Brain Tissue Oxygenation Guided Therapy in Patients with Traumatic Brain Injury: An Umbrella Review of Systematic Review and Meta-Analysis

Abstract The present umbrella review aims to summarize the evidence of the efficacy and benefit of combined brain tissue oxygen monitoring and intracranial pressure (ICP) monitoring compared with ICP monitoring based therapy alone. In this study, we systematically searched five databases to retrieve systematic reviews (SRs) regarding the efficacy of ICP monitoring on patient outcomes following traumatic brain injury (TBI). This overview was prepared following the guidelines established by the Joanna Briggs Institute (JBI) for umbrella reviews. No restrictions were placed on the date, language, or country of publication. Three SRs and meta-analyses met the inclusion criteria for the study. The SRs and meta-analyses (SR-MAs) included randomized controlled trials (RCTs) and observational studies. Specifically, two SRs were rated as high quality by A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2), while one was rated as moderate quality. Two of the SR-MAs reported on the mortality outcome, with two reporting on the functional outcome and one reporting on the length of hospital stay outcome. One of the SRs indicated that using combined brain tissue oxygen monitoring led to a reduction in mortality. Two of the SRs had mixed results. Two articles found that hospital length tends to be shorter with combined therapy than with ICP monitoring-based therapy alone. Our observations suggested that brain tissue oxygen combined with ICP/cerebral perfusion pressure (CPP) guided therapy provides a favorable outcome in TBI patients than standard ICP-/CPP-guided therapy. The combined therapy has little effect on mortality rate, ICP, CPP, and length of stay.


Introduction
Adequate tissue perfusion and oxygenation are crucial in neurocritical care, and their impairment results in brain damage.2][3][4] With technological advancement, ICP monitoring has evolved; however, it is resource-intensive and timeconsuming.Therefore, ICP monitoring has not been routinely done in cases of severe TBI.However, with the recent updates and guidelines by the Brain Trauma Foundation, more centers have adopted the practice of ICP monitoring in severe TBI. 3 While secondary brain injury does not necessarily correlate with changes in ICP or cerebral perfusion pressure (CPP), it should be noted that proper resuscitation efforts aimed at restoring normal ICP and CPP may not always suffice in preventing brain hypoxia following TBI. 5 Still, the only randomized controlled trial (RCT) that compared the ICP-targeted management and clinical management based on physical and radiological examination failed to demonstrate the benefit of invasive ICP monitoring in reducing mortality or improving the outcome. 6As detailed earlier, several other reasons explain how brain tissue oxygenation might be impaired in normal ICP or CPP.As brain tissue oxygen delivery is a rate-limiting step, it has been the main subject of discussion in the recent consensus meeting on the utility of multimodal neuromonitoring in TBI patients. 7The objective of this overview is to summarize the comparative effects and benefits of a neurocritical care protocol of therapy-guided brain tissue oxygenation (BtiO 2 ) and ICP monitoring versus only ICP or CPP monitoring for the treatment of TBI.

Methods
We conducted an umbrella review to summarize the possible benefits and usefulness in a neurocritical care unit of therapyguided BtiO 2 and ICP monitoring in patients with head trauma.The methodology followed the Joanna Briggs Institute (JBI) manual for evidence synthesis in its umbrella review. 8

Participants
All patients with severe closed head trauma with an indication for ICP monitoring according to the Brain Trauma Foundation guidelines were included in the study.

Intervention
Invasive monitoring of ICP was done using different methods (external ventricular drainage, catheter with intraparenchymal sensors, or epidural catheters) and multimodal monitoring that included brain tissue oxygenation measure.

Comparison
Studies described therapy-guided for BtiO2 and ICP monitoring and compared with ICP or CPP alone and clinical and imaging follow-up were inlcuded.

Primary
Mortality was defined as the mortality rate of patients with TBI at follow-up, 1 point on the Glasgow Outcome Scale (GOS), or a modified Rankin scale (mRS) score of 6.

Secondary
Intensive care unit (ICU) stay was defined by median days of ICU stay and complications (cardiovascular, infectious, thromboembolic, ischemic, etc.).

Type of Studies
This review considered systematic reviews of prospective, retrospective, or cross-sectional and observational studies.Systematic reviews that include case reports, case series, and preclinical were excluded.Systematic reviews evaluating noninvasive measurements of ICP as diameter of the optic nerve sheath were excluded.

Search
The following databases were searched for systematic reviews: Cochrane Injuries Group Specialized Register (up to May 2022) and descriptors in health sciences (DeCs) for the ILACS search.We adopted the following search strategy: ("intracranial pressure" OR "cerebrospinal pressure" OR "cerebrospinal fluid") AND (monitor Ã ) AND ("Brain tissue oxygen" OR "Cerebral oxygenation" or "BtiO 2 monitoring" OR "PbtO 2 ") AND (traumatic brain injury OR head trauma OR Craniocerebral Trauma OR head injuries OR Brain injuries) AND (Systematic AND review) OR Meta-analysis) AND (("Animals" [Mesh]) NOT ("Humans" [Mesh] AND "Animals" [Mesh])).The detailed search strategy is shown in The Appendix.

Selection of Studies
Search results were entered into the Mendeley reference manager version 1.19.4 (George Manson University, Fairfax, Virginia, United States).Two reviewers independently reviewed the titles and abstracts for eligibility of the studies.Full texts were extracted and were shortlisted as per the inclusion criteria.Disagreements were resolved by consensus.The results of the search are arranged in a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) flowchart. 9

Assessment of the Quality of the Included Systematic Reviews
The methodological quality of the systematic reviews of included randomized clinical trials was analyzed with the A MeaSurement Tool to Assess systematic Reviews Assess systematic Reviews (AMSTAR) tool 10 (see Appendix).AMSTAR is a valid, reliable, and easy-to-use tool.It consists of 11 items and has content validity to measure the methodological quality, in addition to the reliability of systematic reviews.Each of the 11 items is assigned a score of 1 if it meets the specific criterion or a score of 0 if it does not meet the criterion, is not clear, or is not applicable.The interpretation of the critical appraisal is divided into three levels: 8 to 11 points are of high quality, 4 to 7 points are of moderate quality, and 0 to 3 points are of low quality.

Risk of Bias of the Included Studies
The risk of bias in the included studies is made through the ROBIS (the risk of bias in systematic reviews) tool. 11This tool was completed in three phases: (1) assess relevance (optional), (2) identify concerns with the review process, and (3) judge the risk of bias in the review.Signaling questions were included to help assess specific concerns about potential biases with the review.Phase I was omitted as it was not relevant to the result in the risk of bias assessment.

Results
The initial search identified 72 related articles.After removing duplicates, 50 articles underwent title and abstract screening (►Fig. 1).Of these 30 studies screened, 5 eligible full-text were assessed, 2 were excluded 12,13 with reasons, and 3 systematic review and meta-analysis (SR-MA) were included [14][15][16] in the present umbrella review.

Study Characteristics
All the included studies conducted a meta-analysis and were published in 2012, 2017, and 2022.The included SR-MA had a total of 16 studies, of which 4 were RCTs, 2 were prospective observational studies, 8 were retrospective observational studies, and 1 was a historical control study.The present overview presents a summary from 1,955 patients.Of these, 915 patients had a combined BtiO 2 and ICP monitoring, while 1,040 patients had only ICP monitoring.►Table 1 describes the study design, characteristics, conclusions, and outcome assessment of each study.Individual findings on the outcomes of the included SR-MAs are shown in ►Table 2. Brain Tissue Oxygenation Guided Therapy in TBI Raghuwanshi et al.

Risk of Bias
Two SR-MAs reported on the risk of bias tool used in the study as Cochrane risk of bias tool, Newcastle-Ottawa Scale, and GRADE quality scale, while one SR-MA did not mention the risk of bias assessment (►Fig. 2).Quality assessment of the included SR-MA is shown in ►Tables 3 and 4. According to the AMSTAR tool, two SR-MAs were of high quality, 14,16 while one was of moderate quality 15 (►Table 3).According to the ROBIS tool, there was low risk of bias in most of the domains in two SR-MAs 14,16 and unclear in one SR-MA 15 (►Table 4).

Mortality Rate
Two of the three included SR-MAs reported on the mortality. 14,16One study found an association between increased survival and combined BtiO 2 therapy, 14 while one study did not find any association 16 and the third study suggested that there is improved survival in severe TBI patients with combined BtiO 2 therapy. 15The heterogeneity of the mortality outcome was high in two studies 15,16 and low in one study. 14The pooled analysis showed that there was no obvious differences between the two treatments in the overall mortality rate (risk ratio [RR] ¼ 2.1; 95% confidence interval [CI]: 1.4-3.1;odds ratio [OR] ¼ 0.76; 95% CI: 0.54-1.06;[16]

Favorable Outcome
The favorable outcome was assessed using the Glasgow Outcome Scale/Glasgow Outcome Scale, Extended (-GOS/GOSE) system and functional independence measure (FIM), both based on neurological function recovery.All three included SR-MAs reported on the functional outcome measured using GOS.The heterogeneity of the functional outcome was high.Included SR-MAs showed good functional outcome with the combined BtiO 2 therapy with good outcome (OR: 1.26 [95% CI: 1.04-1.52])and good outcome (OR: 1.31 [95% CI: 0.89-1.93]). 14,16We found that patients treated with PbtO 2 combined therapy achieved better outcomes than those treated with the standard ICP/CPP therapy.

Length of Stay
Only one included SR-MA mentioned the length of hospital stay and found that there were reduced odds of length of hospital stay with the combined therapy. 16

Discussion
Positron emission tomography studies in severe TBI have revealed that perfusion-limited data may not be the sole mechanism for secondary brain injury and ischemia, and other means like intravascular microthrombosis, cytotoxic edema, or mitochondrial dysfunction might be responsible for brain hypoxia.2][23][24][25] Most studies have shown better outcomes and mortality reduction with the BtiO 2 -guided therapy.However, the results were not uniform when comparing the BtiO 2 , ICP-/CPP-guided treatment with ICP/CPP therapy.Therefore, our present overview provided important information on a summary of current evidence on the utility of BtiO 2 monitoring in managing severe TBI.
Severe TBI is defined clinically as a patient having postresuscitation GCS of 8 or less.Patients with severe TBI has a high mortality rate of between 20 and 40%, and a further 20% remain severely disabled and nonfunctional, adding to the morbidity. 26The unfavorable outcome of TBI is mainly related to brain damage at the time of impact.Primary TBI is followed by damage in secondary and tertiary brain injury.Most of the patients who have unfavorable outcomes are due to secondary brain injury that happens primarily due to impaired brain tissue and occurs in perfusion and oxygenation hours, days, and weeks after the primary insult. 2Secondary cerebral ischemic injury has been noted in over 90% of head injury fatalities, leading to a variety of complex and potentially irreversible pathophysiologic events, including hypoxia and ischemia, as well as impaired cerebral metabolism. 13herefore, closely monitoring these intracranial physiological variables is paramount to identifying secondary brain injury before it escalates and becomes irreversible.The classification of neurologic monitoring can be broadly categorized into four types, which include pressure (such as ICP for CPP estimation), blood flow (such as thermal diffusion or transcranial Doppler), electrophysiology (such as electroencephalogram), and metabolic measures (including jugular venous oximetry, cerebral microdialysis, and direct brain tissue oxygen). 13Studies have mentioned that neuromonitoring of the intracranial physiological variables helps in early identification of secondary brain injury and thereby helps in targeting the management for optimal outcome. 13CP monitoring is often described as essential for this purpose, and current management guidelines for severe TBI are centered on the control of ICP and CPP. 15 Prior studies have shown reliable evidence that impaired brain tissue oxygenation, particularly hypoxia, is associated with an increased mortality risk and poor outcome following severe TBI.It has been estimated that one episode of hypoxia doubles the mortality after severe TBI.13,[27][28][29][30][31] The correlation between patient-centered outcomes and information obtained from a BtiO 2 monitor has resulted in the creation of a BtiO 2based treatment approach for severe TBI that serves as an adjunct to current therapies for managing ICP and CPP.A direct BtiO 2 measurement of 10 to 15 mm Hg has been suggested as the critical threshold related with ischemic damage and poor patient outcome.27,[32][33][34][35] The findings suggest that suboptimal brain oxygen levels, indicated by hypoxia levels of less than 10 mm Hg, unfavorably influence clinical outcomes following severe TBI.Furthermore, the use of BtiO 2 probes is deemed safe in this context.[37][38][39] It is anticipated that the results of the ongoing multicenter study Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase 3 (BOOST-3) will further show the comparative

Fig. 1
Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart showing details of study selection.

Fig. 2
Fig. 2 Risk of bias graph: each risk of bias item presented as percentages across all included studies.

Table 1
Characteristic of included systematic review

Table 2
Summary of systematic reviews included in this review

Table 4
Risk of bias assessment with Bristol University's ROBIS tool: review authors' judgments about each risk of bias item for each included systematic review

Table 3
40STAR tool: assessment to methodological quality on systematic review included of brain tissue oxygen and ICP monitoring versus ICP alone.40ConclusionOurresults show that BtiO 2 -based therapy combined with ICP-/CPP-based therapy results in better outcomes after severe TBI than ICP-/CPP-based therapy alone.The results of this study suggest that implementing a clinical protocol targeting both PbtO 2 and ICP, in conjunction with maintaining normal PbtO 2 levels, may potentially enhance the outcome of severe TBI patients.The combined therapy has little effect on the mortality rate, ICP, CPP, and length of stay.
Abbreviations: NA, not applicable; NR, not reported.effectiveness