In this retrospective observational study, we observed that a multimodal evaluation including ICP and PbtO2 could more accurately detect brain hypoperfusion in a heterogeneous population of brain-injured patients. The dynamic hyperoxia test, which allowed to compute the OxR, did not significantly improve the diagnostic accuracy of this multimodal approach to detect brain hypoperfusion. Similar results were observed when traumatic and non-traumatic brain injuries were analyzed separately.

The most accurate technique to quantify CBF in critically ill patients is CTP; indeed, assessment of CBF velocities using transcranial Doppler cannot provide absolute values of CBF [21], while thermodilution techniques are invasive and require repeated calibrations; their use can be limited in patients with fever or when the probe is placed close to large vessels and suffer from progressive drift of measured CBF values, which can result in inappropriate therapeutic decisions [22]. As CTP required patient’s transportation (i.e., increased risk of hypotension, hypoxemia, increased ICP) and is associated with not neglectable radiations exposure [12], bedside surrogates of CBF are necessary to provide continuous and reliable assessment of brain hemodynamics in acute brain-injured patients. Elevated ICP is often used in clinical practice to identify patients at risk of brain hypoperfusion; however, CBF can also be within high ranges after TBI, indicating hyperemia, which would result in a poor correlation of ICP with absolute CBF values [23]. Moreover, brain hypoperfusion can occur also in brain-injured patients with ICP values below the cutoff of 20–22 mmHg, which has been commonly used to define “intracranial hypertension”, independently from cerebral perfusion pressure (CPP) values [14]. Our data are in line with previous studies that reported a limited accuracy for ICP and CPP to predict CBF values or brain hypoperfusion, while a good correlation between PbtO2 and CBF was observed [24,25,26]; moreover, we showed that this correlation was present also for non-traumatic brain injuries, such SAH and ICH. Importantly, the PbtO2 probe was placed into the “at-risk” area (i.e., normal appearing but close to a contusion or injured region), and our results might not be applicable in cases where probe insertion might target different cerebral areas. Moreover, we focused only on the area surrounding the PbtO2 catheter, as we included not only patients with diffuse brain injury (i.e., as it might be the case for TBI patients with diffuse axonal injury), but also many with focal injury (i.e., traumatic contusion or intracerebral hemorrhage), in whom the regional CBF might not correlate adequately with the global CBF of the ipsilateral cerebral hemisphere.

Importantly, median ICP and PbtO2 were within normal values, i.e., clinical scenarios where performing additional measures, including neuroimaging, can be debatable. As such, our findings should be considered as physiological investigations of the relationship between CBF and neuromonitoring data rather than a support to perform more frequently CTP in this setting.

Previous studies have tried to improve the accuracy of multimodal neuromonitoring to detect brain hypoperfusion by adding, as an example, cerebral microdialysis (i.e., in particular, reduced cerebral glucose or high lactate to pyruvate ratio, which might suggest anaerobic metabolism occurring because of tissue hypoxia) [15]. However, cerebral microdialysis is available only in few centers, and interpretation of its data requires one-hour fluid collection, i.e., it might not be sensitive enough to rapid changes in CBF, which could be detected by monitoring systems providing real-time values. The dynamic hyperoxia test at the bedside could potentially help to improve the accuracy of multimodal neuromonitoring to detect brain hypoperfusion. Indeed, normal PbtO2 might be still associated with brain hypoperfusion in patient treated with permissive hyperoxia (i.e., PaO2 > 150 mmHg) [27]; in this setting, normal PbtO2 values would not reflect normal CBF values but the high levels of dissolved oxygen at the arterial capillary side, which might increase interstitial oxygen diffusion and global delivery. Moreover, low PbtO2 values could be observed in the presence of normal or high CBF values, in particular in case of reduced arterial oxygen content (i.e., anemia or hypoxemia) or increased cerebral oxygen consumption (i.e., fever, agitation or fever) [16]. In one study, the OxR was weakly but significantly correlated with ICP and CPP in TBI patients [17]; no direct CBF assessment was performed in this population. However, in a subgroup of patients in whom hyperventilation (i.e., inducing a reduction of CBF) was performed, the OxR was significantly reduced by more than 10%, suggesting a potential relationship between the magnitude of PbtO2 response to hyperoxia and the baseline CBF. In another study including 83 TBI patients, the OxR was significantly different across different ranges of CBF values, being lower for CBF of < 10 or 11–15 mL/100 g × min and higher for CBF > 40 mL/100 g × min) [28].

Which are the clinical implications of our findings? As the increase in PbtO2 following hyperoxia might be reduced in the presence of low CBF, the OxR might be easily used at the bedside to identify patients at risk of brain hypoperfusion. Although absolute OxR values did not increase the accuracy of ICP and baseline PbtO2 to detect brain hypoperfusion in our cohort, the presence of low OxR values (i.e., < 0.2) could identify still some patients with low CBF values despite ICP and PbtO2 within “normal ranges”. Conversely, normal OxR in the presence of slightly elevated ICP with still normal PbtO2 might suggest the presence of cerebral hyperemia; also, isolated low PbtO2 with normal OxR might imply an imbalance between oxygen delivery and consumption that is independent from CBF, i.e., low oxygen content or increased oxygen consumption. This might help to further individualize patients’ care according to the underlying mechanisms resulting in tissue hypoxia. Importantly, it is important to consider that CTP, especially if used in isolation, had limited diagnostic utility to predicting infarct after ischemic stroke [29]; hence, using one single CTP imaging as the “gold standard” to assess hypoperfusion can be somewhat debatable, and, although being used in other studies [15], will deserve further confirmatory analyses in brain-injured patients.

This study has several limitations to acknowledge. First, the study was single-center and local practices might limit generalizability of the results. Second, we included both traumatic and non-traumatic injuries; although these diseases have a significant heterogeneity in pathophysiology and overall management, main results about OxR were similar in the subgroup analysis. Third, we did not specifically assess whether OxR, on admission or repeatedly measured during the ICU stay, might be associated with patients’ outcome, as suggested into another study [17]. Also, we did not evaluate whether fluctuations of ICP and PbtO2 might also provide more clinically relevant information on brain perfusion than baseline ICP/PbtO2 values or OxR in this setting. Fourth, we did not assess how CBF might respond to hyperoxia; in previous studies, the authors observed a slight decrease in ICP following breathing FiO2 100%, which might suggest intact autoregulatory mechanisms, resulting in vasoconstriction in response to elevated oxygen pressure to maintain a constant tissue oxygen delivery [28]. Fifth, the prevalence of brain hypoperfusion in our study was particularly high, reflecting clinical decision of the attending physicians to explore patients at risk of brain hypoperfusion. A prospective study including all brain-injured patients with neuromonitoring, independently on the pretest probability of brain hypoperfusion, could provide a more extensive and reliable assessment of the role of OxR to detect low CBF values in this setting. Sixth, PbtO2 probes were placed in the anterior and middle cerebral artery territories; therefore, changes in posterior vascular territories were not specifically evaluated. Seventh, one may argue that, in the small area where brain oxygenation is measured, CBF would be highly negatively impacted by the instrumented probe. However, regional CBF varied across a wide ranges of values in our study, i.e., many patients had normal or high CBF values. If the tip would have been a reason for low CBF, then oligemia would have been observed in all patients. Moreover, the tip was placed in the region “at risk”, i.e., the cerebral area suffering from contusion, edema or vasospasm; as such, it was expected to have lower regional CBF in the analyzed region than other normal appearing areas (in particular for TBI and ICH). In a previous study [15], a similar methodological approach was used than in our study; also, the authors showed that regional CBF was correlated (although with same variance) with global CBF. Finally, measurement of absolute CBF might not adequately assess the degree of tissue hypoxia; indeed, CBF values within “normal” ranges might still be insufficient for cerebral areas at high metabolic rates or when low arterial oxygen content is present. However, most of therapeutic strategies aim at increasing brain perfusion in acute brain injured patients, and the assessment of CBF remains a relevant end-point in this setting.