Effect of High-Flow Nasal Oxygen vs Standard Oxygen on 28-Day Mortality in Immunocompromised Patients With Acute Respiratory Failure: The HIGH Randomized Clinical Trial

Abstract

Importance: High-flow nasal oxygen therapy is increasingly used for acute hypoxemic respiratory failure (AHRF).

Objective: To determine whether high-flow oxygen therapy decreases mortality among immunocompromised patients with AHRF compared with standard oxygen therapy.

Design, setting, and participants: The HIGH randomized clinical trial enrolled 776 adult immunocompromised patients with AHRF (Pao2 <60 mm Hg or Spo2 <90% on room air, or tachypnea >30/min or labored breathing or respiratory distress, and need for oxygen ≥6 L/min) at 32 intensive care units (ICUs) in France between May 19, 2016, and December 31, 2017.

Interventions: Patients were randomized 1:1 to continuous high-flow oxygen therapy (n = 388) or to standard oxygen therapy (n = 388).

Main outcomes and measures: The primary outcome was day-28 mortality. Secondary outcomes included intubation and mechanical ventilation by day 28, Pao2:Fio2 ratio over the 3 days after intubation, respiratory rate, ICU and hospital lengths of stay, ICU-acquired infections, and patient comfort and dyspnea.

Results: Of 778 randomized patients (median age, 64 [IQR, 54-71] years; 259 [33.3%] women), 776 (99.7%) completed the trial. At randomization, median respiratory rate was 33/min (IQR, 28-39) vs 32 (IQR, 27-38) and Pao2:Fio2 was 136 (IQR, 96-187) vs 128 (IQR, 92-164) in the intervention and control groups, respectively. Median SOFA score was 6 (IQR, 4-8) in both groups. Mortality on day 28 was not significantly different between groups (35.6% vs 36.1%; difference, -0.5% [95% CI, -7.3% to +6.3%]; hazard ratio, 0.98 [95% CI, 0.77 to 1.24]; P = .94). Intubation rate was not significantly different between groups (38.7% vs 43.8%; difference, -5.1% [95% CI, -12.3% to +2.0%]). Compared with controls, patients randomized to high-flow oxygen therapy had a higher Pao2:Fio2 (150 vs 119; difference, 19.5 [95% CI, 4.4 to 34.6]) and lower respiratory rate after 6 hours (25/min vs 26/min; difference, -1.8/min [95% CI, -3.2 to -0.2]). No significant difference was observed in ICU length of stay (8 vs 6 days; difference, 0.6 [95% CI, -1.0 to +2.2]), ICU-acquired infections (10.0% vs 10.6%; difference, -0.6% [95% CI, -4.6 to +4.1]), hospital length of stay (24 vs 27 days; difference, -2 days [95% CI, -7.3 to +3.3]), or patient comfort and dyspnea scores.

Conclusions and relevance: Among critically ill immunocompromised patients with acute respiratory failure, high-flow oxygen therapy did not significantly decrease day-28 mortality compared with standard oxygen therapy.

Trial registration: clinicaltrials.gov Identifier: NCT02739451.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Azoulay reported receiving travel fees from Gilead and receiving personal fees from Gilead, Astellas, Baxter, Alexion, and Ablynx. Dr Lemiale reported being a member of a research group that has received grants from Fisher & Paykel, Alexion, Baxter, Pfizer, and Gilead. Dr Pène reported serving on a data and safety monitoring board for the French Ministry of Health. Dr Barbier reported receiving consulting and speaker fees from Merck Sharp & Dohme France and receiving conference invitations from Pfizer. Dr Girault reported receiving a grant and nonfinancial support from Fisher & Paykel Healthcare. Dr Jaber reported receiving consulting fees from Fisher & Paykel, Drager, and Xenios. Dr Terzi reported receiving speaking fees from Boehringer Ingelheim and Pfizer. Dr Darmon reported receiving grants from Merck Sharp & Dohme and Astute; receiving speaking fees from Merck Sharp & Dohme, Astellas, and Bristol-Myers Squibb; receiving support for organizing educational meetings from Merck Sharp & Dohme, Astellas, and JazzPharma; and receiving nonfinancial support from Sanofi-Aventis. Dr Demoule reported receiving grants from Resmed and the French Ministry of Health; receiving personal fees from Philips, Resmed, Baxter, and Hamilton; and receiving nonfinancial support from Medtronic, Philips, and Fisher & Paykel. No other authors reported disclosures.

Figures

Figure 1.. Flow of Patients Through the HIGH Trial

The number of patients excluded and the reasons for the exclusions were not available in all centers.

Figure 2.. Probability of Day-28 Mortality in Immunocompromised Patients With Acute Respiratory Failure Receiving High-Flow Oxygen Therapy or Standard Oxygen Therapy

Median survival was not reached in either group.

Figure 3.. Hazard Ratios for Day-28 Mortality (Primary Outcome) and Cumulative Incidence of Mechanical Ventilation, Overall and in Predefined Subgroups, in Immunocompromised Patients With Acute Respiratory Failure Receiving High-Flow Oxygen Therapy or Standard Oxygen Therapy

Square sides of data markers are proportional to subgroup sizes, with the exception of the open squares in “All patients” rows. Error bars indicate 95% confidence intervals. The Gail and Simon test for interaction was used.