ICU-ROX: Conservative vs. Liberal Oxygen in Mechanical Ventilation (2019)

“Among adults undergoing mechanical ventilation in the ICU, conservative oxygen therapy, as compared with usual oxygen therapy, did not significantly affect the number of ventilator-free days.”

  • The ICU-ROX Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group

1. Publication Details

  • Trial Title: Conservative versus Liberal Oxygenation Targets for Critically Ill Adults
  • Citation: The ICU-ROX Investigators and the ANZICS Clinical Trials Group. Conservative versus Liberal Oxygenation Targets for Critically Ill Adults. N Engl J Med. 2019;382(11):991-1001. DOI: 10.1056/NEJMoa1903297
  • Published: March 14, 2020, in The New England Journal of Medicine
  • Author: The ICU-ROX Investigators
  • Funding: Health Research Council of New Zealand; and others.

2. Keywords

  • Critical Care, Mechanical Ventilation, Oxygen Therapy, Hyperoxia, Hypoxia, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients in the ICU who are expected to require mechanical ventilation beyond the day of recruitment (Population), does a conservative oxygen therapy strategy (Intervention) compared to a liberal (usual care) oxygen therapy strategy (Comparison) increase the number of ventilator-free days at day 28 (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Both hypoxemia and hyperoxemia are associated with harm in critically ill patients. While supplemental oxygen is life-saving, excessive oxygen (hyperoxia) can cause lung injury and oxidative stress. Previous smaller trials had suggested that a more conservative approach to oxygen therapy might be beneficial, but the evidence was not definitive.
  • Knowledge Gap: A large, pragmatic randomized trial was needed to determine if a conservative oxygen strategy was superior to usual care in a broad population of mechanically ventilated ICU patients.
  • Proposed Hypothesis: The authors hypothesized that a conservative oxygen therapy strategy would be superior to a liberal oxygen strategy in increasing the number of ventilator-free days.

5. Study Design and Methods

  • Design: A multicenter, pragmatic, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 21 intensive care units (ICUs) in Australia and New Zealand.
  • Trial Period: Enrollment ran from September 2015 to May 2018.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU who were receiving mechanical ventilation and were expected to continue for at least the next calendar day.
    • Exclusion Criteria: Included patients with carbon monoxide poisoning, those who were moribund, and those already enrolled in a conflicting trial.
  • Intervention: A conservative oxygen therapy strategy, where the FiO2 was titrated down to 0.21 as long as the arterial oxygen saturation (SpO2) was maintained at 90-96%. The primary goal was to accept the lowest possible SpO2 within this range.
  • Control: A liberal (usual care) oxygen therapy strategy, where there were no specific limits on oxygen administration. Clinicians were free to target any SpO2 ≥90%.
  • Management Common to Both Groups: All other aspects of ICU care, including ventilation strategies and sedation, were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 1000 patients would provide 90% power to detect a 2.5-day difference in ventilator-free days. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: The number of ventilator-free days at day 28.
    • Secondary Outcomes: Included 90-day and 180-day mortality, and the incidence of new organ dysfunction.

6. Key Results

  • Enrollment and Baseline: 1000 patients were randomized (501 to the conservative group and 499 to the liberal group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary outcome. The median number of ventilator-free days was 21.3 in the conservative-oxygen group and 22.1 in the liberal-oxygen group (p=0.47).
  • Secondary Outcomes: There were no significant differences between the groups in 90-day or 180-day mortality.
  • Adverse Events: The incidence of mesenteric ischemia was slightly higher in the conservative-oxygen group, but the overall incidence of serious adverse events was similar in both groups.

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 Wilcoxon rank-sum test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the median number of ventilator-free days between the two groups.
  • Key Statistic(s) Reported: The key statistics were the median values for the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.47 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: In a pre-specified subgroup analysis of patients with suspected hypoxic-ischemic encephalopathy (HIE), conservative oxygen therapy was associated with a significant increase in mortality.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized controlled design provided high-quality evidence on a fundamental aspect of ICU care.
  • Generalizability: The pragmatic design and inclusion of a broad population of ICU patients make the findings highly generalizable to real-world practice in similar healthcare systems.
  • Statistical Power: The study was large and adequately powered to detect a clinically meaningful difference if one existed.
  • Patient-Centered Outcomes: The primary outcome of ventilator-free days is a robust and patient-centered composite outcome.

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 Australia and New Zealand, where the “usual care” for oxygen therapy was already quite conservative, which may have reduced the separation between the groups and diluted the potential effect of the intervention.
  • Other: The signal of harm in the HIE subgroup is a major finding but must be interpreted with caution as it is a subgroup analysis.

10. Conclusion of the Authors

  • The authors concluded that among adult patients undergoing mechanical ventilation in the ICU, a conservative oxygen therapy strategy did not significantly affect the number of ventilator-free days as compared with a liberal oxygen therapy strategy.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provided strong evidence that a routine, protocolized conservative oxygen strategy is not superior to usual care in a general population of mechanically ventilated ICU patients.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients requiring mechanical ventilation.
    • Actionable Intervention: The results suggest that either a conservative or a liberal (but not hyperoxemic) oxygen strategy is an acceptable approach.
  • What This Trial Does NOT Mean: This trial does NOT mean that hyperoxia is safe. It only suggests that in this population, a conservative strategy was not superior to a usual care strategy that already avoided extreme hyperoxia.
  • Implementation Caveats: The key takeaway is the importance of avoiding both hypoxemia and significant hyperoxemia. The signal of harm in patients with HIE suggests that a conservative oxygen strategy should be avoided in this specific population.

12. Context and Related Studies

  • Building on Previous Evidence: The ICU-ROX trial (2019) was one of the first large, multicenter RCTs to address the question of optimal oxygen targets in a general ICU population.
  • Influence on Subsequent Research: The neutral findings of this trial, along with the subsequent, larger HOT-ICU (2021) and UK-ROX (2023) trials, have been highly influential. Together, this “trilogy” of large oxygen trials has provided a consistent message that a one-size-fits-all conservative oxygen strategy is not beneficial for most ICU patients.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether there are specific subgroups of patients (beyond HIE) who might be harmed or helped by a more conservative oxygen strategy.
  • Future Directions: Future research is focused on identifying the optimal oxygen targets for specific disease states, such as ARDS, sepsis, and cardiac arrest.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and fundamental aspect of ICU care.
  • Methods: The large, multicenter, pragmatic RCT design was appropriate and robust. The main methodological weakness is the open-label design. A key point for interpretation is that the “usual care” arm was already quite conservative, which may have made it difficult to show a benefit for the intervention.
  • Results: The study reported a clear neutral finding for its primary outcome, with a narrow confidence interval centered on the null value. The finding of potential harm in the HIE subgroup is a critical safety signal.
  • 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 trial, along with its successors, provides strong evidence that a one-size-fits-all approach to conservative oxygenation is not beneficial and that the focus should be on avoiding the extremes of both hypoxia and hyperoxia.

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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