SUPERNOVA: HFNC in Immunocompromised Patients (2018)

“Among immunocompromised patients with acute respiratory failure, a strategy of initial high-flow nasal cannula oxygen therapy compared with standard oxygen therapy did not significantly reduce the day-28 rate of tracheal intubation.”

— The GRRR-OH Study Group

1. Publication Details

• Trial Title: Effect of a Strategy of Initial High-Flow Nasal Cannula vs Standard Oxygen Therapy on Tracheal Intubation in Immunocompromised Patients With Acute Respiratory Failure: The SUPERNOVA Randomized Clinical Trial.
• Citation: Azoulay E, Lemiale V, Mokart D, et al; for the Groupe de Recherche en Réanimation Respiratoire du patient d’Onco-Hématologie (GRRR-OH). Effect of a Strategy of Initial High-Flow Nasal Cannula vs Standard Oxygen Therapy on Tracheal Intubation in Immunocompromised Patients With Acute Respiratory Failure: The SUPERNOVA Randomized Clinical Trial. JAMA. 2018;320(20):2098-2107. doi:10.1001/jama.2018.14610.
• Published: November 27, 2018, in The Journal of the American Medical Association (JAMA).
• Author: Elie Azoulay, M.D., Ph.D.
• Funding: French Ministry of Health.

2. Keywords

Immunocompromised, Acute Respiratory Failure, High-Flow Nasal Cannula (HFNC), Oxygen Therapy, Noninvasive Ventilation, Tracheal Intubation, Onco-hematology.

3. The Clinical Question

In adult immunocompromised patients with acute hypoxemic respiratory failure (Population), does an initial strategy of high-flow nasal cannula (HFNC) (Intervention) compared to standard oxygen therapy (with noninvasive ventilation as rescue) (Comparison) reduce the rate of tracheal intubation at day 28 (Outcome)?

4. Background and Rationale

• Existing Knowledge: Immunocompromised patients with acute respiratory failure (ARF) have a very high mortality rate, particularly after tracheal intubation. High-flow nasal cannula (HFNC) had been shown to reduce intubation rates in the general population with ARF (FLORALI trial).
• Knowledge Gap: It was unknown if the benefits of HFNC extended to the specific high-risk population of immunocompromised patients, who may have different underlying causes of respiratory failure and a lower tolerance for delayed intubation.
• Proposed Hypothesis: The authors hypothesized that an initial strategy of HFNC would reduce the rate of tracheal intubation at day 28 compared to standard oxygen therapy.

5. Study Design and Methods

• Design: A prospective, multicenter, international, open-label, randomized, controlled trial.
• Setting: 32 intensive care units (ICUs) in France.
• Trial Period: Enrollment from May 2016 to December 2017.
• Population:
  • Inclusion Criteria: Adult patients (≥18 years) with a diagnosis of immunocompromise (e.g., hematologic malignancy, solid tumor, long-term steroids, solid-organ transplant) admitted to the ICU for acute hypoxemic respiratory failure.
  • Exclusion Criteria: Urgent need for intubation, hypercapnia, contraindications to noninvasive ventilation (NIV), or a do-not-intubate order.
• Intervention: High-flow nasal cannula (HFNC) therapy, initiated at 50 L/min and an FiO2 of 1.0.
• Control: Standard oxygen therapy delivered via a nonrebreather face mask. Sessions of noninvasive ventilation (NIV) were allowed as rescue therapy for worsening respiratory distress.
• Management Common to Both Groups: Criteria for tracheal intubation were standardized across both groups.
• Power and Sample Size: The trial was powered to detect a 15% absolute reduction in the intubation rate, requiring 298 patients. The trial was stopped early for futility at a planned interim analysis.
• Outcomes:
  • Primary Outcome: Tracheal intubation rate at day 28.
  • Secondary Outcomes: 28-day mortality, ventilator-free days, ICU and hospital length of stay, and ICU-acquired infections.

6. Key Results

• Enrollment and Baseline: 299 patients were randomized (151 to HFNC, 148 to standard oxygen). The groups were well-matched at baseline.
• Trial Status: The trial was stopped for futility at the first planned interim analysis.
• Primary Outcome: There was no significant difference in the 28-day intubation rate between the HFNC group and the standard oxygen group (38.4% vs 43.9%; P=0.32).
• Secondary Outcomes: There were no significant differences in 28-day mortality (35.8% vs 36.5%), ventilator-free days, or length of stay.
• Adverse Events: The rates of adverse events were similar between the two groups.

7. Medical Statistics

• Analysis Principle: An intention-to-treat analysis was performed.
• Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
• Primary Outcome Analysis: The proportion of patients intubated at day 28 was compared between the two groups.
• Key Statistic(s) Reported: Absolute difference in intubation rate: -5.5% (95% CI, -17.2% to 6.1%; P=0.35).
• Interpretation of Key Statistic(s):
  • Confidence Interval (CI): The 95% CI for the difference is wide and crosses zero (from a 17.2% benefit for HFNC to a 6.1% harm), indicating no statistically significant difference and a high degree of uncertainty.
  • P-value: The p-value of 0.35 confirms the lack of a statistically significant difference.
• Clinical Impact Measures: Not applicable as no benefit was shown for the primary outcome.
• Subgroup Analyses: No significant treatment effects were found in any of the pre-specified subgroups.

8. Strengths of the Study

• Study Design and Conduct: This was the first large, multicenter randomized trial to address this specific and important clinical question in a high-risk population.
• Generalizability: The inclusion of 32 centers and a broad definition of immunocompromise increases the applicability of the findings.
• Clinically Relevant Question: The trial addressed a critical decision point in the management of a very vulnerable patient group.

9. Limitations and Weaknesses

• Internal Validity (Bias): The study was open-label (unblinded). A key limitation is that the control group was permitted to use NIV as a rescue therapy (and 44% did), which may have improved their outcomes and diluted any potential benefit of HFNC.
• External Validity (Generalizability): The findings are specific to immunocompromised patients and a strategy where NIV is available as a rescue for standard oxygen.
• Other: The trial was stopped early for futility, which can sometimes lead to an overestimation of the lack of effect, though in this case, the result was quite definitive.

10. Conclusion of the Authors

“Among immunocompromised patients with acute respiratory failure, a strategy of initial high-flow nasal cannula oxygen therapy compared with standard oxygen therapy did not significantly reduce the day-28 rate of tracheal intubation. These findings do not support the systematic use of high-flow nasal cannula for this indication.”

11. To Summarize

• Impact on Current Practice: This trial provided important negative evidence that tempered the enthusiasm for using HFNC in all patients with respiratory failure. It demonstrated that in the specific context of immunocompromised patients, HFNC was not superior to a strategy of standard oxygen with NIV available as a rescue. It supports the idea that both are reasonable initial strategies.
• Specific Recommendations:
  • Patient Selection: For adult immunocompromised patients with acute hypoxemic respiratory failure.
  • Actionable Intervention: An initial strategy of either HFNC or standard oxygen therapy (with the availability of NIV for rescue) are both acceptable. There is no evidence to support the routine, preferential use of HFNC in this population.
  • Expected Benefit: No difference in intubation rates or mortality was demonstrated.
• What This Trial Does NOT Mean: This trial does not mean HFNC is ineffective or should not be used. It simply means it was not superior to an alternative active strategy (standard O2 + rescue NIV).
• Implementation Caveats: The key is close monitoring for treatment failure with any non-invasive strategy in this high-risk population to ensure timely intubation when necessary.

12. Context and Related Studies

• Building on Previous Evidence: This trial provided crucial context to the FLORALI trial (2015), which had shown a mortality benefit for HFNC over standard oxygen and NIV in a general population of patients with ARF. SUPERNOVA suggests that this benefit may not be generalizable to the immunocompromised subgroup.
• Influence on Subsequent Research: This trial has highlighted the importance of studying interventions in specific, high-risk populations rather than extrapolating from general ICU trials.

13. Unresolved Questions & Future Directions

• Unresolved Questions: Is there a specific subgroup of immunocompromised patients (e.g., those with specific underlying diseases or types of lung injury) who might still benefit from HFNC over other modalities?
• Future Directions: Future research may focus on better identifying which non-invasive support strategy is best suited for different phenotypes of respiratory failure in immunocompromised patients.

14. External Links

• Original Article: Effect of a Strategy of Initial High-Flow Nasal Cannula vs Standard Oxygen Therapy on Tracheal Intubation in Immunocompromised Patients With Acute Respiratory Failure

15. Framework for Critical Appraisal

• Clinical Question: The question was highly relevant, testing a promising therapy in a very high-risk and distinct patient population.
• Methods: The multicenter RCT design was appropriate. The main methodological limitation that complicates interpretation is the open-label design and the allowance of NIV as a rescue therapy in the control arm, making it a comparison of two active treatment strategies rather than HFNC vs. simple standard oxygen.
• Results: The trial had a clear neutral result for its primary outcome of intubation, as well as for mortality.
• Conclusions and Applicability: The authors’ conclusion is well-supported by the data. The results are highly applicable to ICUs that care for immunocompromised patients and have both HFNC and NIV available, providing evidence that either approach is a reasonable first step.

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.