Take-home message
In two large prospective multicenter cohorts of traumatic brain injured patients, arterial and supplemental oxygen levels varied widely across centers during the first seven days after admission to the intensive care unit.
Exposure to high arterial blood oxygen or high supplemental oxygen—a therapeutic gas immediately titratable at the bedside—was independently associated with 6-month mortality, regardless of brain injury severity.

Introduction

In patients with traumatic brain injury (TBI), hypoxemia is a major predictor of hospital and 6-month mortality [1]. Oxygen supplementation aims to reverse tissue hypoxia and, thus, improve cell viability, organ function, and survival in critically ill patients [2]. However, this may lead to administering more oxygen than needed to patients admitted to the intensive care unit (ICU) [3].

While hyperbaric oxygen is known to be neurotoxic [4], it is not clear whether high normobaric oxygen levels may play a detrimental role in the brain [5]. Hyperoxia, i.e., high inspiratory oxygen fraction, may be associated with excitotoxicity in severe TBI [6]. Furthermore, hyperoxemia, i.e., high blood oxygen partial pressure levels, may potentially worsen organ injury and impact the case fatality rate of critically ill patients with TBI [7, 8]. Therefore, not only too low but even extreme hyperoxemia might cause injury in TBI patients, as David et al. showed [9]. Data on more than 36,000 mixed ICU patients mechanically ventilated with early arterial partial pressure of oxygen (PaO2) suggested an independent U-shape association with hospital mortality [10]. A recent metanalysis of 32 studies in acute brain-damaged patients highlighted that hyperoxemia, differently defined across studies, was associated with an increased risk of poor neurological outcomes [11]. Patients with a poor neurological outcome also had a significantly higher maximum PaO2 and mean PaO2. These associations were present, especially in patients with subarachnoid hemorrhage and ischemic stroke, but not in traumatic brain injured.

Currently, there is no evidence to support the role of hyperoxemia or hyperoxia in a large real-world dataset of critically ill patients admitted to ICU with severe TBI [12,13,14].

Therefore, we described variability across centers in the blood oxygen levels (i.e., PaO2) and oxygen supplementation distributions (i.e., inspiratory oxygen fraction, FiO2) and investigated whether high PaO2 and FiO2 levels are associated with worse 6-month outcomes. We validated our findings in the multicenter Australian OzENTER-TBI database [15]. Finally, we explored whether PaO2 and FiO2 levels may contribute differently to outcomes in the presence of increasing levels of glial fibrillary acidic protein (GFAP), a biomarker of brain injury severity.

The aims of this study are to:

  1. 1.

    Describe the values and the differences in PaO2 and FiO2 in the first week from ICU admission in mechanically ventilated TBI patients across centers in CENTER-TBI;

  2. 2.

    assess whether high levels of PaO2 or FiO2 are independently associated with 6-month mortality and unfavorable neurologic outcome in CENTER-TBI;

  3. 3.

    evaluate whether the impact of high levels of oxygen exposure or high levels of supplemental oxygen on 6-month outcome could be worsened by increasing brain injury severity, as assessed by acute (first 24 h) serum levels of GFAP in the CENTER-TBI cohort.

All these objectives (except the last one) were subsequently validated in an external cohort of patients with traumatic brain injury from OzENTER-TBI. Hypotheses of the current analyses were that exposure to high oxygen and FiO2 levels in TBI patients mechanically ventilated and admitted to ICU may promote brain injury and have a negative impact on both functional neurological disability and survival.