Brain Tissue Oxygen Levels as a Perspective Therapeutic Target in Traumatic Brain Injury. Retrospective Cohort Study

Traumatic brain injury (TBI) is a significant public health burden, with 69 million cases reported annually throughout the world. The incidence of TBI is approximately 1,200 cases per 100,000 persons [1]. Management of severe TBI currently focuses on minimizing secondary brain injury, with particular attention centred on the identification and treatment of elevated intracranial pressure (ICP). As ICP-guided therapy and complex management of pressure elevations may serve to improve outcomes after TBI, this strategy has been included in the current Guidelines for the Management of Severe Brain Injury [2]. However, as secondary brain injury may develop despite normal ICP levels, other parameters might be monitored to enhance patient outcomes [3, 4]. Recently an attempt has been made to integrate multimodality monitoring (ICP, PbtO2, and auto regulatory status) into decision support algorithms [5].

One parameter of interest in this regard is brain tissue oxygenation (PbtO₂). Neurons have only a limited capacity to survive without sufficient oxygen. Short periods of reduced PbtO₂ can lead to secondary brain injury and ischemia even in the absence of an observed increase in ICP [6, 7]. Although studies that addressed this issue were assessed during the preparation of recent guidelines, the evaluations that were available at that time yielded conflicting results. Therefore, no recommendations regarding PbtO₂ monitoring were included. However, several studies that focus on the role of PbtO₂ monitoring in the management of TBI patients have been published since that time. In one trial, 50 patients were randomized for treatment with traditional ICP-guided therapy or PbtO₂-guided management. The survival rate for the patients in the PbtO₂-guided group increased significantly at 3 and 6 months after the acute injury [8]. In 2017, Okonkwo et al. [9] published the results of a randomized trial in which outcomes of TBI patients treated with an ICP protocol alone or with an ICP protocol together with PbtO₂ monitoring were compared. The results of this study revealed that patients managed with the combined PbtO₂ and ICP monitoring protocol experienced less brain tissue hypoxia, reduced mortality, and increased rates of good recovery compared to patients managed with the ICP protocol alone. However, Green et al. [10] conducted a retrospective study of 74 patients treated for severe TBI in which outcomes from a group of 37 patients who underwent ICP monitoring alone were compared to those of another 37 patients who were managed with both ICP-guided and PbtO₂-guided monitoring. In this latter study, survival and functional outcomes did not differ between groups at the time of hospital discharge.

As the results of these more recent studies also remain conflicting, we felt that more research into this question was needed. The present study aimed to analyse the effects of PbtO₂-guided management on the outcomes in patients who were admitted to our Level I Trauma Centre for treatment of severe TBI compared with management guided by monitoring of intracranial pressure solely. Results of this study may help to determine the role of PbtO₂ in the effective management of TBI patients.

This retrospective study was approved by the Ethics Committee of University Hospital Brno. Informed consent was waived because of the retrospective design of the study (Ref. Nr. 09-170221/EK, date of approval February 17, 2021). All patients admitted to the Department of Anaesthesiology and Intensive Care Medicine and the Department of Neurosurgery of University Hospital Brno (Level 1 Trauma Centre) for treatment of severe TBI between January 2010 and December 2015 were screened for eligibility. Inclusion criteria were as follows: severe TBI with a Glasgow Coma Scale (GCS) score ≤ 8 at admission, monitoring performed using ICP-guided protocols alone or ICP and PbtO₂ protocols, and age between 18 and 65 years. Patients were excluded if they presented with dilated and fixed pupils or died within the first 24 hours after admission.

Patients were divided into two groups. In one group (ICP) the management was guided by monitoring of ICP. In the second group (ICP+PbtO2) the management was guided by monitoring of ICP and monitoring of PbtO2 (Integra Licox® Brain Tissue Oxygenation Monitoring System, Integra LifeScience, Saint Priest, France).

Seventy-seven patients were admitted to the Level I Trauma Centre for the treatment of severe TBI who fulfilled our inclusion criteria. Thirty-seven patients were managed via a protocol that included monitoring of both ICP and PbtO₂ and included in the ICP+PbtO₂ group while 40 patients were managed with ICP-guided monitoring alone and included in the ICP group. Patient demographics, mechanism of injury, type of injury, Injury Severity Score, need for vasopressors at admission, initial heart rate, initial mean arterial pressure, initial ICP, initial GCS, initial CT-based categories of injury, Marshall CT classification, and the need for surgery are summarized in Table 1. Characteristics of study groups were compared and there was no statistically significant difference identified. Twenty four (60.0%) of the patients in the ICP group received transfusion of packed red blood cells. The mean number of transfusion units administered was 3.8 ± 3.4. In the ICP+PbtO₂ the packed red blood cells was administered to 21 (56.8%) of patients. In this group the mean number of transfusion units administered was 4.2 ± 2.6. The number of patients who received transfusion and the mean number of units transfuse didn’t differ significantly (p value 0.773 and 0.566 respectively). Cerebral monitoring data are outlined in Table 2.

The mean ICP was lower in the patients who were managed with PbtO₂ and ICP-guided monitoring compared with those who were monitored with ICP alone, although this difference did not achieve statistical significance. The mean arterial oxygen partial pressure was significantly higher in the group of patients managed with PbtO₂ (112.5 versus 140.3 mmHg, p = 0.045), while the mean cerebral perfusion pressure and arterial partial pressure of CO₂ were similar between the two groups.

The median GOS scores at 30 days after TBI were similar in both groups of patients; better outcomes overall were observed at 6 months post-TBI. At this later time point, the median GOS score was significantly higher (p = 0.013) in the group that was managed with the PbtO₂ monitoring protocol. Mortality rates recorded at 6 months for patients managed with ICP alone versus those managed with ICP and PbtO₂ were 20% and 10.8%, respectively, although these differences did not achieve statistical significance. Except for one patient in the PbtO₂ group who died secondary to the progression of respiratory insufficiency caused by severe lung injury, a direct or indirect association between TBI and cause of death was found in all remaining patients. Favourable outcomes (GOS scores of 4 or 5) were observed more frequently in the patient group that was monitored using the PbtO₂ protocol (p = 0.029). We didn´t found any difference in incidence of favourable outcomes and mechanism nor type of injury. Details of this analysis are shown in Table 3.

The management of TBI patients focuses on the prevention of secondary brain injury. Brain tissue hypoxia is one of the major mechanisms underlying secondary brain injury and has been associated with unfavourable outcomes. Therefore, strategies and management based on monitoring of brain tissue oxygenation may have a positive impact on clinical outcomes in TBI patients. Results from several studies in which severe TBI was managed by monitoring PbtO₂ revealed trends towards lower mortality rates and more favourable outcomes [9]. However, other studies found that PbtO₂ monitoring resulted in no positive effects [13, 14]. Recent meta-analysis of tree randomised controlled trials analysed data from 214 patients and found positive effect on mortality when PbtO₂ guided management was used. There was no positive effect on neurological outcome, however the certainty of evidence was very low [15]. Current guidelines for the management of severe TBI discussed the contradictory nature of these findings [2]. In contrast to the previous guidelines, PbtO₂ monitoring is no longer recommended [11]. However, protocols were recently published that can be used to direct the management of TBI patients using both ICP and PbtO₂ monitors [16]. Of significant interest, PbtO₂ monitoring is included in the current guidelines for the Management of Paediatric Severe Traumatic Brain Injury [17].

In the present study, we performed a retrospective analysis of outcomes in TBI patients who were managed with both ICP and PbtO₂ monitoring or with ICP monitoring alone.

The impact of PbtO₂ monitoring on mortality reported in several previous studies remained unclear and unconvincing [10, 12, 13, 14 18]. In our study, although overall mortality was lower in the group of patients managed with PbtO₂ monitoring (10.8% versus 20% for the group managed with ICP-guided protocols alone), this finding did not achieve statistical significance. We also recognize that the studies that reported significantly lower mortality rates among those managed with PbtO₂ monitoring used historical controls [13, 14]. Reduced mortality rates associated with ICP and PbtO₂ monitoring were reported in several studies, although, similar to our findings, none of the differences achieved statistical significance [8, 9, 10 19]. While the mortality rates in our study were lower than those reported by Green et al. [10], these researchers evaluated mortality only at the time of hospital discharge. By contrast, our study included an analysis of mortality up to and including 180 days after the acute injury. We note that our dataset covered a period that was 10 years later than that evaluated by Green et al. [10]; some of the differences may relate to overall progress made in general patient care since that time. We also recognize that our patient cohort was younger than that enrolled in this earlier study.

Our results indicate that patients managed with ICP and PbtO₂ monitoring have more favourable outcomes than patients managed with ICP monitoring alone. Specifically, our findings revealed a statistically significant difference in GOS scores in these patient groups at 6 months after TBI. A trend toward improved outcomes was found one month after TBI, but the difference was not statistically significant. Our results suggest that recovery after TBI is a long process. Similar results were reported in other studies [8, 20, 21].

Favourable outcomes are an important indicator of treatment success [22, 23, 24]. Favourable outcomes may be defined as scores of 4–5 on the GOS or 5–8 on the Glasgow Outcome Scale-Extended (GOS-E) [23, 24, 25]. Our results included a higher fraction of patients with favourable outcomes compared to results reported by Okonkwo et al. [9]. Specifically, our findings included a higher rate of positive outcomes among those managed with ICP and PbtO₂ (64% versus 41%) and ICP alone (40% versus 31%). Similarly, Lin et al. [8] reported favourable outcomes in fewer than 30% of the patients in both groups at one month after injury. Collectively, these results suggest that patients managed by ICP and PbtO₂ monitoring are more likely to exhibit favourable outcomes as their neurological conditions develop and improve over time. Thus, patient outcomes might be evaluated over longer periods to obtain a true assessment of the impact of these management strategies. We didnť find any difference in incidence of favourable outcomes regarding mechanism and type of injury, however numbers of patients in assessed categories were small which may have influenced the results.

This study has several limitations. First, this study was designed as a retrospective analysis and is associated with the limitations inherent in all studies of this type. Second, this was a single-centre study that included a limited number of patients and thus lacks external validity. Third, the positioning of the PbtO₂ and/or ICP probes was not standardized; the site of insertion was determined independently by each of the attending neurosurgeons. Fourth, the retrospective design and relatively small sample size may be a source of selection and performance biases. Finally, the GOS evaluation was challenging, especially identifying patients in the GOS category 3. This category was considered to be an adverse outcome; however, it was not always easy to determine whether a patient’s disability was the direct result of the TBI as opposed to associated injuries.

Several studies reported positive trends with respect to mortality and outcomes of TBI patients who were managed by PbtO₂ monitoring, while others did not [9, 12, 18 ]. Therefore, the role of PbtO₂ in the management of TBI patients and its impact on patient outcomes remains unresolved. Results of our study suggest that management of adult TBI patients using PbtO₂ monitoring might have a positive impact on clinical outcomes. The BOOST3 trial (ClinicalTrials.gov identifier: NCT03754114) which is currently ongoing (anticipated completion date of July 2023), aims to evaluate the impact of multimodal ICP and PbtO2 treatment on neurological outcomes.

Appropriate monitoring and management of TBI to prevent secondary brain injury remain challenging. The role of PbtO₂-based guidance in the management of TBI remains an unresolved but promising subject for future research. Results of well-designed randomized controlled trials will be needed to clarify the role of PbtO₂ monitoring in TBI patients.