Conservative versus Liberal Oxygenation Targets in Intensive Care Unit Patients (ICONIC): A Randomized Clinical Trial

Abstract

Rationale: Supplemental oxygen is widely administered to ICU patients, but appropriate oxygenation targets remain unclear. Objectives: This study aimed to determine whether a low-oxygenation strategy would lower 28-day mortality compared with a high-oxygenation strategy. Methods: This randomized multicenter trial included mechanically ventilated ICU patients with an expected ventilation duration of at least 24 hours. Patients were randomized 1:1 to a low-oxygenation (Pa_O2, 55-80 mm Hg; or oxygen saturation as measured by pulse oximetry, 91-94%) or high-oxygenation (Pa_O2, 110-150 mm Hg; or oxygen saturation as measured by pulse oximetry, 96-100%) target until ICU discharge or 28 days after randomization, whichever came first. The primary outcome was 28-day mortality. The study was stopped prematurely because of the COVID-19 pandemic when 664 of the planned 1,512 patients were included. Measurements and Main Results: Between November 2018 and November 2021, a total of 664 patients were included in the trial: 335 in the low-oxygenation group and 329 in the high-oxygenation group. The median achieved Pa_O2 was 75 mm Hg (interquartile range, 70-84) and 115 mm Hg (interquartile range, 100-129) in the low- and high-oxygenation groups, respectively. At Day 28, 129 (38.5%) and 114 (34.7%) patients had died in the low- and high-oxygenation groups, respectively (risk ratio, 1.11; 95% confidence interval, 0.9-1.4; P = 0.30). At least one serious adverse event was reported in 12 (3.6%) and 17 (5.2%) patients in the low- and high-oxygenation groups, respectively. Conclusions: Among mechanically ventilated ICU patients with an expected mechanical ventilation duration of at least 24 hours, using a low-oxygenation strategy did not result in a reduction of 28-day mortality compared with a high-oxygenation strategy. Clinical trial registered with the National Trial Register and the International Clinical Trials Registry Platform (NTR7376).

Keywords: hyperoxia; hypoxia; intensive care medicine; mechanical ventilation; oxygen.

Figure 1.

Consolidated Standards of Reporting Trials flow diagram. The full list of inclusion and exclusion criteria can be found in Appendixes E1 and E2. Data were available for primary and secondary outcomes of all patients. *Patients were withdrawn from the study only if exclusion criteria were present at the time of inclusion. This was checked within 24 hours after randomization. CI = cardiac index; P/F = Pa_O2/Fi_O2 ratio; VA-ECMO = venoarterial extracorporeal membrane oxygenation.

Figure 2.

Median Pa_O2 per day during mechanical ventilation. The Pa_O2 values were calculated on the basis of median Pa_O2 values per day by study group, whereas median values were taken per patient per day before aggregating the data. Lines represent the achieved median Pa_O2 per oxygenation group. Faded areas around the lines represent the interquartile ranges. The dotted horizontal lines represent the boundaries of the higher and lower targets. Blood gas data were not available for seven patients in the low-oxygenation group and for one patient in the high-oxygenation group.

Figure 3.

Kaplan-Meier survival curve of survival until Day 28. On Day 28, 129 (38.5%) patients had died within the low-oxygenation group and 114 (34.7%) had died in the high-oxygenation group. Statistical analysis of the Kaplan-Meier curve showed no significant difference (P = 0.4; adjusted for study site, P = 0.4).