The paramount parameter: arterial oxygen tension versus arterial oxygen saturation as target in trials on oxygenation in intensive care
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KeywordsOxygen inhalation therapy Hyperoxia Hypoxia Intensive care units Respiratory insufficiency Critical illness
Handling Oxygenation Targets in the Intensive Care Unit
Intensive care unit
Arterial oxygen tension
Arterial oxygen saturation
Oxygenation targets in critically ill patients admitted to the intensive care unit (ICU), in particular in patients with acute hypoxaemic respiratory failure, are still a matter of debate. There is mounting evidence for potential harm through hyperoxia [1, 2, 3]. Nevertheless, the optimal oxygenation targets, which minimise hyperoxia while maintaining sufficient oxygenation to avoid harm through hypoxia, remain unclear. Therefore, larger randomised clinical trials on the subject are needed. Several observational studies  as well as interventional before-and-after trials [1, 5] and three small randomised controlled trials [2, 3, 6] have added valuable, although not definitive, evidence to the field. Arterial oxygen saturation (SaO2) or pulse oximetry (SpO2) has been the primary parameter defining the target range in most of the interventional studies conducted. We would like to dispute this preference of SaO2 and SpO2 over arterial oxygen tension (PaO2) as the target parameter. Hence, this proposition for debate.
The general hypothesis of the studies on oxygen use in the ICU is that the dangers of oxygen toxicity are underestimated, and that the negative impact of hyperoxia is significant, even when compared to the risks of hypoxia following conservative oxygenation strategies [1, 2, 5, 6]. Hence, studies proposing more conservative oxygenation targets have been conducted primarily in the effort to avoid hyperoxia. The parameters PaO2 and SaO2 are linked as visualised in the oxygen dissociation curve . The interval of PaO2 in ICU patients spans upwards from approximately 7.3 kPa (55 mmHg) [8, 9, 10]. In this area, the oxygen dissociation curve is rather flat  and covers only a small range of SaO2 values. The SaO2 range becomes even narrower with hyperoxaemic levels of PaO2 depending on its definition, which varies from over 13.3 kPa (100 mmHg) to over 64.9 kPa (487 mmHg) , while the corresponding SaO2 encompasses only four numeric values from 97% to 100%. This limits the control of hyperoxaemia if SaO2 is used as the target parameter of oxygenation. Furthermore, when SaO2 defines the oxygenation target in clinical trials, the narrow SaO2 spectrum will likely result in a larger risk of an overlap of PaO2 or SaO2 between the conventional and interventional study groups.
One could argue that the use of SaO2 over PaO2 offers the possibility to use the non-invasive measurement of oxygenation, SpO2. The correlation between SaO2 and SpO2 is generally high which makes SpO2 invaluable in the continuous monitoring and titration of oxygen supplementation in the ICU . Nevertheless, SpO2 is unreliable as a measure of arterial oxygenation in patients with sepsis , in patients with use of vasopressors , in patients with high or low body temperature , and in patients with hypoxaemia [12, 13]. Therefore, SpO2 cannot be used in the ICU without intermittent measurements of SaO2 for comparison as remarkable differences above 4.4 percentage points  may occur. Furthermore, SpO2 has been shown inadequate in identifying and in quantifying hyperoxaemia defined as PaO2 above 16.7 kPa (125 mmHg) at SpO2 levels above 96% . Thus, targeting normoxaemic oxygenation levels in the upper part of the normal reference interval by using SpO2 would inarguably lead to episodes of definitive hyperoxaemia. Moreover, at the steep slope of the oxygen dissociation curve , where the differentiation in SaO2 is the highest, SpO2 is also inadequate in correctly identifying the oxygenation level in the ICU as SpO2 above 94% is necessary to avoid a risk of having SaO2 below 90% . This fact further narrows the spectrum of differentiation when using SpO2.
An argument for using SaO2 over PaO2 is that under normal, healthy conditions more than 98% of the transported oxygen is bound to haemoglobin . Therefore, SaO2 in combination with the haematocrit or haemoglobin level represents the most direct parameter for expressing the amounts of oxygen actually carried in the arterial blood whereas PaO2 is only a secondarily derived parameter. However, the oxygen dissociation curve  shows that SaO2 and PaO2 are mutually dependent, and so this point remains essentially theoretical. Additionally, with increasing hyperoxaemia SaO2 loses its value due to the rigid ceiling of SaO2 at 100%. Furthermore, since the formation of reactive oxygen species is closely linked to the free amounts of oxygen  and since the reactive oxygen species contribute importantly to the detrimental effects of hyperoxia , PaO2 is probably the parameter with the tightest relationship to the toxic properties of oxygen. As these toxic properties are what trials on the subject strive to minimise, one could claim that this connection is just as important as the link between SaO2 and the total oxygen content of the blood.
In clinical practice, both SaO2 and PaO2 are commonly used to guide oxygen therapy, particularly in the ICU setting, as the majority of acute critically ill ICU patients require arterial cannulation for haemodynamic monitoring. For evaluating arterial oxygenation, a recent survey of northern European ICU physicians has shown that PaO2 was preferred to SaO2 .
In summary, to define the oxygenation target levels precisely, to reduce the risk of unwanted hyperoxaemia, and to minimise overlap between conventional and interventional groups, in clinical trials of higher versus lower oxygenation targets in the ICU population, PaO2 is in our opinion the superior target parameter as compared to SaO2. This is also reflected in clinicians’ self-reported preferences. Therefore, we advocate the use of PaO2 as the primary target parameter of arterial oxygenation in future clinical trials that aim to establish the evidence of how to use medical oxygen in patients admitted to the ICU.
OLS’ PhD project is funded by a grant from Innovation Fund Denmark.
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BSR conceived the idea for the editorial. OLS drafted the primary manuscript. OLS and BSR revised the manuscript together. Both authors have read and approved the final manuscript.
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Both authors are involved in an ongoing investigator-initiated randomised trial targeting oxygenation in acutely ill patients in the ICU, the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial (ClinicalTrials.gov NCT03174002), OLS as coordinating investigator and BSR as sponsor and primary investigator.
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