Editorial 

December 10, 2024

Reevaluating Respiratory Support in Acute Respiratory Failure—Insights From the RENOVATE Trial and Implications for Practice

Yonathan Freund, Amelie Vromant

JAMA. Published online December 10, 2024. doi:10.1001/jama.2024.25869

There is a fundamental question in emergency medicine: Is high-flow nasal oxygen an appropriate alternative to noninvasive ventilation across varied presentations of acute respiratory failure? In this issue of JAMA, a multicenter, adaptive, randomized clinical trial, conducted by the RENOVATE Investigators and the BRICNet Authors,¹ explored the noninferiority of high-flow nasal oxygen vs noninvasive ventilation in reducing endotracheal intubation or death within 7 days across 5 distinct acute respiratory failure patient groups, including a dedicated COVID-19 cohort.

The authors¹ deserve recognition for the trial’s ambitious scope and adaptive design that allowed for real-time adjustments to improve relevance and applicability. They reported using high-flow nasal oxygen for undifferentiated acute respiratory failure is noninferior to noninvasive ventilation for the composite primary outcome of death or endotracheal intubation within 7 days.¹ However, as the emergency medicine community considers these findings, several important questions arise regarding their clinical implications and the feasibility of changing current practice.

Heterogeneity and Equipoise

A key challenge in interpreting the results from the RENOVATE trial¹ stems from the heterogeneity across the acute respiratory failure population enrolled, which included patients with acute hypoxemic respiratory failure, exacerbations of chronic obstructive pulmonary disease (COPD), acute heart failure, and COVID-19. The substantial sample sizes in the hypoxemic and COVID-19 patient groups reinforce the conclusion of the noninferiority of high-flow nasal oxygen, which is useful clinical information because current evidence has not resulted in a recommendation of high-flow nasal oxygen in these patients.^2-4

However, caution is warranted in interpreting the results for the COPD and acute heart failure groups with smaller sample sizes. In particular, the role of high-flow nasal oxygen remains uncertain for patients with hypercapnia (such as those with COPD exacerbations) because its physiological effect on elevated Paco₂ level has not been definitively established.⁵

Despite the adaptive design and the bayesian analysis with borrowing that were supposed to increase the robustness of the results in each patient group, the conclusions drawn from the group with a smaller sample size might be viewed as hypothesis generating rather than definitive. Furthermore, the post hoc analysis without dynamic borrowing cannot conclude noninferiority in the COPD group. For patients with acute heart failure, previous preliminary reports suggested that high-flow nasal oxygen may be a fair alternative to noninvasive ventilation, with no clear difference in clinical outcomes.^6-8

Noninferiority Margin and Clinical Relevance

The noninferiority margin (a 10% absolute difference translating to an odds ratio of 1.55) in the RENOVATE trial¹raises further considerations. For a composite outcome as consequential as endotracheal intubation or death, this margin could represent a substantial risk tolerance. Although the results demonstrate noninferiority, the point estimates across most patient groups, aside from acute heart failure, generally favored noninvasive ventilation, although only slightly. Thus, a tighter margin may have offered a clearer view of the comparative safety and effectiveness of high-flow nasal oxygen.

Secondary Outcomes and Lack of Patient-Centered Outcomes

Although the potential comfort advantage of high-flow nasal oxygen vs noninvasive ventilation has intuitive appeal, its clinical significance remains uncertain given the lack of benefits for the secondary outcomes. Notably, even though high-flow nasal oxygen is considered more comfortable and is generally associated with easier patient communication and mobility, its median duration of use was notably longer than noninvasive ventilation (approximately 24 hours vs 4 hours).

The RENOVATE trial¹ did not report on patient comfort with ventilatory mode in detail, leaving its importance unquantified. To truly justify high-flow nasal oxygen as a standard option, it is essential to incorporate patient-centered and patient-reported outcomes in future studies.⁹ These measures would provide clearer evidence of any added benefit that high-flow nasal oxygen might offer, focusing on those that affect patients’ daily experience and long-term satisfaction with treatment, which are critical in clinical decision-making.

Future trials with direct comfort metrics could further elucidate the benefits of high-flow nasal oxygen in settings where comfort is prioritized, but emergency department physicians must weigh the procedural complexity and resource demands of high-flow nasal oxygen against the accessibility of noninvasive ventilation. Furthermore, implementing high-flow nasal oxygen in some settings may require the involvement of a specialist for setup and monitoring, which adds an additional consideration vs noninvasive ventilation, which is a more familiar and widely accessible option in emergency settings.

Conclusions

The RENOVATE trial¹ contributes valuable evidence on the comparability of high-flow nasal oxygen vs noninvasive ventilation across diverse acute respiratory failure etiologies. However, due to patient heterogeneity, a broad noninferiority margin, and limited secondary outcome data, the trial’s findings invite careful consideration rather than a wholesale shift in clinical practice.

The inclusion of patient-centered and patient-reported outcomes is essential for determining if high-flow nasal oxygen can provide a true benefit beyond noninferiority in clinical outcomes. Ultimately, respiratory support choices should prioritize the patient experience as well as survival metrics, ensuring that the chosen approach aligns and optimizes both.