Mar 162013

(image: Wikipedia)
High-Frequency Oscillatory Ventilation (HFOV) for ARDS
Two Randomized Trials: Early HFOV Doesn't Help, May Harm

High-frequency oscillatory ventilation (HFOV) has been proposed as a first-line therapy for acute respiratory distress syndrome (ARDS). By delivering 3-15 breaths per second of tiny tidal volumes (~70 mL), HFOV has appeal as the "ultimate" lung protective ventilator mode. Trials for HFOV in ARDS have been inconclusive due to their small size and/or lack of appropriate control arms, but didn't show any clear harm. This week, there is clear evidence that HFOV is not superior to conventional low-tidal volume ventilation for ARDS, and may be quite harmful -- this according to 2 large randomized trials published in the New England Journal of Medicine, just in time for the Society of Critical Care Medicine 2013 meeting.

What They Did

Niall Ferguson et al (OSCILLATE trial) randomized 548 people at 39 centers in 5 countries (including the U.S. and Canada) with ARDS to either HFOV or conventional low-tidal volume ventilation. In-hospital mortality was the primary outcome.

Meanwhile, Duncan Young et al (OSCAR trial) randomized 795 people with ARDS at 13 U.K. centers to receive HFOV or low-tidal volume ventilation. Primary outcome was 30-day mortality of any cause.
What They Found

In OSCILLATE, 47% in the HFOV group died in-hospital, vs. 35% receiving conventional low-tidal volume ventilation (RR for death with HFOV of 1.33 [1.09 - 1.64; p=0.005]). The trial was stopped for harm at this point, far short of its planned 1,200 patient enrollment, when statistical analyses showed a near impossibility of equivalence or benefit from HFOV. As if that weren't enough,

  • Those in the HFOV arm also required more sedatives (8 mg/hr of midazolam vs 6 mg/hr);
  • More patients in the HFOV group received paralytic agents (83% vs. 68%);
  • More receiving HFOV required vasopressors or other vasoactive drugs (91% vs. 84%, p=0.01) and for longer: 5 days vs. 3 days (p=0.01).

By contrast, Duncan et al (OSCAR trial) found an identical ~41% 30-day mortality in both groups. After covariate adjustment, the odds ratio for survival in the conventional low-tidal volume group was 1.03 (p=0.87). Again in OSCAR, patients receiving high-frequency oscillatory ventilation required higher doses of sedatives and greater use of neuromuscular blocking agents compared to patients receiving conventional ventilation, as in OSCILLATE.

What It Means

High-frequency oscillatory ventilation (HFOV) has always had intuitive appeal as the ultimate lung-protective strategy for mechanical ventilation in ARDS, but as the lengthening history of randomized trials in critical care (and medicine in general) shows, theoretical benefits are all too often simply that: theoretical. This double-barrel blast of well-conducted clinical trials will in all likelihood end the use of "the oscillator" as a first-line method of mechanical ventilation for ARDS.

But why the divergent results between the groups? Relying on OSCILLATE alone, use of HFOV as first-line ARDS treatment appears tantamount to malpractice, while examining OSCAR alone leaves the door open just a crack for using high-frequency oscillatory ventilation ... not to mention endless rounds of re-analysis and additional clinical trials. Ask the real academics to explain this better than I, but here are some possibilities:

Better adherence with low-tidal volume ventilation in OSCILLATE compared to OSCAR? It's worth considering, since ventilator settings are known to change mysteriously overnight, and even top academic centers adhere to low tidal volumes less than half the time (outside of clinical trials).

Subtle differences in the use of HFOV between the trials? Seemingly minor protocol differences could have resulted in systematically different variables: either under-distension of alveoli in OSCILLATE relative to OSCAR, resulting in inadequate ventilation with a greater need for sedation, paralysis and vasopressors; or overdistension relative to OSCAR,  causing alveolar trauma with worsened outcomes relative to the control group.

There's nothing I see in the described design or the results to suggest this. But because HFOV relies on multiple chaos-prone physical phenomena (e.g. "pendelluft") to achieve alveolar inflation, and actual local alveolar tidal volumes during HFOV have been shown to be significantly higher than expected, it's conceivable that small protocol differences could have resulted in physiologically significant differences in effects.

Other unmeasured differences in patients, or in the care between the trials. Although it's easy to invoke this black box to explain differences between trial outcomes, it's always a possibility, especially in these multicenter trials conducted in different countries with different demographics and health care systems (OSCAR mainly in the U.K, OSCILLATE mostly in Canada and the U.S.).

takeawayClinical Takeaway: Sometimes it's good to be conventional. Stick with low-tidal volume mechanical ventilation as first-line treatment for ARDS. High-frequency oscillatory ventilation remains a defensible option as a rescue mode for those who cannot be oxygenated or ventilated using conventional mechanical ventilation. And that chugga-chugga-chugga sound will continue to set nerves on edge throughout the ICU.

Duncan Young et al. High-Frequency Oscillation for Acute Respiratory Distress Syndrome. OSCAR Trial. NEJM 2013; DOI: 10.1056/NEJMoa1215716 (January 22, 2013 online)

Niall Ferguson et al. High-Frequency Oscillation in Early Acute Respiratory Distress Syndrome. OSCILLATE Trial. NEJM January 22 2013.

NEJM Editorial by Atul Malhotra and Jeffrey Drazen

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High frequency oscillation ventilation fails as 1st-line treatment for ARDS (RCTs)