HOT-ICU: Oxygen Targets in Acute Hypoxemic Respiratory Failure (2021)

“Among adult patients in the ICU with acute hypoxemic respiratory failure, there was no significant difference in 90-day mortality between patients assigned to a lower oxygenation target and those assigned to a higher oxygenation target.”

  • The HOT-ICU Investigators

1. Publication Details

  • Trial Title: Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure
  • Citation: Schjørring OL, Klitgaard TL, Perner A, et al. Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure. N Engl J Med. 2021;384(14):1301-1311. DOI: 10.1056/NEJMoa2032510
  • Published: April 8, 2021, in The New England Journal of Medicine
  • Author: Ole L. Schjørring, M.D., Ph.D.
  • Funding: The Novo Nordisk Foundation and others.

2. Keywords

  • Acute Hypoxemic Respiratory Failure, Oxygen Therapy, Hyperoxia, Hypoxia, Mechanical Ventilation, Randomized Controlled Trial

3. The Clinical Question

  • In adult ICU patients with acute hypoxemic respiratory failure (Population), does a strategy of targeting a lower arterial oxygen level (PaO2 of 60 mm Hg) (Intervention) compared to a strategy of targeting a higher arterial oxygen level (PaO2 of 90 mm Hg) (Comparison) affect 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Supplemental oxygen is a life-saving therapy for hypoxemia, but both insufficient oxygen (hypoxia) and excessive oxygen (hyperoxia) are known to be harmful. Hyperoxia can cause lung injury and oxidative stress. Previous observational studies and smaller trials had suggested that a more conservative approach to oxygen therapy might be beneficial, but the optimal oxygenation target was unknown.
  • Knowledge Gap: There was no high-quality evidence from a large, multicenter randomized trial to define the optimal PaO2 target for critically ill patients. It was unknown if a lower, more restrictive target would be superior to a higher, more liberal target.
  • Proposed Hypothesis: The authors hypothesized that targeting a lower PaO2 would be superior to targeting a higher PaO2 in reducing 90-day mortality.

5. Study Design and Methods

  • Design: A multicenter, stratified, parallel-group, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 35 intensive care units (ICUs) in Europe.
  • Trial Period: Enrollment ran from June 2017 to August 2020.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU with acute hypoxemic respiratory failure (defined as requiring an FiO2 of at least 0.50 or mechanical ventilation).
    • Exclusion Criteria: Included patients with carbon monoxide poisoning or those with a do-not-resuscitate order.
  • Intervention: A lower-oxygenation strategy, where the FiO2 was titrated to maintain a PaO2 target of 60 mm Hg (8.0 kPa).
  • Control: A higher-oxygenation strategy, where the FiO2 was titrated to maintain a PaO2 target of 90 mm Hg (12.0 kPa).
  • 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 2928 patients would provide 90% power to detect a 5% absolute risk reduction in 90-day mortality. (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: All-cause mortality at 90 days.
    • Secondary Outcomes: Included the proportion of patients with new shock or myocardial ischemia, and the number of days alive without life support.

6. Key Results

  • Enrollment and Baseline: 2928 patients were randomized (1462 to the lower-target group and 1466 to the higher-target group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality. 618 of 1441 patients (42.9%) in the lower-target group died, compared with 613 of 1447 patients (42.4%) in the higher-target group (p=0.64).
  • Secondary Outcomes: There were no significant differences between the groups in any of the secondary outcomes, including the number of days alive without life support.
  • Adverse Events: The 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 logistic regression model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: Adjusted Odds Ratio (OR) for death at 90 days: 1.02 (95% CI, 0.88 to 1.17; P-value: 0.76).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of Death in Intervention Group) / (Odds of Death in Control Group).
      • Calculation: The paper reports the adjusted result as 1.02.
      • Clinical Meaning: An OR of 1.02 suggests a non-significant 2% higher odds of death in the lower-oxygenation group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.88 to 1.17.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a 12% benefit to a 17% harm.
    • P-value: The p-value of 0.76 is much higher than the 0.05 threshold, indicating the result is 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: No significant differences were found in any of the pre-specified subgroups.

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 35 diverse ICUs across Europe make the findings highly generalizable to a broad population of critically ill patients.
  • Statistical Power: The study was very large and adequately powered to confidently rule out a modest but clinically important mortality difference.
  • Patient-Centered Outcomes: The primary outcome of 90-day 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 population was a heterogeneous group of patients with hypoxemic respiratory failure from various causes.
  • Other: The separation in achieved PaO2 between the two groups was modest, which may have made it more difficult to detect a true difference in outcomes.

10. Conclusion of the Authors

  • The authors concluded that among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in a lower 90-day mortality than a higher oxygenation target.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provided strong evidence that there is no survival benefit to targeting a higher PaO2 level (90 mm Hg) over a more conservative, lower level (60 mm Hg).
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients with acute hypoxemic respiratory failure.
    • Actionable Intervention: The results suggest that targeting a lower PaO2 of 60 mm Hg is a safe and acceptable strategy.
  • What This Trial Does NOT Mean: This trial does NOT mean that hypoxia is safe. It only suggests that in this stable ICU population, a PaO2 of 60 mm Hg was not inferior to a PaO2 of 90 mm Hg.
  • Implementation Caveats: The key takeaway is that avoiding hyperoxia is a reasonable clinical goal, and there is no evidence to support aggressively targeting “supranormal” oxygen levels.

12. Context and Related Studies

  • Building on Previous Evidence: The HOT-ICU trial (2021) was designed to provide a more definitive answer to the question of optimal oxygen targets than previous, smaller trials like the ICU-ROX trial (2019).
  • Influence on Subsequent Research: The definitive neutral findings of this trial, along with others, have been highly influential in shaping international guidelines, which now generally recommend a more conservative approach to oxygen therapy in the ICU.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal oxygen target in specific subgroups of patients (e.g., those with traumatic brain injury or cardiac arrest) remains an area of investigation.
  • Future Directions: Future research may focus on using more advanced monitoring to guide oxygen therapy in a more personalized manner.

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, randomized controlled trial design was appropriate and robust. The main methodological weakness is the open-label design.
  • Results: The study reported a clear neutral finding for its primary outcome, with a narrow confidence interval centered on the null value. This provides strong evidence against a meaningful clinical benefit of a higher oxygen target in this population.
  • 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 “negative” trial that is practice-changing by providing strong evidence that a more aggressive strategy is not superior to a more conservative one.

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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