VACEP's EBM Review Series: High-Flow Nasal Oxygen vs Noninvasive Ventilation for Acute Respiratory Failure
VACEP Evidence-Based Medicine for General Emergency Physicians Series
Authors: Christopher Fahlsing, MD, PGY4 & Dean Cataldo, DO (LT, MC, USN) | Naval Medical Center Portsmouth
Reviewer: Andrea L. Klein, MD, MPH & Andrew B. Moore, MD, MCR | Virginia Tech Carilion Department of Emergency Medicine
The VACEP Evidence-Based Medicine Review Series allows Virginia emergency medicine residents and attendings to share and analyze a recent peer-reviewed clinical study. You can also read the full article, High-Flow Nasal Oxygen vs Noninvasive Ventilation in Patients with Acute Respiratory Failure - The RENOVATE Randomized Clinical Trial, from the Journal of the American Medical Association’s December 2024 edition.
CASE
A 72-year-old male presents to the ED with worsening dyspnea, cough, and peripheral edema over the past 3 days. His past medical history includes congestive heart failure (EF 40%) and chronic obstructive pulmonary disease (COPD) not on home O2. On examination:
He is tachypneic with accessory muscle use
He has coarse breath sounds
He has an oxygen saturation of 85% on room air
His respiratory acidosis on arterial blood gas (pH 7.30, PaCO₂ 58 mm Hg)
Despite bronchodilators and standard nasal cannula oxygen, his respiratory distress persists
What’s your plan for respiratory support?
STUDY SUMMARY
Acute respiratory failure (ARF) is frequently encountered in the emergency department (ED). High-flow nasal oxygen (HFNO) and noninvasive ventilation (NIV) are two noninvasive strategies for managing ARF [1-3].
While HFNO is associated with greater patient comfort, ease of use, and enhanced secretion clearance, NIV has demonstrated efficacy in reducing the work of breathing and improving gas exchange [4-7].
The compared effectiveness of these modalities, however, remains unclear. The RENOVATE trial addresses this gap by evaluating the noninferiority of HFNO to NIV in preventing endotracheal intubation or death within 7 days.
METHODS
The RENOVATE trial was an unblinded, prospective, multicenter, randomized, non-inferiority trial conducted at 33 hospitals in Brazil from 2019 to 2023. It enrolled 1,800 patients with ARF, randomized 1:1 to HFNO (n = 883) or NIV (n = 883), and stratified into five subgroups:
Nonimmunocompromised with hypoxemia
Immunocompromised with hypoxemia
COPD exacerbation with respiratory acidosis
Acute cardiogenic pulmonary edema (ACPE)
Hypoxemic COVID-19
The trial used a Bayesian adaptive design, a statistical approach that allows for real-time adjustments based on accumulating data, with dynamic borrowing, which integrates information across related subgroups to enhance statistical power.
This approach aimed to balance prior and new data to optimize the analysis while accounting for potential heterogeneity. Noninferiority was defined by a posterior probability ≥0.992 for an odds ratio (OR) <1.55, meaning HFNO would be considered noninferior to NIV if there was at least a 99.2% probability that the OR was below this threshold.
About the EBM Review Series
This is a literature review series started by the University of Virginia’s Josh Easter, MD, MSc, a VACEP board member working to connect the academic community in Virginia. We invite each residency in Virginia (and D.C.) to create a faculty/resident team to submit and review articles. Sign up to submit one.
Goals
Provide a brief monthly synopsis of a high yield article germane to the practice of emergency medicine for distribution to all VACEP members
Provide an opportunity for a peer reviewed publication and invited presentation for faculty and trainees
Foster an academic community focused on evidenced based medicine for emergency medicine residency programs in the region
RESULTS
The primary outcome of intubation or death within 7 days occurred in 39% of HFNO patients (344/883) versus 38% of NIV patients (336/883), demonstrating noninferiority (OR 1.07; 95% credible interval [CrI] 0.87-1.31; posterior probability 0.999).
Subgroup analysis found HFNO noninferior in all but the immunocompromised group, where outcomes were worse (57.1% vs. 36.4%), leading to early trial termination for this subgroup.
Serious adverse event rates (e.g., any life-threatening event, hospitalization, prolonged hospitalization, persistent disability, or death) were similar between HFNO (9.4%) and NIV (9.9%). However, post hoc analyses without dynamic borrowing revealed differences in smaller subgroups.
For ACPE, HFNO became more favorable (initial OR 0.97 / post hoc OR 0.52). Conversely, for COPD, HFNO shifted towards worse rates (initial OR 1.05 / post hoc OR 1.48). In the immunocompromised group, HFNO showed worse outcomes (initial OR 1.07 / post hoc OR 2.56), consistent with early trial termination.
ANALYSIS
The RENOVATE trial provides valuable insights into the management of ARF and the comparative efficacy of HFNO and NIV. While HFNO demonstrated overall noninferiority to NIV, limitations in subgroup analyses and methodological considerations require attention.
Strengths
Robust Design: The Bayesian adaptive framework efficiently utilized data with dynamic borrowing across subgroups, enabling frequent interim analyses and recruitment adjustments.
Diverse Patient Cohort: The study included a broad spectrum of ARF etiologies, enhancing generalizability to diverse ED populations.
Well-Defined Protocols: Detailed intervention protocols ensured consistency in delivery and weaning.
Safety Profile: Comparable adverse event rates between HFNO and NIV underscore HFNO's safety as an alternative therapy.
Clinically Relevant Outcomes: The composite endpoint of intubation or death within 7 days is highly relevant for emergency physicians managing ARF patients.
Operational Simplicity: HFNO is easier to administer and better tolerated by patients, offering significant practical advantages.
Limitations
Unblinded Design: Clinician knowledge of the assigned intervention could introduce biased intubation decisions.
Small Subgroup Sizes: Subgroups such as COPD and immunocompromised patients had wide credible intervals, limiting the strength of conclusions.
Dynamic Borrowing: Although this method is efficient and enhances statistical power, as the post hoc analyses demonstrate, it may obscure true subgroup-specific effects.
Composite Outcome: Combining intubation and death reduces the clinical clarity of each component’s impact.
Noninferiority Margin: The chosen margin (OR <1.55) reflects a 10% absolute difference in the composite outcome, which may be too lenient for a critical endpoint like intubation or death [2]. A stricter margin might have provided a more conservative and clinically acceptable benchmark for evaluating noninferiority in these vulnerable groups.
Lack of Patient-Centered Outcomes: Comfort and quality-of-life benefits, often cited as HFNO strengths, were not rigorously evaluated, leaving gaps in understanding its full clinical impact. Additionally, HFNO had a longer median duration of use (24 hours vs. 4 hours for NIV), raising questions about whether comfort translates to meaningful clinical benefits [3].
Implementation Challenges: HFNO requires specialized equipment and training, which may be a barrier in resource-limited settings.
CLINICAL IMPLICATIONS
HFNO demonstrates noninferiority to NIV in most ARF scenarios, making it a practical and comfortable alternative for patients who may not tolerate NIV. However, the noninferiority findings should be interpreted cautiously due to subgroup-specific variability and the leniency of the noninferiority margin, which could have significant clinical implications for high-risk populations (e.g., immunocompromised patients or those with acute on chronic respiratory failure in extremis). Immunocompromised patients likely benefit more from NIV, and COPD patients may still prefer NIV due to its established efficacy in hypercapnic ARF.
For emergency physicians, HFNO offers advantages in patient comfort and ease of use but requires careful consideration in cases of hypercapnic respiratory failure or immunosuppression. NIV, particularly bilevel positive airway pressure (BiPAP), provides adjustable inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP) [8,9].
Therefore, BiPAP can effectively reduce the work of breathing, improve alveolar ventilation, and correct hypercapnia more efficiently than HFNO, which provides only minimal levels of positive end-expiratory pressure (PEEP). Alternatively, HFNO delivers heated, humidified oxygen at high flow rates (up to 60 L/min), which helps wash out dead space, reduce inspiratory resistance, and maintain airway patency, improving oxygenation [10].
However, its inability to provide substantial ventilatory support limits its efficacy in conditions requiring active removal of CO2, such as COPD exacerbations. Conversely, NIV with BiPAP actively assists ventilation by increasing tidal volume and reducing the work of breathing, making it a preferred option for patients with acute hypercapnic respiratory failure [8,9,11].
Supporting literature emphasizes that NIV has significantly reduced the need for intubation in hypercapnic respiratory failure, particularly in COPD exacerbations [8].
Studies indicate that NIV decreases respiratory muscle fatigue, improves alveolar ventilation, and provides effective pressure support that HFNO cannot achieve [9].
Conversely, HFNO has been demonstrated to be beneficial in hypoxemic respiratory failure by ensuring a high fraction of inspired oxygen (FiO2) delivery and reducing inspiratory effort, making it particularly useful in conditions such as pneumonia or early ARDS [12,13].
The RENOVATE trial findings align with prior research suggesting that HFNO may be less effective in conditions with increased ventilatory demand but remains a viable alternative in select patients who cannot tolerate NIV. Additionally, evidence suggests that nasal BiPAP, commonly used in pediatric critical care (also referred to as nasal intermittent positive pressure ventilation [NIPPV]), could be a reasonable alternative in adult populations [14,15].
By delivering BiPAP through a nasal interface, it improves comfort and adherence while reducing reliance on a full-face mask [9].
However, studies have shown that full-face masks achieve greater CO₂ reduction at 6 hours, suggesting that nasal BiPAP may be less effective for patients requiring more aggressive CO₂ clearance [15].
Further research is needed to determine whether this hybrid approach can effectively bridge the gap between HFNO and traditional NIV by offering greater pressure support while maintaining ease of use.
In practice, selecting between HFNO and NIV should be guided by the patient’s clinical presentation, tolerance, and available hospital resources. While NIV remains the standard of care for hypercapnic respiratory failure, HFNO offers a more comfortable, well-tolerated option in hypoxemic respiratory failure scenarios. Emergency physicians should weigh patient-specific factors, clinical trajectories, and available resources when deciding between HFNO and NIV.
CONCLUSION
You initiate HFNO for your patient and monitor for clinical improvement or signs of deterioration. Based on the RENOVATE trial’s findings, HFNO is a viable alternative to NIV in this setting, offering comparable efficacy with greater patient comfort.
The RENOVATE trial provides a foundation for expanding HFNO use in ARF management but also underscores the need for tailored and patient-centered approaches. Future studies should further explore its efficacy in specific subgroups, particularly immunocompromised patients. This trial highlights the importance of individualized patient care and optimizing respiratory support strategies in emergency medicine.
REFERENCES:
RENOVATE Investigators and the BRICNet Authors, Maia IS, Kawano-Dourado L, et al. High-Flow Nasal Oxygen vs Noninvasive Ventilation in Patients With Acute Respiratory Failure: The RENOVATE Randomized Clinical Trial. JAMA. Published online December 10, 2024. doi:10.1001/jama.2024.26244
Frat JP, Le Pape S, Thille AW. Is High-Flow Oxygen the Standard for All Patients With Acute Respiratory Failure?. JAMA. Published online December 10, 2024. doi:10.1001/jama.2024.25906
Freund Y, Vromant A. Reevaluating Respiratory Support in Acute Respiratory Failure-Insights From the RENOVATE Trial and Implications for Practice. JAMA. Published online December 10, 2024. doi:10.1001/jama.2024.25869
Carron M, Freo U, BaHammam AS, et al. Complications of non-invasive ventilation techniques: a comprehensive qualitative review of randomized trials. Br J Anaesth. 2013;110(6):896-914. doi:10.1093/bja/aet070
Mauri T, Turrini C, Eronia N, et al. Physiologic Effects of High-Flow Nasal Cannula in Acute Hypoxemic Respiratory Failure. Am J Respir Crit Care Med. 2017;195(9):1207-1215. doi:10.1164/rccm.201605-0916OC
Cortegiani A, Crimi C, Noto A, et al. Effect of high-flow nasal therapy on dyspnea, comfort, and respiratory rate. Crit Care. 2019;23(1):201. Published 2019 Jun 5. doi:10.1186/s13054-019-2473-y
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Munshi L, Mancebo J, Brochard LJ. Noninvasive Respiratory Support for Adults with Acute Respiratory Failure. N Engl J Med. 2022;387(18):1688-1698. doi:10.1056/NEJMra2204556
Wang Y, Liu Y, Liu K, He Y, Ding H. Noninvasive Positive Pressure Ventilation versus High-Flow Nasal Cannula for Chronic Obstructive Pulmonary Disease: An Updated Narrative Review. Int J Chron Obstruct Pulmon Dis. 2024;19:2415-2420. Published 2024 Nov 9. doi:10.2147/COPD.S487994
Baldomero AK, Melzer AC, Greer N, et al. Effectiveness and Harms of High-Flow Nasal Oxygen for Acute Respiratory Failure: An Evidence Report for a Clinical Guideline From the American College of Physicians. Ann Intern Med. 2021;174(7):952-966. doi:10.7326/M20-4675
Mehta S, Jay GD, Woolard RH, et al. Randomized, prospective trial of bilevel versus continuous positive airway pressure in acute pulmonary edema. Crit Care Med. 1997;25(4):620-628. doi:10.1097/00003246-199704000-00011
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
Frat JP, Coudroy R, Thille AW. Non-invasive ventilation or high-flow oxygen therapy: When to choose one over the other?. Respirology. 2019;24(8):724-731. doi:10.1111/resp.13435
Lemyre B, Deguise MO, Benson P, Kirpalani H, Ekhaguere OA, Davis PG. Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants. Cochrane Database Syst Rev. 2023;7(7):CD005384. Published 2023 Jul 19. doi:10.1002/14651858.CD005384.pub3
Sadeghi S, Fakharian A, Nasri P, Kiani A. Comparison of Comfort and Effectiveness of Total Face Mask and Oronasal Mask in Noninvasive Positive Pressure Ventilation in Patients with Acute Respiratory Failure: A Clinical Trial. Can Respir J. 2017;2017:2048032. doi:10.1155/2017/2048032
Disclaimer: The views expressed in this review article are those of the author(s) and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. We are military service members. This work was prepared as part of our official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.
