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Low- vs. High-Normal Oxygenation Targets and Organ Dysfunction in Critically Ill
Quick Takes
- Although previous observational data have demonstrated a U-shaped relationship between PaO2 and mortality among critically ill patients, earlier randomized trials comparing oxygenation targets have produced inconsistent findings.
- Among 400 critically ill patients assigned to conventional (high-normal, PaO2 = 14-18 kPa) versus conservative (low-normal, PaO2 = 8-12 kPa) targeted oxygenation, no significant differences in organ recovery, mortality, or other clinically important outcomes were observed.
- Actual oxygenation in the high-normal group was substantially below the targeted range, a factor that may have obscured any possible benefit offered by one oxygenation target versus the other.
Study Questions:
Hyperoxemia has been associated with adverse outcomes after cardiac arrest, with possible mechanisms including increased ischemia/reperfusion injury, pulmonary toxicity, and vasoconstriction. However, defining thresholds for hyperoxemia have been inconsistent. Does a conservative (low-normal), as opposed to conventional (high-normal), targeted oxygenation strategy improve organ recovery and other clinically important outcomes among critically ill adult patients?
Methods:
In a multicenter trial involving four participating hospitals in the Netherlands, patients were randomly assigned to low-normal (PaO2 = 8-12 kPa [60-90 mm Hg]) versus high-normal (PaO2 = 14-18 kPa [105-135 mm Hg], per local clinical standard) targeted oxygenation. Inclusion criteria included ≥2 criteria for systemic inflammatory response syndrome (SIRS) and anticipated intensive care unit (ICU) length of stay >48 hours, with all subjects stratified by age, sex, and admission indication (medical, surgical, or trauma). Oxygenation was titrated by adjustments in FiO2 or positive end-expiratory pressure (PEEP), with study protocol limiting FiO2 and PEEP to <0.60 and ≤10 cm H2O unless deemed to be clinically necessary. The primary outcome was ranked Sequential Organ Failure Assessment (SOFA) score from day 1 to day 14. Secondary outcomes included the highest nonrespiratory SOFA score, number of documented hypoxemic episodes, duration of mechanical ventilation, and ICU length of stay and mortality.
Results:
Four hundred patients were enrolled (205 in low-normal and 195 in high-normal arms). Median oxygenation was 10.8 (interquartile range [IQR], 9.8-12.0) versus 12.8 (IQR, 10.9-14.9) kPa in the low-normal versus high-normal groups. Median SOFARANK score, the primary outcome, did not differ significantly (-35 [IQR, -65 to 0] vs. -40 [IQR, -76 to -4.5] in the low-normal vs. high-normal groups, p = 0.06), with treatment effect unchanged after adjustment for stratification variables. Secondary outcomes, including highest nonrespiratory SOFA score, duration of mechanical ventilation, length of ICU stay, and mortality during ICU or hospital stay, did not differ significantly between low-normal versus high-normal oxygenation targeted groups.
Conclusions:
Among critically ill adult patients with SIRS and anticipated ICU stay >48 hours, targeted oxygenation in a low-normal range (8-12 kPa) was not associated with improved clinical outcomes, including organ recovery, duration of mechanical ventilation, or mortality during hospitalization or ICU stay compared to targeted oxygenation within a high-normal range consistent with local institutional standard (14-18 kPa).
Perspective:
The protocol in this study utilized a smaller difference (effect size) between targeted PaO2 ranges compared to those chosen in the two prior studies that showed improved outcome with relatively lower oxygenation targets. Therefore, although lower targeted oxygenation as defined may have some true association with improved outcome, this study may be underpowered to detect any such possible small but important difference. Also, while the actual achieved oxygenation in the low-normal versus high-normal oxygenation groups differed significantly, the high-normal group’s oxygenation fell well below the targeted range, a factor that may have obscured any true benefit afforded by the more conservative oxygen management strategy.
Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Implantable Devices, SCD/Ventricular Arrhythmias
Keywords: Critical Illness, Heart Arrest, Intensive Care Units, Length of Stay, Multiple Organ Failure, Myocardial Ischemia, Organ Dysfunction Scores, Positive-Pressure Respiration, Reperfusion Injury, Respiration, Artificial, Secondary Prevention, Systemic Inflammatory Response Syndrome, Vasoconstriction
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