To the best of our knowledge, this is the most extensive multicenter study describing oxygen derangements after aSAH. For the first time, we assessed the role of both hypoxemia and hyperoxemia in aSAH patients, including the concept of oxygen variability that could account for unfavorable outcome. Moreover, this is the first study evaluating the occurrence of ARDS using the Berlin definition in this population. The large size of our cohort and the inclusion of three different centers make this study well representative for the evaluation of the incidence and effects on patients' outcomes of respiratory derangements after aSAH.
According to our results:
- episodes of oxygenation derangements, i.e., hyperoxemia and hypoxemia, are frequent in aSAH patients, whereas
- the incidence of ARDS after aSAH reaches only 3.6% within the first week of ICU admission.
- the duration of mechanical ventilation, neurological status at admission (GCS), and PaO2 variability are all independent factors for unfavorable outcome. We also confirmed that hypoxemia and ARDS are associated with unfavorable outcome after aSAH.
The main goal of mechanical ventilation in aSAH patients is to provide adequate oxygenation and to prevent the risk of hypoxemia, which is a well-known cause of secondary brain injury . The recommended target of oxygenation as per PaO2 values in brain-injured patients with healthy lungs is > 75 mmHg, whereas in those suffering from ARDS, lower PaO2 targets (55-80 mmHg) are suggested . Also, oxygenation derangements are frequent, with an incidence ranging from 43% to 92% in aSAH patients .
Supplemental oxygen is a fundamental part of the acute management of these patients; however, aggressive treatment of hypoxemia might lead to the patients’ exposure to unnecessarily high levels of FiO2, even higher than the values strictly necessary to maintain physiologic values of PaO2, sometimes for a prolonged amount of time.
Although moderate hyperoxemia can increase cerebral oxygenation as measured by near-infrared spectrometry (NIRS), its clinical implications remain unclear [28, 29]. Indeed, hyperoxemia can have detrimental effects on the patients' outcome by several pathophysiological mechanisms, including oxidative damage and an increase in reactive oxygen species production, deriving from high tissue oxygen tension with consequent mitochondrial damage and lipid peroxidation, leading to neuronal cells apoptosis. Several cohort studies support the hypothesis that hyperoxemia could be detrimental in the emergency room  and after cardiac arrest . Although the effects are particularly pronounced following long-term exposition to high PaO2 levels, several studies suggest that even short term hyperoxemia can lead to increased mortality and morbidity, especially in brain-injured patients [31, 32].
A randomized trial  which compared two targets of PaO2 (70 vs. 100 mm Hg or arterial oxygen saturation (SaO2) between 94% and 98% vs. SaO2 values between 97% and 100%) found that a conservative target for oxygen therapy is associated with reduced ICU mortality (absolute risk reduction of 0.086 [95% CI, 0.017-0.150]). More recently, a retrospective analysis of an extensive database confirmed these results for severe but not for mild hyperoxemia after cardiac arrest .
We also found that PaO2 variability was independently associated with poor outcome. PaO2 variability could cause the so-called “reperfusion injury,” defined as the tissue damage resulting from the restoring of appropriate oxygen and blood supply after a period of hypoxemia . Low oxygen arterial pressure is responsible for tissue hypoxemia or ischemia, which can be followed by reperfusion upon PaO2 increase. Such a reperfusion mechanism could increase neuro-inflammation and brain damage . Thus, PaO2 variability could be a surrogate marker for relative ischemia-reperfusion injury in the brain, which could cause secondary brain injury. Indeed, in pediatric intensive care, oxygen variability measured on the plethysmography has recently been shown to predict chronic lung disease [11, 12] or the need for hospitalization .
ARDS after aSAH can be consequent to several factors, including neurogenic pulmonary edema (NPE), aspiration pneumonia, or ventilator-associated pneumonia. In our study, we did not investigate the etiology of ARDS, but the incidence of aspiration pneumonia and the presence of pathological pulmonary secretions was similar in patients with and without ARDS. The peak of incidence of ARDS was in the first 24 hours, corresponding to that of NPE, thus suggesting that probably NPE was the leading cause of ARDS in our cohort.
A retrospective study reported an incidence of PaO2/FiO2 ratio <300 in nearly one-third of patients with aSAH (27%) . However, other authors suggested that the prevalence of ARDS is much lower, ranging from 4 to 18% [34, 35]. The results of our study suggest that the incidence of ARDS is even lower when compared to previous literature [1,3-5]. The reason could be related to the increasing application of protective ventilation strategies  in our institutions over the last years. The beneficial effect of protective lung ventilation and respiratory strategies are well established in the general ICU population and the operating room [36, 37]. However, the application of these techniques in neuro-critical care patients is contrasting because of this group’s specific therapeutic needs and ventilator targets, and for the potential risks of lung-protective ventilation strategies on intracranial pressure and cerebral perfusion pressure. However, recent studies support the use of protective strategies and, in particular, of low driving pressure and low tidal volumes even in brain-injured patients.
Of note, we chose to evaluate the ARDS incidence according to the daily worst PaO2/FiO2 value. Thus, we might have overestimated the incidence of ARDS, as daily lowest PaO2/FiO2 could be the result of temporary episodes of hypoxemia such as those occurring during an atelectasis episode, during the transports to the radiologic suite, or during an angiographic procedure.
We also showed that patients with ARDS have more frequent episodes of hyperoxemia, a trend towards more frequent episodes of hypoxemia, and a subsequent increased PaO2 variability. Several causes could explain the high PaO2 variability found in ARDS patients. Aggressive treatment of hypoxemia might have led to higher levels of FiO2 and, therefore, high levels of PaO2. Also, patients with ARDS are more susceptible to episodes of derecruitment, atelectasis, and desaturation, promptly treated with high FiO2 and recruitment maneuvers by the attending physician, causing rapid changes in oxygenation values.
One of the limits of this hypothesis is that the PaO2 variability might represent the combined predictive value of both hypoxemia and hyperoxemia and therefore present a better predictive value than each variable alone. Nevertheless, in the multivariate model, hypoxemia had a modest predictive value, and PaO2 variability presented a predictive value independent from hypo- and hyperoxemia, supporting its independent impact on the outcome.
Several limitations to this study need to be mentioned. First, we evaluated ARDS secondary to subarachnoid hemorrhage within the first seven days after the ICU admission, evaluating its occurrence on days one, three, and seven. The median ventilation time in our cohort was 2.00 [0.00, 11.00] days; therefore, patients could have developed ARDS afterward, which could result in an underestimation of the real incidence of ARDS in this group of patients.
Second, we focused on the early outcome after aSAH, at ICU discharge. However, the evaluation of long-term neurological outcome in aSAH would have provided a much stronger message to our study. Third, we have reported associations but not causality, due to the retrospective observational design of this study; moreover, a retrospective data collection resulted in the lack of precise and complete data regarding ventilation and other confounders that might have influenced the patients’ outcome. Finally, we evaluated the daily PaO2 through discontinuous arterial blood gases analysis that might represent less accurately the PaO2 variability when compared to continuous measures.