This systematic review and meta-analysis shows no difference in mortality at day 90 when aggregating data from RCTs comparing lower and higher oxygenation targets. For secondary outcomes, a significant effect favoring lower oxygenation targets was identified with regards to serious adverse events..
The following study strengths and limitations should be considered. First, this meta-analysis includes important secondary patient centered outcomes such as support-free days and serious adverse events. Second, in order to ensure comprehensiveness of the data, corresponding authors were contacted for additional data. Also, established guidelines, such as the PRISMA and GRADE approach, were used to ensure the quality of our methodology and certainty of evidence.
A key limitation is that all trials on oxygenation in ICU patients used different targets. Several varying thresholds were used for PaO2 targets. Moreover, some trials used SpO2 targets rather than PaO2 targets and one study managed liberal oxygenation by applying an FiO2 of 1.0 (irrespective of SpO2) during the first 24 hours while not using different SpO2 or PaO2 targets afterwards. A PaO2 of 90 mmHg can correspond with a SpO2 of 100% but also 93%, partially depending on the underlying disease. Therefore, a higher PaO2 cannot be consistently translated into a fixed SpO2 (23). As thresholds differ, a patient could be categorized in the higher oxygenation group in one trial, whereas this could be the lower oxygenation group in the other trial.Moreover, in some studies chosen oxygenation targets can overlap (15, 18), suggesting there may not be a true comparison between a ‘high’ and a ‘low’ group.
Another limitation is the heterogeneity of the ICU population in combination with the heterogenous treatment effect that can be expected from oxygen therapy in certain subgroups. For example, in vasodilatory septic shock, arterial hyperoxia may be beneficial due to antibacterial properties and the counteraction of vasodilation (24, 25), while in ischemia and reperfusion injuries, such as myocardial infarction, hyperoxia may have detrimental effects (26). Recent reviews explored the optimal oxygen targets per subgroup by underlying disease (27, 28) and no optimal oxygen target per subgroup could be identified, though it seems justifiable to avoid both hypoxemia and excess hyperoxemia. Hence, the key question remains whether we should settle for a one-strategy-that-fits all (optimal) oxygen therapy approach, or whether optimal oxygen strategies can be applied per subgroup.
None of the included trials were blinded, which can be considered a limitation since the latest literature could have imposed bias towards the beneficial effect of lower oxygenation targets (29, 30). Therefore, clinicians may be more prone to adhere to the lower targets, making it more difficult to create contrast in oxygenation between two different groups. However, owing to the design of the trial, it was essentially unfeasible to blind clinicians for the assigned treatment group. Despite lack of blinding and early stopping bias, an overall low risk of bias (Figure 2 and 3) and low heterogeneity was observed with a moderate to high certainty of evidence (Table 1). Taken together, this provides a reasonable degree of certainty that there is no or little evidence for important differences in mortality between compared oxygenation targets.
Our findings are in line with recent systematic reviews showing that different oxygenation strategies did not have a significant impact on mortality (9, 31). However, the findings are in contrast to previously published reviews (5, 32, 33), that support a conservative oxygen strategy. A simple explanation for these contradictions might be that patients either simply do not benefit from a lower oxygenation strategy or that the achieved lower and higher PaO2 in both groups lack sufficient contrast to be able to detect a difference. In the included trials it has proven to be difficult to accomplish a clinical contrast between the intervention and the control group. The majority of the trials that reported on the achieved oxygenation show a difference of 10 to 20 mmHg (15, 17-19, 21). Our sensitivity analysis using a meta-regression framework (Figure 9 and additional files) shows that trials with a smaller achieved difference (10-20 mm Hg) (15, 17-19, 21) and studies with a larger achieved difference (25-70 mm Hg) (10, 16, 22) both show heterogenous results. It should be noted that achieved differences are in the same order of magnitude for most studies (10-30 mm Hg) despite one outlier (70 mm Hg). When a large difference is achieved there is a sign that patients may benefit from a lower oxygenation target. Though, due to lack of significant results, this may also be originated by chance. Furthermore, when specifically targeting a very high or low target a significant clinical difference may be achieved but neither the intervention nor the control group may then represent usual care. Accordingly, the present study may demonstrate that a broad range of less extreme achieved oxygenation falls within a fairly safe category.
The different results amongst included trials can be explained by secondary factors such as early stopping bias, subgroup analysis and not choosing a truly hyperoxic target. Taking all included trials that reported on achieved targets together, an average higher oxygenation around 110 mm Hg was achieved, with an individual maximum of 185 mm Hg (16). The hypothesis that 110 mm Hg is not a truly hyperoxic target is supported by earlier literature that showed a significant increase in mortality in the hyperoxic group, where hyperoxia was defined as PaO2 > 300 mmHg (26). Our meta-regression analysis (figure 9) shows that when a hyperoxic target of 185 mm Hg is achieved (16), patients may have a lower risk of mortality in the lower oxygenation group. In line, these results are not significant and the more severe the higher target, the less it represents usual care and the higher the chances of mortality.
A new finding in our meta-analysis resulted from studying serious adverse events. We found that adverse events are more likely to occur in the higher oxygenation groups. As in previous studies, serious adverse events should be critically reviewed to evaluate whether the event is consistent with the natural history of the critical illness (34). If a large difference is observed, similar to the difference found in our meta-analysis, it might be attributable to the different interventions. As serious adverse events can highly impair patient health and quality of life the potential negative impact of higher targets may also be a compelling argument to adhere to a lower oxygenation strategy. However, the results on adverse events are dominated by one study (18) and a low number of studies reported on the individual adverse events groups. Even though this finding, concerning adverse events , is an important signal for clinical practice guidelines, more robust data is needed for a compelling conclusion.