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Standard oxygen by mask or nasal prongs has been the first-line therapy for patients with acute hypoxemic respiratory failure (AHRF), followed by intubation to provide invasive mechanical ventilation for patients for whom this approach has failed. Although intubation and subsequent invasive mechanical ventilation can be lifesaving, these procedures are associated with many complications1 and some patients with comorbidities—for example, those who are immunosuppressed—have disproportionately high morbidity and mortality.2 Two technologies have been developed to bridge the therapy gap between standard oxygen therapy and invasive mechanical ventilation: noninvasive ventilation (NIV) and high-flow nasal oxygen therapy. Although there is controversy about how these technologies fit in the management of AHRF, they share a similar proliferation based on early enthusiasm followed by widespread adoption and over time a tempering of expectations related to ongoing evaluation in randomized clinical trials.
Although NIV was first introduced in the 1940s, its popularity for the care of immunosuppressed patients with AHRF increased when initial clinical trials reported substantial improvements in mortality and a reduction in rates of endotracheal intubation.3,4 These data and an observational study of 1302 immunosuppressed patients were the basis for a conditional recommendation for the use of NIV in immunocompromised patients with AHRF before intubation in the current European Respiratory Society/American Thoracic Society guidelines.5 However, a recent multicenter, randomized trial by Lemiale et al6 of 374 immunosuppressed patients showed that early NIV compared with standard oxygen therapy was not associated with clinical benefits. In addition, a post hoc analysis of the FLORALI trial, comparing high-flow nasal oxygen therapy with NIV and standard oxygen therapy in AHRF, suggested that NIV might be associated with an increased risk of intubation and mortality in this subgroup of patients with AHRF.7
Given the pendulum swing in optimism for NIV, could there be a role for high-flow nasal oxygen therapy in immunocompromised patients? This technology has been widely adopted, and its popularity has been driven by early positive studies, the improvement in physiologic parameters seen during its use (particularly an increase in the ratio of Pao2 to fraction of inspired oxygen [Fio2]), and a general ease of application.8,9 However, robust studies clarifying the niche this technology best serves have been lacking, especially in the immunosuppressed patient population.
In this issue of JAMA, Azoulay and colleagues10 address this question. In this multicenter trial, the authors recruited 776 immunosuppressed patients with AHRF and randomized them to receive high-flow nasal oxygen therapy vs standard oxygen therapy. Based on their calculated Pao2:Fio2 ratio both at and 6 hours after randomization and the high mortality in both the intervention and the control groups, the population studied was appropriate in regard to degree of hypoxemia and severity of illness to warrant consideration of innovative therapies beyond routine initial oxygen therapy to improve outcome. However, no significant benefit from use of high-flow oxygen therapy was seen. Intubation rates were similar in both groups, 150 of 388 (38.7%) with high-flow oxygen therapy and 170 of 388 (43.8%) with standard oxygen therapy. Similarly, 28-day mortality was not significantly different between groups—138 of 388 (35.6%) with high-flow oxygen therapy and 140 of 388 (36.1%) with standard oxygen therapy.
There may have been some adverse effects of high-flow nasal oxygen therapy in the trial. The authors point out that patients who received high-flow oxygen therapy had a longer intensive care unit (ICU) stay when compared with patients receiving standard oxygen therapy (8 days vs 6 days), although the difference was not statistically significant (P = .07). This observation is common in clinical practice, whereby patients with AHRF who receive high-flow oxygen therapy are considered to need a high-maintenance, high-cost admission to an ICU until they can be transitioned to standard oxygen therapy. Furthermore, because there are no precise guidelines for weaning from high-flow therapy, its use may lead to increased and perhaps unnecessary use of hospital and critical care resources.
The medical community’s craving for innovation often fuels overzealous enthusiasm for positive results of interventions in preliminary studies that are subsequently contradicted when larger, multicenter trials are undertaken.11 One reason for early enthusiasm is that physicians do not want to withhold potentially beneficial therapies from patients. This is especially true in critical care when the intervention is perceived to have a pathophysiologic rationale. However, once a technology has been adopted, it is difficult to de-adopt, even if later, more robust evidence suggests that its continued use is unjustified.16 Even when trials have negative results, researchers and clinicians often seek to find subgroups that may have some benefit (such as with trials of colloids in shock or of activated protein C in severe sepsis) so that innovation is not wasted. However, if therapies are posited to have a role in important subgroups, it is important that such a role be demonstrated with adequate rigor in prospective clinical trials.12,13
It is conceivable that one reason there has been such an embrace of high-flow nasal oxygen therapy is publication bias. Researchers may not submit their negative studies because they perceive their results are uninteresting, or journal priorities and the agenda of funding groups may influence the dissemination of information from completed clinical trials by limiting publication.14 However, trials that fail to demonstrate positive effects of new technologies or therapies often have clinical utility. The trial by Azoulay et al, despite its negative findings, helps clarify the application of high-flow oxygen therapy in the immunosuppressed patient population. It is important to publish high-quality, negative randomized clinical trials to prevent excessive application of therapies that are not beneficial and, once popularized, may take years to find their proper application.
Given the available evidence, the important clinical question is in which patients with AHRF should high-flow nasal oxygen therapy be used? Based on the post hoc subgroup analysis in the FLORALI trial, high-flow oxygen therapy used in patients with severe hypoxemia (Pao2:Fio2 ratio ≤200 mm Hg) was associated with a reduced rate of intubation, which likely drove the mortality benefit of high-flow oxygen therapy compared with NIV and standard oxygen therapy.15 However, the patients in the current study by Azoulay et al had severely impaired oxygenation yet did not benefit. Thus, based on current information, high-flow oxygen therapy should not be considered a preferred therapy for immunosuppressed patients with AHRF, and additional studies including assessment of other technologies to avoid invasive ventilation are clearly needed.
Corresponding Author: Jesse B. Hall, MD, Section of Pulmonary and Critical Care Medicine, University of Chicago, 5841 S Maryland Ave, MC 6026, Chicago, IL 60637 (email@example.com).
Published Online: October 24, 2018. doi:10.1001/jama.2018.14287
Conflict of Interest Disclosures: Dr Patel reported grants from Parker B. Francis Foundation. No other disclosures were reported.
Dugan KC, Hall JB, Patel BK. High-Flow Nasal Oxygen—The Pendulum Continues to Swing in the Assessment of Critical Care Technology. JAMA. Published online October 24, 2018. doi:10.1001/jama.2018.14287