Effect of Low-Normal vs High-Normal Oxygenation Targets on Organ Dysfunction in Critically Ill Patients: A Randomized Clinical Trial

Abstract

Importance: Hyperoxemia may increase organ dysfunction in critically ill patients, but optimal oxygenation targets are unknown.

Objective: To determine whether a low-normal Pao2 target compared with a high-normal target reduces organ dysfunction in critically ill patients with systemic inflammatory response syndrome (SIRS).

Design, setting, and participants: Multicenter randomized clinical trial in 4 intensive care units in the Netherlands. Enrollment was from February 2015 to October 2018, with end of follow-up to January 2019, and included adult patients admitted with 2 or more SIRS criteria and expected stay of longer than 48 hours. A total of 9925 patients were screened for eligibility, of whom 574 fulfilled the enrollment criteria and were randomized.

Interventions: Target Pao2 ranges were 8 to 12 kPa (low-normal, n = 205) and 14 to 18 kPa (high-normal, n = 195). An inspired oxygen fraction greater than 0.60 was applied only when clinically indicated.

Main outcomes and measures: Primary end point was SOFARANK, a ranked outcome of nonrespiratory organ failure quantified by the nonrespiratory components of the Sequential Organ Failure Assessment (SOFA) score, summed over the first 14 study days. Participants were ranked from fastest organ failure improvement (lowest scores) to worsening organ failure or death (highest scores). Secondary end points were duration of mechanical ventilation, in-hospital mortality, and hypoxemic measurements.

Results: Among the 574 patients who were randomized, 400 (70%) were enrolled within 24 hours (median age, 68 years; 140 women [35%]), all of whom completed the trial. The median Pao2 difference between the groups was -1.93 kPa (95% CI, -2.12 to -1.74; P < .001). The median SOFARANK score was -35 points in the low-normal Pao2 group vs -40 in the high-normal Pao2 group (median difference, 10 [95% CI, 0 to 21]; P = .06). There was no significant difference in median duration of mechanical ventilation (3.4 vs 3.1 days; median difference, -0.15 [95% CI, -0.88 to 0.47]; P = .59) and in-hospital mortality (32% vs 31%; odds ratio, 1.04 [95% CI, 0.67 to 1.63]; P = .91). Mild hypoxemic measurements occurred more often in the low-normal group (1.9% vs 1.2%; median difference, 0.73 [95% CI, 0.30 to 1.20]; P < .001). Acute kidney failure developed in 20 patients (10%) in the low-normal Pao2 group and 21 patients (11%) in the high-normal Pao2 group, and acute myocardial infarction in 6 patients (2.9%) in the low-normal Pao2 group and 7 patients (3.6%) in the high-normal Pao2 group.

Conclusions and relevance: Among critically ill patients with 2 or more SIRS criteria, treatment with a low-normal Pao2 target compared with a high-normal Pao2 target did not result in a statistically significant reduction in organ dysfunction. However, the study may have had limited power to detect a smaller treatment effect than was hypothesized.

Trial registration: ClinicalTrials.gov Identifier: NCT02321072.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.. Patient Selection, Randomization, and Flow Through the Trial

ICU indicates intensive care unit. aScreening details were not reported by all 4 participating centers. For the 2 centers that did report screening data, results are available in the eFigure 2 in Supplement 2. bSIRS criteria: (1) temperature >38 °C or <36 °C; (2) heart rate >90 beats/min; (3) respiratory rate >20 breaths/min or Paco2 <32 mm Hg; or (4) white blood cell count >12 ×109/L, <4 ×109/L, or >10% immature (band) forms. cExclusion criteria: admitted after elective surgery, known pulmonary arterial hypertension, severe acute respiratory distress syndrome (ARDS), pregnancy, severe chronic obstructive pulmonary disease, do-not-intubate order, carbon monoxide or cyanide intoxication, methemoglobinemia, sickle cell disease, or known cardiac right-to-left shunting. Reasons for exclusion were not reported by all participating centers. Data for the reporting centers are available in eFigure 2 in Supplement 2. dRandomization was stratified in a 1:1 ratio by age (<50, 50-70, and >70 years), sex, and reason of admittance (medical, surgical, or trauma). eThis patient developed severe ARDS immediately after randomization.

Figure 2.. Pao2 by Treatment Group for Patients Alive in the Intensive Care Unit Days 1 to 15

Boxes represent medians and interquartile ranges, whiskers extend to the lowest and highest observations within 1.5 × interquartile range (IQR), and the circles represent outlier observations. Plotted values were based on a median of 5 (IQR, 3 to 7) arterial blood gas measurements per patient per day, which were time-weighted and averaged per patient-day before aggregation by study group. The median Pao2 difference between the study groups was −1.93 kPa (95% CI, −2.12 to −1.74; P < .001), with significant differences on each study day except day 12 (P = .07). Boxes are offset for readability. To convert Pao2 to mm Hg, divide by 0.133.

Figure 3.. Cumulative SOFARANK Outcomes by Treatment Group

The primary end point was a ranked outcome of nonrespiratory organ failure quantified by the nonrespiratory components of the Sequential Organ Failure Assessment (SOFA) score. For each patient, the daily SOFA score minus the baseline SOFA score was summed over the first 14 study days. The resulting score was used to rank participants from fastest organ failure improvement (lowest scores) to worsening organ failure or death (highest scores). The figure shows that patients randomized to a high-normal Pao2 target had nonsignificantly lower (better) scores. The median SOFARANK score was −35 points (interquartile range [IQR], −63 to 0) in the low-normal group vs −40 points (IQR, −76 to −4.5) in the high-normal group (median difference, 10 points [95% CI, 0 to 21]; P = .06).