OSCILLATE: High-Frequency Oscillation in ARDS (2013)

“In this trial of patients with moderate-to-severe ARDS, early application of HFOV, as compared with a conventional-ventilation strategy that included high PEEP and recruitment maneuvers, did not reduce, and may have increased, in-hospital mortality.”

  • The OSCILLATE Trial Investigators

1. Publication Details

  • Trial Title: High-Frequency Oscillation in Early Acute Respiratory Distress Syndrome
  • Citation: Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med. 2013;368(9):795-805. DOI: 10.1056/NEJMoa1215554
  • Published: February 28, 2013, in The New England Journal of Medicine
  • Author: Niall D. Ferguson, M.D., M.Sc.
  • Funding: The Canadian Institutes of Health Research.

2. Keywords

  • ARDS, Acute Respiratory Distress Syndrome, High-Frequency Oscillatory Ventilation (HFOV), Mechanical Ventilation, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with moderate to severe ARDS (Population), does a strategy of early high-frequency oscillatory ventilation (HFOV) (Intervention) compared to a strategy of standard, conventional mechanical ventilation with lung recruitment maneuvers (Comparison) reduce in-hospital mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: High-frequency oscillatory ventilation (HFOV) is a mode of ventilation that uses very small tidal volumes at very high frequencies. It was hypothesized to be a “super” lung-protective strategy that could maintain lung recruitment and prevent ventilator-induced lung injury even more effectively than standard low-tidal-volume ventilation.
  • Knowledge Gap: Despite its physiological appeal and use in some centers as a rescue therapy, there was no high-quality evidence from a large, pragmatic randomized trial to determine if HFOV was superior to a modern, protocolized conventional ventilation strategy that also included aggressive lung recruitment.
  • Proposed Hypothesis: The authors hypothesized that a strategy of early HFOV would be superior to a high-quality conventional ventilation strategy in reducing in-hospital mortality in patients with moderate to severe ARDS.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 39 intensive care units (ICUs) in 5 countries (Canada, USA, Saudi Arabia, Chile, and India).
  • Trial Period: Enrollment ran from September 2009 to August 2012.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with moderate to severe ARDS (PaO2:FiO2 ratio ≤ 200 mm Hg on a PEEP of ≥5 cm H2O) who had been mechanically ventilated for less than 72 hours.
    • Exclusion Criteria: Included contraindications to HFOV (e.g., severe obstructive airway disease, high intracranial pressure) and patients for whom death was deemed imminent.
  • Intervention: Patients were randomized to receive high-frequency oscillatory ventilation (HFOV) according to a standardized protocol.
  • Control: Patients were randomized to receive ongoing conventional mechanical ventilation according to a standardized, best-practice protocol that included low tidal volumes, high PEEP, and lung recruitment maneuvers.
  • Management Common to Both Groups: Both groups were managed with a lung-protective strategy. The control group protocol was detailed and represented a very high standard of care.
  • Power and Sample Size: The authors calculated that a sample size of 1100 patients would provide 80% power to detect a 7% absolute risk reduction in in-hospital mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: All-cause in-hospital mortality.
    • Secondary Outcomes: Included duration of ventilation, length of ICU stay, and cause of death.

6. Key Results

  • Enrollment and Baseline: 548 patients were randomized (273 to HFOV and 275 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data monitoring committee after an interim analysis showed a significantly higher mortality rate in the HFOV group.
  • Primary Outcome: In-hospital mortality was significantly higher in the HFOV group: 123 of 273 patients (47%) in the HFOV group died, compared with 99 of 275 patients (35%) in the conventional-ventilation group (p=0.005).
  • Secondary Outcomes: Patients in the HFOV group required vasopressors for a longer duration and received higher doses.
  • Adverse Events: The primary adverse event was death, which was more common in the HFOV group.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for in-hospital death: 1.33 (95% CI, 1.09 to 1.64; P-value: 0.005).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the result as 1.33.
      • Clinical Meaning: The RR of 1.33 means that patients in the HFOV group had a 33% higher relative risk of dying in the hospital compared to the conventional-ventilation group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 1.09 to 1.64.
      • Clinical Meaning: Since this entire range is above the line of no effect (1.0), it confirms that the result is statistically significant and demonstrates a clear signal of harm.
    • P-value: The p-value of 0.005 is well below the 0.05 threshold, indicating the result is statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Increase (ARI):
      • Formula: ARI = (Risk in Intervention Group) – (Risk in Control Group)
      • Calculation: ARI = 47% – 35% = 12%.
      • Clinical Meaning: For every 100 patients with ARDS treated with HFOV, about 12 additional deaths occurred.
    • Number Needed to Harm (NNH):
      • Formula: NNH = 1 / ARI
      • Calculation: NNH = 1 / 0.12 = 8.3, which is rounded down to 8.
      • Clinical Meaning: You would only need to treat 8 patients with HFOV instead of conventional ventilation to cause one additional death.
  • Subgroup Analyses: The finding of harm was consistent across all pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on an important clinical question.
  • Generalizability: The inclusion of 39 diverse ICUs across five countries increases the applicability of the findings.
  • Statistical Power: Although stopped early, the trial was large enough to detect a clear and significant signal of harm.
  • Patient-Centered Outcomes: The primary outcome of in-hospital mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The study was conducted in a system where clinicians may have had variable experience with HFOV, which could have affected the results.
  • Other: The trial was stopped early for harm, which was ethically necessary.

10. Conclusion of the Authors

  • The authors concluded that in adults with moderate-to-severe ARDS, a strategy of early HFOV does not reduce, and may increase, in-hospital mortality.

11. To Summarize

  • Impact on Current Practice: This was a major practice-changing trial. Its definitive finding of harm, combined with the neutral result of the concurrent OSCAR trial, effectively ended the routine use of HFOV as a primary ventilation strategy for ARDS.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients with moderate to severe ARDS.
    • Actionable Intervention: Do not use HFOV as a routine, first-line ventilation strategy.
  • What This Trial Does NOT Mean: This trial does NOT mean that HFOV has absolutely no role in the ICU. It may still be considered as a rescue therapy in highly selected patients who are failing all other forms of conventional ventilation, but this is not supported by high-level evidence.
  • Implementation Caveats: The key takeaway is that a well-executed, protocol-based conventional lung-protective ventilation strategy is the standard of care, and HFOV is not only not superior but may be harmful.

12. Context and Related Studies

  • Building on Previous Evidence: The OSCILLATE trial (2013) was designed to provide a definitive answer to the question of HFOV’s efficacy, which had been debated for years based on smaller, conflicting studies and physiological theory.
  • Influence on Subsequent Research: The definitive neutral-to-harmful findings of this trial and the concurrent OSCAR trial (2013) were highly influential and led to a rapid de-adoption of HFOV in adults and a major shift in international ARDS guidelines.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear signal of harm.
  • Future Directions: The failure of HFOV to improve outcomes has reinforced the importance of optimizing conventional lung-protective ventilation and has shifted the focus of ARDS research towards other adjunctive therapies, such as prone positioning and neuromuscular blockade.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a complex and expensive technology that was thought to be a promising new standard of care for ARDS.
  • Methods: The multicenter, pragmatic RCT design was appropriate and robust. A key strength is that the control arm represented a very high standard of modern, protocolized ARDS care, making the comparison a fair and relevant test. The main methodological weakness is the open-label design.
  • Results: The study reported a clear and statistically significant increase in harm (NNH of 8) for its primary outcome. This finding was so robust that the trial was stopped early.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. This is a classic example of a high-quality trial that was profoundly practice-changing by providing strong evidence that a more complex and expensive intervention is not only not superior but is actively harmful compared to a well-executed standard of care.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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