patients registered a PaO2/FiO2 < 64 (i.e., adjusted OR was 0.68; 95% CI, 0.3-1.50; P = 0.34). Further studies are needed to confirm the benefit of HFOV over conventional low tidal volume ventilation in severe ARDS patients. HFOV should not be used in patients with mild-moderate ARDS. These patients should be managed with strict low tidal volume ventilation. The role of HFOV in severe ARDS remains debatable.

This analysis suggests further research should be conducted in this subpopulation of patients with very severe ARDS using HFOV as rescue therapy.

REFERENCES

  1. Sud S, et al. High frequency oscillation in patients with acute lung injury and acute respiratory distress syndrome (ARDS): Systematic review and meta-analysis. BMJ 2010 May 18;340:c2327. doi: 10.1136/bmj.c2327.
  2. Young D, et al. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med 2013;368:806-813.
  3. Ferguson ND, et al. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med 2013;368:795-805.
  4. Sud S, et al. High-frequency oscillatory ventilation versus conventional ventilation for acute respiratory distress syndrome. Cochrane Database Syst Rev 2016 Apr 4;4:CD004085. doi: 10.1002/14651858.CD004085.pub4.
  5. Fan E, et al. An official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine clinical practice guideline: Mechanical ventilation in adult patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2017;195:1253-1263.