Effect of High-Flow Oxygen Therapy vs Conventional Oxygen Therapy on Invasive Mechanical Ventilation and Clinical Recovery in Patients With Severe COVID-19: A Randomized Clinical Trial

Abstract

Importance: The effect of high-flow oxygen therapy vs conventional oxygen therapy has not been established in the setting of severe COVID-19.

Objective: To determine the effect of high-flow oxygen therapy through a nasal cannula compared with conventional oxygen therapy on need for endotracheal intubation and clinical recovery in severe COVID-19.

Design, setting, and participants: Randomized, open-label clinical trial conducted in emergency and intensive care units in 3 hospitals in Colombia. A total of 220 adults with respiratory distress and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of less than 200 due to COVID-19 were randomized from August 2020 to January 2021, with last follow-up on February 10, 2021.

Interventions: Patients were randomly assigned to receive high-flow oxygen through a nasal cannula (n = 109) or conventional oxygen therapy (n = 111).

Main outcomes and measures: The co-primary outcomes were need for intubation and time to clinical recovery until day 28 as assessed by a 7-category ordinal scale (range, 1-7, with higher scores indicating a worse condition). Effects of treatments were calculated with a Cox proportional hazards model adjusted for hypoxemia severity, age, and comorbidities.

Results: Among 220 randomized patients, 199 were included in the analysis (median age, 60 years; n = 65 women [32.7%]). Intubation occurred in 34 (34.3%) randomized to high-flow oxygen therapy and in 51 (51.0%) randomized to conventional oxygen therapy (hazard ratio, 0.62; 95% CI, 0.39-0.96; P = .03). The median time to clinical recovery within 28 days was 11 (IQR, 9-14) days in patients randomized to high-flow oxygen therapy vs 14 (IQR, 11-19) days in those randomized to conventional oxygen therapy (hazard ratio, 1.39; 95% CI, 1.00-1.92; P = .047). Suspected bacterial pneumonia occurred in 13 patients (13.1%) randomized to high-flow oxygen and in 17 (17.0%) of those randomized to conventional oxygen therapy, while bacteremia was detected in 7 (7.1%) vs 11 (11.0%), respectively.

Conclusions and relevance: Among patients with severe COVID-19, use of high-flow oxygen through a nasal cannula significantly decreased need for mechanical ventilation support and time to clinical recovery compared with conventional low-flow oxygen therapy.

Trial registration: ClinicalTrials.gov Identifier: NCT04609462.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Cavalcanti reported receipt of nonfinancial support from Fisher & Paykel (provision of equipment and supplies for another trial assessing high-flow oxygen therapy through a nasal cannula). No other disclosures were reported.

Figures

Figure 1.. Flow of Participants Through the Trial

aDefined as any serious medical condition or clinical laboratory test result abnormality that, in an investigator’s judgement, could prevent safe patient participation and completion of the study. Patients for whom therapeutic limitations were anticipated or moribund patients were included in this category. bNew York Heart Association (NYHA) class I indicates no symptoms with normal physical activity (asymptomatic); class II, mild symptoms with normal physical activity; class III, moderate symptoms with activities of daily living; and class IV, symptoms at rest. cCOPD indicates chronic obstructive pulmonary disease. Global Initiative for Chronic Obstructive Lung Disease (GOLD) airflow limitations are determined by spirometry and divided into 4 grades: 1, mild (forced expiratory volume in first second of expiration [FEV1] ≥80% predicted); 2, moderate (FEV1 50%-79% predicted); 3, severe (FEV1 30%-49% predicted); and 4, very severe (FEV1 <30% predicted). GOLD C corresponds to patients with severe or very severe airflow limitation (spirometric grades 3 and 4) and/or 2 or more exacerbations per year and/or 1 or more hospitalized exacerbations per year, and a Modified British Medical Research Council (mMRC) questionnaire on breathlessness grade of 0 to 1 or a Chronic Obstructive Pulmonary Disease Assessment Test (CAT) score less than 10. GOLD D corresponds to patients with severe or very severe airflow limitation (spirometric grades 3 and 4) and/or 2 or more exacerbations per year and/or 1 or more hospitalized exacerbations per year, and an mMRC grade of 2 or higher or a CAT score of 10 or higher. dChild-Pugh scores are calculated by assessing ascites (1 point for none, 2 points for slight, and 3 points for moderate), serum bilirubin level (1 point for <2.0 mg/dL, 2 points for 2.0-3.0 mg/dL, and 3 points for >3.0 mg/dL), serum albumin level (1 point for ≥3.5 g/dL, 2 points for 2.8-3.5 g/dL, and 3 points for <2.8 g/dL), prolongation of prothrombin time (1 point for <4 seconds, 2 points for 4-6 seconds, and 3 points for >6 seconds), and encephalopathy (1 point for none, 2 points for grade 1 or 2, and 3 points for grade 3 or 4). Child-Pugh class C is a total score of more than 9 points. eOne patient randomized to conventional oxygen therapy received high-flow oxygen therapy according to the decision of the attending physician. This patient was included in the conventional oxygen therapy group for the primary analysis. fPatients were analyzed according to their randomization group, excluding those withdrawing consent and those transferred to nonparticipating hospitals. Because of the hospital emergency situation during the pandemic and in agreement with the recommendation by the ethical and biomedical research committee of the coordinating center, patients who were transferred to other hospitals (for health insurance–related reasons) before 72 hours had elapsed since enrollment were excluded from the primary analysis because of limitations on providing further protocolized management and impossibility of ensuring adequate follow-up. All co–primary outcome data were recorded for these patients until transfer.

Figure 2.. Cumulative Intubation and Clinical Recovery Through Day 28 (Co–Primary Outcomes)

The effect of treatments on cumulative incidence of intubation and recovery rates was calculated with a Cox proportional hazards model adjusted for hypoxemia severity, age, and comorbidities.

Figure 3.. Results of the Prespecified Subgroup Analysis on Intubation and Clinical Recovery

The widths of the CIs were not adjusted for multiplicity and therefore cannot be used to infer treatment effects. A hazard ratio less than 1 for intubation indicates benefit with use of high-flow oxygen therapy. A hazard ratio greater than 1 for clinical recovery indicates benefit with use of high-flow oxygen therapy.