In this study, including an heterogeneous population of brain injured patients, increasing CPP resulted in a significant increase of the brain oxygenation in most of patients. The “optimal” CPP, i.e. the CPP value corresponding to the absence of tissue hypoxia, was higher than recommended targets (i.e. around 80 mmHg). Half of patients showed a significant increase in PbtO2 during the CPP challenge, in particular if they had lower PbtO2 values at baseline. The effects of CPP on PbtO2 changes were similar in the following days of assessment. Non-invasive neuromonitoring could not adequately predict PbtO2 changes during CPP increase.
The improvement in PbtO2 values during CPP increase using vasopressors has also been reported in previous studies. Johnston et al. reported a significant increase in brain oxygenation when CPP was increased from 70 mm Hg to 90 mmHg [8]; these changes were also associated with an increase in cerebral blood flow and a decrease in oxygen extraction fraction (OER). However, as CPP challenge resulted in a greater proportional increase in PbtO2 than OER, the authors concluded that this intervention could potentially increase the oxygen gradient between the vascular and tissue compartments. In another study, increasing CPP resulted also in a significant increase in PbtO2 [9]. Our study included a larger population of patients, included other diseases than TBI and tested two different CPP targets above the baseline values. Although below the lower limit of autoregulation (i.e. the value of CPP corresponding to the direct dependency of cerebral blood flow from the systemic driving pressure) PbtO2 is dependent on CPP [17], autoregulation might be impaired or the lower limit shifted towards higher thresholds in brain injured patients, so that recommended CPP targets can also result in concomitant tissue hypoxia, in the absence of elevated ICP. As such, the presence of PbtO2 monitoring could be useful in these patients to optimize CPP and avoid tissue hypoxia, rather than targeting fixed values [18]. Moreover, this CPP challenge should be performed in those patients with low PbtO2 values at the baseline, in the absence of intracranial hypertension or hypoxemia. Increasing CPP in patients with normal PbtO2 at baseline would result in less significant oxygen improvement and no theoretical effect on tissue metabolism. In one study, Stocchetti et al. also reported that PbtO2 regularly improved after 22 CPP challenges, in particular when low oxygen values were present at the baseline [19]. Baseline PbtO2 below 20 mm Hg was often associated with CPP values within normal ranges. Interestingly, increasing CPP with other drugs than norepinephrine, such as dopamine, might result in less predictable CPP increase and less significant PbtO2 increase [20, 21]. Moreover, PbtO2 would change in response to CPP challenge if placed into “at-risk” areas, as in our study, while effects might be minimal if the catheter is inserted into normal-appearing parenchyma [20].
It has been suggested that cerebral hemodynamics after an acute brain injury could be assessed using non-invasive monitoring, such as cerebral blood flow velocities or cerebral autoregulation indices. Individualized CPP values based on optimal autoregulation status has also been suggested in TBI patients [22]; however, targeting “safe” CPP values based on the plateau curve of autoregulation could not correspond to adequate brain oxygenation in some patients [23] and clinicians should therefore understand that a stable cerebral blood flow over time might potentially result in insufficient oxygen delivery to the brain tissue, if oxygen is not monitored. As such, it is not surprising that changes in PbtO2 during the CPP challenge would not correlate with changes in mFV or PI, two parameters derived from the analysis of cerebral blood flow velocities that are commonly used to estimate cerebral hypoperfusion in the presence of intracranial hypertension [24]. In SAH patients, no correlation was observed between PbtO2 measurements and simultaneously TCD recording [25]. In another study including TBI patients, episode of cerebral hypoxia had all mFV < 40 cm/s, however no correlation was observed between PbtO2 and mFV in the whole cohort [26]. Similarly, NPi assessment using automated pupillometry could reflect elevated ICP [27]; however, as tissue hypoxia may occur even within normal ICP values, the lack of sufficient correlation between PbtO2 and NPi changes was expected.
This study has several limitations to acknowledge. First, the small sample size, monocentric and retrospective design might introduce some significant selection biases and limit the generalizability of our findings, although characteristics of included and excluded patients were similar. Second, although we suggested the need for higher than recommended CPP targets, MAP transducer was zeroed at the atrium level, while some centers would place the zero-reference point next to cerebral anatomical structures, i.e. foramen of Monro, resulting in 10–15 lower CPP for this latter approach, depending on the elevation of the head of the bed (usually 15–30°) [28]. Third, some patients had normal PbtO2 levels at baseline; as such, lower than recommended CPP targets might have been theoretically used, still maintaining adequate oxygen levels. However, lower CPP values would be outside of routine management in brain injured patients and future studies should prospectively evaluate the safety of such approach. Forth, we only assessed short-terms effects of increasing CPP, while persistently high CPP values might be associated with an increased risk of acute respiratory failure, at least in TBI patients, and would not result in better neurological outcome than standard targets [24, 25]. Fifth, we defined tissue hypoxia as a PbtO2 < 20 mmHg; ischemic thresholds for PbtO2 have been tested using the association of this value with patients’ outcome; a recent study identified a threshold of 19 mmHg which adequately separated patients with unfavorable and favorable neurological outcome after TBI [30]. However, the ischemic threshold might vary among different brain disease and within patients and the presence of concomitant metabolism monitoring (i.e. microdialysis) might be helpful to identify ischemic levels of PbtO2 when they would be associated with low cerebral glucose levels and increased lactate/pyruvate ratio.