Monitoring of patients with critical illness has expanded significantly over the past several decades. As for hemodynamics, respiratory or renal functions, several studies have underlined the importance of monitoring brain function, not only in patients with a primary brain injury [i.e., traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), post-anoxic brain injury], but also in those with a systemic disease, such as sepsis, acute pancreatitis, or cardiogenic shock, who may present different alterations of cerebral function and potentially may develop secondary brain injuries (1), which can impact on long-term functional and cognitive recovery (2).

In patients suffering from TBI, the combination of intracranial pressure (ICP) and cerebral perfusion pressure (CPP)-guided therapy is recommended for the current management of these patients (3); similarly, ICP and CPP are the cornerstone of management of severe non-traumatic brain injury patients, although the evidence suggesting that such approach might impact on long-term outcomes remain limited (4). Importantly, increased ICP could be a late and insensitive indicator of some secondary brain injuries (5, 6); in particular, the occurrence of tissue hypoxia may occur even in the absence of intracranial hypertension and, when untreated or refractory to therapeutic interventions, is associated with an increased risk of poor neurological outcome in brain injured patients (7, 8). As such, rather than protocolizing therapies to target fixed ICP and CPP values for all patients, independently from the underlying brain injury, comorbid diseases, and the severity of brain edema, the implementation of brain tissue oxygen pressure (PbtO₂) monitoring could be helpful to individualize ICP and CPP values based on cerebral oxygenation.

Although higher than recommended CPP targets (i.e., >60 mmHg) have been associated with adequate PbtO₂ values in heterogeneous populations of brain injured patients, few prospective studies have evaluated the effects of increasing CPP using vasopressors on PbtO₂ in such patients. In one small study (n = 11) on TBI patients, increasing CPP from 70 to 90 mmHg with norepinephrine resulted in a significant increase in PbtO₂ (from 17 ± 8 to 22 ± mmHg), despite brain metabolism was only marginally affected (8). In another study including 14 TBI patients, increasing CPP resulted also in a significant increase in PbtO₂, although this was measured after a challenge of inspired oxygen at 100% on the ventilator (9). However, all these studies did not specifically investigate the proportion of patients requiring higher than recommended CPP to obtain adequate PbtO₂ values, neither whether this CPP target would change along the hospital stay.

The aim of this study was therefore to evaluate which level of CPP corresponds to an adequate PbtO₂ in an heterogeneous population of brain injured patients. Secondary aims were to assess: (a) whether this level of CPP change over time and (b) the characteristics of patients requiring higher than recommended CPP targets to have optimal brain oxygenation values.

In this study, including a 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 in 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 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 also resulted into 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. Importantly, this CPP challenge should be performed only 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 (16). 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 (17, 18). 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 (17).

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. As such, because PbtO₂ is dependent on CPP 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) (19), recommended CPP targets can still result in tissue hypoxia in the absence of elevated ICP, as autoregulation might be impaired or the lower limit shifted toward higher CPP thresholds in brain injured patients (20). Individualized CPP values based on optimal autoregulation status has also been suggested in TBI patients (20); however, targeting “safe” CPP values based on the plateau curve of autoregulation could not correspond to adequate brain oxygenation in some patients (21). In one study (19), PbtO₂ was pressure dependent when autoregulation was impaired, while it remained within stable values if autoregulation was intact. However, tissue hypoxia could occur even within normal autoregulation indices (19), thus suggesting that only the presence of PbtO₂ monitoring could help to optimize CPP and avoid tissue hypoxia. 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 (22). In SAH patients, no correlation was observed between PbtO₂ measurements and, simultaneously, TCD recording (23). 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 (24). Unfortunately, we did not specifically assess cerebral autoregulation in our study and could not provide additional data to the relationship between autoregulatory status and brain oxygenation. Similarly, NPi assessment using automated pupillometry could reflect elevated ICP (25); 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 and monocentric and retrospective design might introduce 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., the foramen of Monro, which would result in 10–15 mmHg lower CPP, depending on the elevation of the head of the bed (usually 15–30°) (26). Third, many patients had baseline ICP, CPP, and PbtO₂ within normal values at baseline, which might not entirely justify a daily “CPP challenge.” However, the duration of CPP challenge was short, being supervised by an experienced intensivist, and was clinically relevant, as conducted in a well-designed approach, and informative for daily patient management. Interestingly, in those patients with normal PbtO₂ levels at baseline, 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. Fourth, the procedure was considered as safe (i.e., no complications were recorded); however, we did not assess changes in cerebral metabolism (i.e., glucose or lactate/pyruvate ratio), which might have also been influenced by changes in brain hemodynamics. Fifth, CPP augmentation was not compared with other interventions able to increase PbtO₂ in brain injured patients (i.e., increase in FiO₂ and arterial hyperoxia) (27). As such, whether increased CPP rather than, as an example, increased FiO₂ would result in similar effects on brain oxygenation or would have a different safety profile in brain injured patients remains unknown. Sixth, 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 (28). Seventh, 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 (29). 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. Eighth, the cerebrovascular pathophysiology among the different types of acute brain injury is different; in particular, SAH patients can develop delayed cerebral ischemia between 4 and 15 days after the injury, whereas cerebral hyperemia and intracranial hypertension may be more common in TBI patients. As such, our findings are also relevant to the very early phase after the injury and in the absence of uncontrolled intracranial hypertension. Finally, we provided different descriptive analyses without multivariable assessment, as the number of events was limited; however, multiple statistical comparisons exposes to the inflation of false positive tests within dependent datasets.

In this heterogeneous population of acute brain injured patients, PbtO₂ monitoring suggested the need for higher than recommended CPP targets to avoid tissue hypoxia. A higher response in brain oxygenation to the CPP challenge was observed in those patients with low PbtO₂ values at baseline. The effects of CPP increase over brain oxygenation are consistent over time.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethical Committee of the Erasme Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

FST, SS, and MK conceived the study protocol. AQ and FST performed the transcranial Doppler. MK, EG, and LP collected the data. HN, LP, and MK analyzed the data. FST, MK, JC, and OD drafted the present manuscript. SS, EG, LP, and AQ critically revised the manuscript. All authors read and approved the final manuscript.

FST is the Scientific Advisor for Neuroptics Inc. and received lecture fees from Integra LifeSciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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