Lower vs Higher Oxygenation Target and Days Alive Without Life Support in COVID-19: The HOT-COVID Randomized Clinical Trial

Abstract

Importance: Supplemental oxygen is ubiquitously used in patients with COVID-19 and severe hypoxemia, but a lower dose may be beneficial.

Objective: To assess the effects of targeting a Pao2 of 60 mm Hg vs 90 mm Hg in patients with COVID-19 and severe hypoxemia in the intensive care unit (ICU).

Design, setting, and participants: Multicenter randomized clinical trial including 726 adults with COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 11 ICUs in Europe from August 2020 to March 2023. The trial was prematurely stopped prior to outcome assessment due to slow enrollment. End of 90-day follow-up was June 1, 2023.

Interventions: Patients were randomized 1:1 to a Pao2 of 60 mm Hg (lower oxygenation group; n = 365) or 90 mm Hg (higher oxygenation group; n = 361) for up to 90 days in the ICU.

Main outcomes and measures: The primary outcome was the number of days alive without life support (mechanical ventilation, circulatory support, or kidney replacement therapy) at 90 days. Secondary outcomes included mortality, proportion of patients with serious adverse events, and number of days alive and out of hospital, all at 90 days.

Results: Of 726 randomized patients, primary outcome data were available for 697 (351 in the lower oxygenation group and 346 in the higher oxygenation group). Median age was 66 years, and 495 patients (68%) were male. At 90 days, the median number of days alive without life support was 80.0 days (IQR, 9.0-89.0 days) in the lower oxygenation group and 72.0 days (IQR, 2.0-88.0 days) in the higher oxygenation group (P = .009 by van Elteren test; supplemental bootstrapped adjusted mean difference, 5.8 days [95% CI, 0.2-11.5 days]; P = .04). Mortality at 90 days was 30.2% in the lower oxygenation group and 34.7% in the higher oxygenation group (risk ratio, 0.86 [98.6% CI, 0.66-1.13]; P = .18). There were no statistically significant differences in proportion of patients with serious adverse events or in number of days alive and out of hospital.

Conclusion and relevance: In adult ICU patients with COVID-19 and severe hypoxemia, targeting a Pao2 of 60 mm Hg resulted in more days alive without life support in 90 days than targeting a Pao2 of 90 mm Hg.

Trial registration: ClinicalTrials.gov Identifier: NCT04425031.

Figure 1.. Flow of Participants in the HOT-COVID Trial

^aNumber of exclusions adds to more than total excluded because patients could have more than 1 reason for trial exclusion at screening. ^bProvided data at baseline and for the analysis of serious adverse events. ^cAll data were deleted on request of patients or next of kin in accordance with national regulations.

Figure 2.. Values for Pao₂, Sao₂, and Fio₂ According to Oxygenation Strategy

Daily medians were calculated from patient-level daily means of the 12-hour lowest and highest Pao₂, with concomitant values for arterial oxygen saturation (Sao₂) and fraction of inspired oxygen (Fio₂). Whiskers represent IQRs. A, For the entire 90-day intervention period, the higher oxygenation group had a median Pao₂ of 91 mm Hg (IQR, 84-96 mm Hg), while the lower oxygenation group had a median Pao₂ of 71 mm Hg (IQR, 68-75 mm Hg). B, For the entire 90-day intervention period, the higher oxygenation group had a median Sao₂ of 95.5% (IQR, 94.3%-96.2%), while the lower oxygenation group had a median Sao₂ of 92.9% (IQR, 91.9%-93.9%). C, For the entire 90-day intervention period, the higher oxygenation group had a median Fio₂ of 0.68 (IQR, 0.57-0.81), while the lower oxygenation group had a median Fio₂ of 0.54 (IQR, 0.45-0.69). Similar presentations of the full 90-day intervention period are presented in eFigures 2-4 and data on the number of patients contributing oxygenation data are presented in eTable 2 in Supplement 2.

Figure 3.. Distribution of Use of Life Support and Death and Subgroup Analyses

COPD indicates chronic obstructive pulmonary disease; Fio₂, fraction of inspired oxygen; Sao₂, arterial oxygen saturation. Panel A shows the percentages of patients who were deceased, alive and receiving life support, and alive without life support during the 90-day follow-up period. Panel B shows the results of the primary analysis and subgroup analyses of the primary outcome of days alive without life support over 90 days. All analyses were adjusted for the stratification variable of site. Mean differences and 95% CIs are based on a general linear model with an identity link, bootstrapped with 10 000 repetitions. The size of the data markers corresponds to the number of patients in each subgroup. A statistically significant interaction (P = .001) was found for heterogeneity of treatment effects for patients with or without shock at baseline.