Low-Normal Oxygen Target Fails to Improve ICU Outcomes

Significant uncertainty remains regarding oxygenation targets for critically ill patients in ICUs, and findings from a newly published clinical trial may do little to clarify how much oxygen therapy is optimal.

The multicenter, randomized clinical trial found that among 400 critically ill patients with systemic inflammatory response syndrome (SIRS), treatment with low-normal partial pressure of oxygen (Pao₂) targets did not result in significant reductions in organ dysfunction compared to treatment with high-normal Pao₂ targets.

Differences between the two treatment groups in 90-day mortality duration of mechanical ventilation and ICU length of stay were also found to be clinically insignificant; however, the researchers acknowledged that the study may have had limited power to detect a smaller treatment effect than they hypothesized.

And, in commentary published with the study online Aug. 21 in JAMA, experts in the field concluded that the trial did not “provide the definitive answer on the optimal targets for oxygen therapy and will not change clinical practice.”

The potentially negative effects of hyperoxemia (Pao₂ > 16 kPa), characterized in a 2008 study, include pulmonary toxicity, augmented ischemia/reperfusion injury and systemic vasoconstriction with decreased organ perfusion.

“These effects may impair rather than improve tissue oxygen delivery. Conversely, hyperoxemia may also have benefit,” wrote Harry Gelissen, MD, and colleagues with the Amsterdam Infection and Immunity Institute, Amsterdam, the Netherlands. “Systemic vasoconstriction may curtail vasodilation in patients with SIRS and favorably redistribute blood flow to organs. Hyperoxemia may also have antimicrobial effects.”

The researchers noted that no fewer than 6 previous randomized trials and a 2018 meta-analysis comparing low versus high oxygenation targets showed conflicting results.

“Two of these trials and the meta-analysis reported reduced mortality for lower oxygenation targets, while 4 trials showed no difference in outcome. One trial reported an increased incidence of mesenteric ischemia in the low oxygenation target group,” they wrote.,

Gelissen et al noted that these trials had significant limitations, including the failure to specifically enroll patients with systemic inflammation who might benefit most from hyperoxemia and the failure to define an upper limit for inspired oxygen fraction (F10₂) to attain higher oxygen saturation measured by pulse oximetry (Spo₂) targets, “thereby potentially exposing patients to possible pulmonary oxygen toxicity.”

They further noted that 4 of the studies use SPo₂-based targets for oxygenation instead of Pao2 targets, which are more accurate.

Their study was designed to avoid some of these limitations and determine whether a low-normal Pao₂ target compared to a high-normal Pao₂ target reduces organ dysfunction in critically ill patients with SIRS.

Enrollment occurred from mid-February 2015 to October 2018, with follow up lasting until January of 2019. All adult patients admitted to one of 4 area ICUs with 2 or more SIRS criteria and expected stay of longer than 48 hours. Of the close to 10,000 patients screened for eligibility, 574 were randomized and 400 (70%) were enrolled and completed the trial.

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.

The study’s primary endpoint was SOFA_RANK, which was a ranked outcome of non-respiratory 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).

The median age of the patients included in the analysis was 68 years, and 140 (35%) were female. The median PaO₂ difference between the groups was −1.93 kPa (95% CI, −2.12 to −1.74; P<0.001).

The analysis revealed:

• The median SOFA_RANK score was −35 points in the low-normal PaO₂ group vs −40 in the high-normal PaO₂ group (median difference, 10; 95% CI, 0-21; P=0.06).
• No significant difference was seen in median duration of mechanical ventilation (3.4 vs 3.1 days; median difference, −0.15; 95% CI, −0.88 to 0.47; P=0.59) and in-hospital mortality (32% vs 31%; odds ratio, 1.04; 95% CI, 0.67-1.63; P=0.91).
• Mild hypoxemic measurements occurred more often in the low-normal group (1.9% vs 1.2%; median difference, 0.73; 95% CI, 0.30-1.20; P<0.001).
• 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.

“Among critically ill patients with at least 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,” the researchers concluded.

Commentary writer Eddy Fan, MD, PhD, of Toronto General Hospital, and colleagues, wrote that while the study by Gelissen et al did not answer the question is was designed to address, there are “several implications for future research.”

“Importantly, the results confirm that definitive knowledge is lacking regarding how to optimally titrate oxygen in critically ill patients,” they wrote. “In addition, the novel primary outcome used in this trial opens a discussion on advantages and disadvantages of different outcomes for trials in critical care.”

The commentary writers’ noted that several ongoing trials of oxygen therapy – including UK-ROX (16,500 patient enrollment target ) and Mega-ROX (40,000 patient enrollment target) may provide more clarity on optimal oxygenation for critically ill ICU patients.

“The enormous sample sizes required for these studies underline the issues that Gelissen et al. sought to overcome with a surrogate outcome,” they wrote. “While SOFA_RAND score is not an ideal surrogate outcome, further research on the development of novel end points for clinical trials is needed to provide researchers with tools to reliably determine the efficacy of different treatment strategies.”

“Meanwhile, clinicians should avoid targeting excessively low or high Pao₂ levels in critically ill patients until the results of further trials become available,” they added.

1. Among critically ill patients with systemic inflammatory response syndrome, treatment with low-normal partial pressure of oxygen (Pao₂) targets did not result in significant reductions in organ dysfunction compared to treatment with high-normal Pao₂ targets.

2. Differences between the two treatment groups in 90-day mortality duration of mechanical ventilation and ICU length of stay were also found to be clinically insignificant.

Salynn Boyles, Contributing Writer, BreakingMED™

This trial was funded by the Netherlands Organization for Health Research and Development. The researchers reported no relevant disclosures. Commentary writer Martin Urner reported having a patent for an injectable formulation for treating inflammatory reactins or ischemia reperfusion events.

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