ICU Journal Club- COVID HighFlow

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

Blog written by Dr Jose Chacko

Design and setting

Randomized controlled trial conducted across three centers in Columbia over 5 months from August 2020 to January 2021. Patients were randomized 1:1 to high flow nasal cannula (HFNC) or conventional oxygen. It was an unblinded trial, the main investigators were unaware of study group outcomes until unlocking of the database. Web-based randomization, stratified by study site.

Included

Adult patients with suspected or confirmed infection with SARS-CoV-2 and acute respiratory failure, with P/F ratio less than 200, and clinical signs of respiratory distress, including the use of accessory muscles and tachypnea of more than 25/min. The time interval between fulfilling criteria for respiratory failure and randomization was less than 6 hours.

Excluded

PCO2 more than 55 mm Hg, poor LV function with EF less than 40%, advanced COPD, hospitalization for COPD within the last year, peripheral demyelinating disease, advanced cirrhosis, anatomical abnormalities that precluded the use of HFNC, patients who were not expected to survive, pregnancy.

HFNC arm

Initial settings: flow of 60 l/min, FiO2: 1.0. FiO2 was adjusted to maintain oxygen saturation of 92% or higher. Flow rate decreased in case of patient discomfort. HFNC therapy continued until intubation or when criteria were met for weaning of therapy. Criterial for weaning included improvement in respiratory distress, P/F ratio higher than 200 mm Hg, oxygen saturation 92% or more with less than 9 l/min of conventional oxygen therapy. If patients developed recurrent hypoxemia after weaning, HFNC therapy could be recommenced unless immediate intubation was required.

Conventional oxygen arm

Oxygen was administered through any low-flow device, including nasal prongs, masks (with or without reservoir), or ventimasks, alone or in combination. Flow rate and FiO2 were adjusted for an oxygen saturation of 92% or more. Oxygen therapy was continued until intubation or recovery.

Common management

Awake prone was resorted to at clinician discretion. The decision for intubation was based on pre-specified criteria. Patients who were on HFNC were continued on this therapy during laryngoscopy and intubation. The use of HFNC was allowed as appropriate in both groups after extubation. Non-invasive ventilation was not used in the study, based on local recommendations. Steroids, antibiotics, and antivirals were administered as appropriate. Patients were followed up until 28 days; when the hospital discharge occurred before 28 days, follow up was carried out through a telephonic interview.

The authors calculated sample size based on an intubation rate of 60% according to previous experience. The sample size was 196 patients to demonstrate a reduction in intubation rate by 20% in the HFNC arm (80% power, 2-sided alpha of 0.05). For a reduction in the time to recovery by 2 days, the sample size was 160 patients (80% power, 2-sided alpha of 0.05). Thus, a sample size of 196 patients was chosen. However, during the course of the pandemic, patients had to be transferred from study centers to non-study centers for continued care due to logistical reasons. Continued protocolized care and follow-up were difficult in these patients, and hence, they were excluded from the final analysis. Hence, the final sample size was re-set to 220 patients to allow for transfer outs.

The investigators screened 652 patients; 432 were excluded for various reasons. Thus, 220 patients were randomized, 99 included from the HFNC group and 100 from the conventional oxygen therapy arm in the final analysis. Six patients from the HFNC group and seven from the conventional oxygen therapy group were transferred to another facility.

Outcomes

Co-primary outcome 1. Intubation rate within 28 days: significantly lower with HFNC: 34/99 (34.3%) vs. 51/100 (51%) Hazard ratio: (hazard ratio, 0.62; 95% CI, 0.39-0.96; P = .03)

Number of patients who showed clinical recovery in 28 days: 77/99 (77.8%) vs. 71 (71%)

Co-primary outcome 2. Time to clinical recovery in 28 days: Defined as a reduction of 2 or more points on a modified 7-category ordinal scale from the time of randomization. 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 = 0.047)

Secondary outcomes (HFNC vs. conventional oxygen)

No of patients intubated within 7 days 31.3 vs. 50%

No of patients intubated within 14 days 34% vs. 51%

Ventilation-free days at 28 days: 28 (19–28) vs. 24 (14-28) (significantly less with HFNC)

RRT, ICU and hospital LOS: not different

Mortality at days 14 and 28 not different

Suspected bacterial pneumonia: 13 patients (13.1%) vs. 17 (17.0%)

Bacteremia: 7 (7.1%) vs 11 (11.0%).

Tertiary outcomes

The duration of HFNC or conventional oxygen therapy prior to intubation not significantly different

Time spent on an FiO2 of more than 70% was significantly higher with conventional oxygen therapy.

Extrapulmonary organ involvement at 7 days was not different, based on the SOFA scores

Subgroup analysis

Age 60 or more vs. less than 60: less intubation with age less than 60

P/F ratio 100 or more vs. less than 100: Not different

IL-6 level 100 pg/ml or more vs. less than 100 pg/ml: less intubation at less than 100 pg/ml

No difference in subgroups regarding time to clinical recovery

Subgroup analyses were exploratory in nature, not adjusted for multiple other parameters.

Post-hoc sensitivity mixed-model analysis

Using study site as random effect showed no difference in the primary outcome – favored HFNC with reduced intubation rates and increased probability of clinical recovery.

Limitations – 

Assumed 20% reduction in intubation rates – may be unrealistic hence, reduced sample size

Sample size calculated based on intubation rate of 60%; actual intubation rate was 42.7%; sample size may have been inadequate

NIV was not used in the study

Thirteen patients were transferred and not included in the final analysis

A large number of exclusions 432/652 (66.2%)

Limited external validity (study based on only three centres in Columbia)

Unblinded, possible bias

Only short term (28 days) outcome was studied.

Summary – 

An overall good trial that supports the use of high flow oxygen therapy in patients with Severe COVID-19.