FLORALI: High-Flow Oxygen vs. Standard Oxygen or NIV in Respiratory Failure (2015)

“In patients with acute hypoxemic respiratory failure and without hypercapnia, treatment with high-flow nasal oxygen, standard oxygen therapy, or noninvasive ventilation did not result in a significantly different intubation rate. However, mortality was lower in the high-flow-oxygen group than in the other two groups.”

  • The FLORALI Study Group

1. Publication Details

  • Trial Title: High-Flow Nasal Cannula Oxygen during Respiratory Failure in the Critically Ill — A Multicenter Randomized Clinical Trial
  • Citation: Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015;372(23):2185-2196. DOI: 10.1056/NEJMoa1503326
  • Published: June 4, 2015, in The New England Journal of Medicine
  • Author: Jean-Pierre Frat, M.D.
  • Funding: French Ministry of Health

2. Keywords

  • Acute Hypoxemic Respiratory Failure, High-Flow Nasal Oxygen (HFNO), Noninvasive Ventilation (NIV), Mechanical Ventilation, Randomized Controlled Trial

3. The Clinical Question

  • In adult ICU patients with acute hypoxemic respiratory failure (Population), does treatment with high-flow nasal oxygen (Intervention) compared to standard oxygen therapy or noninvasive ventilation (NIV) (Comparison) reduce the rate of tracheal intubation at 28 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Standard oxygen therapy and noninvasive ventilation (NIV) were the mainstays of treatment for acute hypoxemic respiratory failure. However, standard oxygen provides limited and imprecise oxygen delivery, and NIV is often poorly tolerated. High-flow nasal oxygen (HFNO) was an emerging therapy that could deliver heated, humidified oxygen at high flow rates, providing a more comfortable and reliable alternative.
  • Knowledge Gap: It was unknown if HFNO was superior to standard oxygen or NIV in preventing the need for intubation in patients with acute hypoxemic respiratory failure.
  • Proposed Hypothesis: The authors hypothesized that HFNO would be superior to standard oxygen and NIV in reducing the rate of intubation at 28 days.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 23 intensive care units (ICUs) in France and Belgium.
  • Trial Period: Enrollment ran from February 2011 to December 2012.
  • Population:
    • Inclusion Criteria: Adult patients with acute hypoxemic respiratory failure (defined by specific respiratory rate and PaO2:FiO2 criteria) who did not have hypercapnia.
    • Exclusion Criteria: Included an immediate need for intubation, contraindications to NIV, and a decision to withhold life-sustaining treatment.
  • Intervention: Patients were randomized to one of three groups:
  • High-Flow Nasal Oxygen (HFNO): Oxygen delivered via a high-flow nasal cannula.
  • Standard Oxygen: Oxygen delivered via a standard nonrebreather face mask.
  • Noninvasive Ventilation (NIV): Delivered via a face mask for at least 8 hours per day.
  • Control: The standard oxygen and NIV groups served as the comparators.
  • Management Common to Both Groups: In all groups, the decision to intubate was based on pre-specified criteria of worsening respiratory distress.
  • Power and Sample Size: The authors calculated that a sample size of 300 patients would provide 80% power to detect a 20% absolute risk reduction in the intubation rate. (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: The proportion of patients who required tracheal intubation within 28 days of randomization.
    • Secondary Outcomes: Included 90-day mortality, ventilator-free days, and ICU length of stay.

6. Key Results

  • Enrollment and Baseline: 310 patients were randomized (114 to HFNO, 94 to standard oxygen, and 102 to NIV). 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 of intubation rate between the three groups. 38% of patients in the HFNO group were intubated, compared with 47% in the standard oxygen group and 50% in the NIV group (p=0.18 for the overall comparison).
  • Secondary Outcomes: A key secondary outcome, 90-day mortality, was significantly lower in the HFNO group (12%) compared to both the standard oxygen group (23%) and the NIV group (28%).
  • Adverse Events: The incidence of adverse events was similar across the 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 chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who were intubated among the three groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates for the primary and key secondary outcomes, with their associated P-values.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.18 for the primary outcome is higher than the 0.05 threshold, indicating that the result was not statistically significant. The p-value for the difference in 90-day mortality between HFNO and the other groups was statistically significant.
  • Clinical Impact Measures (for the secondary outcome of 90-day mortality, comparing HFNO to NIV):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 28% – 12% = 16%.
      • Clinical Meaning: For every 100 patients treated with HFNO instead of NIV, about 16 additional deaths were prevented at 90 days.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.16 = 6.25, which is rounded down to 6.
      • Clinical Meaning: You would need to treat only 6 patients with HFNO instead of NIV to prevent one additional death.
  • Subgroup Analyses: In a post-hoc analysis of the subgroup of patients with more severe hypoxemia (PaO2:FiO2 ≤ 200), the intubation rate was significantly lower in the HFNO group.

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 23 diverse ICUs increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The study focused on the crucial outcomes of intubation and mortality.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label, which introduces a risk of performance bias. The primary outcome was negative, so the positive finding for the secondary outcome of mortality should be interpreted with caution and is considered hypothesis-generating.
  • External Validity (Generalizability): The study excluded patients with hypercapnia, so the results do not apply to patients with COPD exacerbations.
  • Other: The trial was stopped after the first interim analysis, which can sometimes overestimate the treatment effect.

10. Conclusion of the Authors

  • The authors concluded that in patients with acute hypoxemic respiratory failure, treatment with high-flow nasal oxygen did not result in a significantly different intubation rate as compared with standard oxygen therapy or noninvasive ventilation.

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that, despite being technically “negative” for its primary outcome, was profoundly practice-changing due to the large and significant mortality benefit seen with HFNO. It established HFNO as a first-line therapy for acute hypoxemic respiratory failure.
  • Specific Recommendations:
    • Patient Selection: For adult patients with acute hypoxemic (non-hypercapnic) respiratory failure.
    • Actionable Intervention: High-flow nasal oxygen should be considered as the initial respiratory support strategy.
    • Expected Benefit: This intervention may reduce mortality compared to standard oxygen or NIV.
  • What This Trial Does NOT Mean: This trial does NOT mean that NIV has no role in respiratory failure. Its findings are specific to patients with primarily hypoxemic (not hypercapnic) failure.
  • Implementation Caveats: Patients treated with HFNO still require close monitoring for signs of respiratory fatigue or worsening, as a delay in intubation can be harmful.

12. Context and Related Studies

  • Building on Previous Evidence: The FLORALI trial (2015) was the first large, multicenter RCT to provide high-quality evidence on the role of HFNO in this patient population.
  • Influence on Subsequent Research: The definitive positive mortality signal in this trial led to the widespread adoption of HFNO as a standard of care and was a critical piece of evidence during the COVID-19 pandemic.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The precise mechanism by which HFNO reduced mortality without reducing the intubation rate is not fully understood. The optimal timing for escalating from HFNO to intubation also remains an area of clinical judgment.
  • Future Directions: Future research is focused on identifying which patients are most likely to succeed or fail with HFNO and on combining HFNO with other strategies like prone positioning in awake patients.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a novel and promising respiratory support therapy.
  • Methods: The multicenter RCT design was appropriate. The main methodological weakness is the open-label design. The most important point for interpretation is that the trial was negative for its primary outcome but positive for a key secondary outcome.
  • Results: A positive secondary outcome in a trial that is negative for its primary outcome should always be interpreted with caution, as it has a higher risk of being a false-positive result due to multiple comparisons. However, the large magnitude and statistical significance of the mortality benefit in this trial lent it a great deal of credibility.
  • Conclusions and Applicability: The authors’ cautious conclusion is a fair reflection of the primary outcome data. However, the clinical community has largely interpreted the totality of the evidence from this trial as being strongly supportive of HFNO due to the powerful mortality signal. The findings are broadly applicable to the management of acute hypoxemic respiratory failure.

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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