|Year : 2018 | Volume
| Issue : 4 | Page : 401-416
The neuroprotection effect of oxygen therapy: A systematic review and meta-analysis
Z Deng, W Chen, J Jin, J Zhao, H Xu
Department of Orthopedics, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu, China
|Date of Acceptance||01-Jun-2017|
|Date of Web Publication||02-Apr-2018|
Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, No. 305, Zhongshan East Road, Nanjing 210002, Jiangsu
Dr. J Zhao
Department of Orthopedics, Jinling Hospital, School of Medicine, Nanjing University, No. 305, Zhongshan East Road, Nanjing 210002, Jiangsu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
This study reviews the oxygen therapy (normobaric oxygen [NBO] and hyperbaric oxygen [HBO]) in both stroke and traumatic brain injury (TBI) patients and meta-analyzes the efficacy of two oxygen therapies in different kinds of injuries. In stroke patients, NBO showed significant improvement in reperfusion rate while there is no favorable outcome effect of HBO treatment. In patients with TBI, HBO showed significant improvement of Glasgow outcome scale score and reduction of overall mortality while NBO may play a favorable role in improving brain metabolism.
Keywords: Hyperbaric oxygen, meta-analysis, neuroprotection, normobaric oxygen, stroke, traumatic brain injury
|How to cite this article:|
Deng Z, Chen W, Jin J, Zhao J, Xu H. The neuroprotection effect of oxygen therapy: A systematic review and meta-analysis. Niger J Clin Pract 2018;21:401-16
|How to cite this URL:|
Deng Z, Chen W, Jin J, Zhao J, Xu H. The neuroprotection effect of oxygen therapy: A systematic review and meta-analysis. Niger J Clin Pract [serial online] 2018 [cited 2019 Mar 20];21:401-16. Available from: http://www.njcponline.com/text.asp?2018/21/4/401/229089
| Introduction|| |
Central nervous system (CNS) injuries, such as stroke, traumatic brain injury (TBI), spinal cord injury, and neurodegenerative diseases, are main causes of death and disability and lead to substantial economic burden around the world. To minimize damage and induce recovery of salvageable tissue, various methods had been tried. For example, in stroke, more than 200 clinical trials had been completed by now, but the most effective treatment was still tissue plasminogen activator, which was introduced in 1995. Inspired by more tolerance of cerebral ischemia in patients under general anesthesia, medical gases, such as oxygen, hydrogen, and volatile anesthetic gases, were gradually introduced into clinical application., Among all the medical gases, oxygen is the easiest one to get and has the widest application.
Oxygen accounts for 20.9% in air and is crucial for brain metabolism. Due to its safety, wide availability, good tolerance, and permeability through blood–brain barrier (BBB), oxygen therapy has been broadly investigated both in animal models and patients. To increase oxygen supply for CNS, oxygen therapy could be divided into two types: normobaric oxygen (NBO) therapy and hyperbaric oxygen (HBO) therapy. NBO therapy is the administration of high concentrations of oxygen through a facemask at normal atmospheric pressure while HBO therapy is a treatment in which the patient breathes 100% oxygen while being exposed to environmental pressure >1 atmosphere absolute.
The researches mainly concerned stroke and TBI when investigating the neuroprotective effect of oxygen, but the outcomes as well as oxygen paradigm varied among trials. Consequently, we conduct this study to review the current comparative clinical trials of oxygen therapy among nervous system injuries. The aim of our study is to compare the efficacy and safety among NBO and HBO in the situation of stroke and TBI. We hope our study could clarify the function of oxygen therapy in different kinds of nervous system injuries and give an overall view of oxygen on neuroprotection, which is hoped to be a good indicator in clinical practices.
| Methods|| |
We conducted a computer-assisted systematic search of PubMed databases from their commencement to February 2016, attempting to find all publications on clinical trials of oxygen therapy in CNS injury. Key words and medical subject heading (Mesh) terms for the search of PubMed were as follows: (“oxygen inhalation therapy” [Mesh]) OR (“hyperbaric oxygenation” [Mesh]) OR “normobaric oxygen therapy” AND (“stroke” [Mesh]) OR (“brain injuries” [Mesh]) OR “acute ischemic stroke (AIS)” OR “TBI” AND “Clinical trial”. We also reviewed the bibliographies of relevant articles to identify additional studies that might have been missed.
We screened titles and abstracts of identified papers to exclude studies that clearly did not meet the inclusion criteria. Full texts of those selected for further review were retrieved and evaluated. To ensure the comparability of all the studies, we set some criteria for study selection, which were as follows: (1) they were comparative studies of oxygen therapy either pre- and post-treatment or treatment and controls; (2) they must be conducted on human; animal trials and in vitro experiments were excluded; (3) reviews, meta-analysis, and meeting reports were excluded; (4) studies from same authors with same patients were excluded; (5) all the publications were in English and full texts could be found.
Methodological quality evaluation
We evaluated the methodological quality of all randomized controlled trials (RCT) using 7-point modified Jadad scoring system. Meanwhile, observational studies, including case–control studies and cohort studies, were evaluated based on the 9-star Newcastle-Ottawa Scale. 4–7 points of Jadad scoring system and 6-9 stars of Newcastle-Ottawa Scale were defined as good quality of the studies.
All data were extracted according to the criteria. Discrepancies were discussed and resolved by consensus. Data extracted from each study included the first author, year of publication, types of studies, regions of the population investigated, number of patients of different groups, age, gender, assessment score of nervous system, score improvement, overall mortality rate and rate of people who achieved good results, and other assessment in the studies.
STATA Statistical Software was used for all the analyses (version 12.0, STATA Corporation, College Station, TX, USA). The measure of estimated effect of interest was odds ratio or weighted mean difference with 95% confidence interval. We used two models to calculate the pooled relative risk estimates: a fixed-effects model known as the Mantel-Haenszel method  and a random-effects model known as the DerSimonian-Laird method. We used the Cochran Q test to evaluate the heterogeneity of the studies  and the quantity I2 was also calculated.,I2 is the proportion of total variation contributed by between-study variation, and values of 25%, 50%, and 75% have been regarded as representing low, moderate, and high heterogeneity, respectively. When I2 was over 50%, a random-effects model was used to calculate the pooled relative risk estimates. On the contrary, a fixed-effects model was used. Publication bias was evaluated to find whether the results of the studies were homogeneous. The funnel graph, the Egger regression asymmetry test, and the Begg-Mazumdar adjusted rank correlation test  were used. When the p value of Egger's test and Begg's test is <0.05, we considered obvious bias among the studies.
| Results|| |
We found 956 records in PubMed databases and 3 records from references. With our selection criteria, 25 studies were identified in our study, including 4 studies which compared NBO and control in stroke patients,,,, four studies which compared HBO and control in stroke patients,,,, 9 studies which compared NBO treatment efficacy in TBI patients,,,,,,,,, and 9 studies which compared HBO treatment efficacy in TBI patients [Figure 1].,,,,,,,, [Table 1], [Table 2], [Table 3], [Table 4] summarize the characteristics of all the included studies.
|Table 1: Characteristics of studies that compared normobaric oxygen treatment and controls in stroke patients|
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|Table 2: Characteristics of studies that compared hyperbaric oxygen treatment and controls in stroke patients|
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|Table 3: Characteristics of studies that compared normobaric oxygen treatment and controls in Traumatic brain injury patients|
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|Table 4: Characteristics of studies that compared Hyperbaric oxygen treatment and controls in traumatic brain injury patients|
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Methodological quality evaluation results
For RCTs, there were 7 of 11 studies defined as good quality (4–7 points) [Table 5]. On the other side, for observational studies, 4 of 7 studies were defined as good quality (6–9 stars) [Table 6].
|Table 5: Assessment of methodological quality of randomized control trials using 7-point modified Jadad scoring system|
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|Table 6: Methodological quality of included observational studies based on 9-star Newcastle-Ottawa Scale|
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Comparison of efficacy between normobaric oxygen treatment and controls in stroke patients
Four studies were included to compare the efficacy between NBO treatment and controls in stroke patients and modified Rankin Scale (mRS), diffusion-weighted imaging (DWI) lesion volume, and reperfusion rate were analyzed. Meta-analyses indicated that NBO treatment showed significantly better efficacy than control in the matter of reperfusion rate while there was no statistical significant difference in mRS score and DWI lesion volume. The heterogeneity was considered low and no obvious publication bias was found [Figure 2] and [Table 7].
|Figure 2: Forest plots and Begg's funnel plots of studies comparing normobaric oxygen treatment with controls in patients with stroke. (a) Forest plot and Begg's funnel plots conducted using modified Rankin Scale score. (b) Forest plot and Begg's funnel plots conducted using diffusion-weighted imaging lesion volume. (c) Forest plot and Begg's funnel plots conducted using reperfusion rate|
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Comparison of efficacy between hyperbaric oxygen treatment and controls in stroke patients
Four studies were included in the comparison. Mortality, favorable outcome rate, and mRS score improvement rate were involved in the meta-analysis. Improvement rate of mRS score was significantly improved in HBO treatment, while there was no difference in final mortality and favorable outcome rate. The studies involved showed low heterogeneity and no obvious bias [Figure 3] and [Table 7].
|Figure 3: Forest plots and Begg's funnel plots of studies comparing hyperbaric oxygen treatment with controls in patients with stroke. (a) Forest plot and Begg's funnel plots conducted using modified Rankin Scale score improvement rate. (b) Forest plot and Begg's funnel plots conducted using mortality. (c) Forest plot and Begg's funnel plots conducted using favorable outcome rate|
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Comparison of efficacy between normobaric oxygen treatment and controls in traumatic brain injury patients
A total of nine studies were included to compare the efficacy between NBO treatment and controls in TBI patients and metabolism indicators, such as intracranial pressure (ICP), brain tissue oxygen pressure (PbO2), lactate, pyruvate and glucose, were analyzed. Meta-analysis revealed that the PbO2 and lactate/pyruvate ratio in brain significantly increased in NBO group compared with controls, while the ICP, lactate, and glucose had no significant difference between groups. Due to different machine to monitor the metabolic indicators in brain, the heterogeneity among studies was large and there might have been some kind of publication bias [Figure 4] and [Table 7].
|Figure 4: Forest plots and Begg's funnel plots of studies comparing normobaric oxygen treatment with controls in patients with traumatic brain injury. (a) Forest plot and Begg's funnel plots conducted using intracranial pressure. (b) Forest plot and Begg's funnel plots conducted using brain tissue oxygen pressure. (c) Forest plot and Begg's funnel plots conducted using lactate. (d) Forest plot and Begg's funnel plots conducted using pyruvate. (e) Forest plot and Begg's funnel plots conducted using lactate/pyruvate ratio. (f) Forest plot and Begg's funnel plots conducted using glucose|
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Comparison of efficacy between hyperbaric oxygen treatment and controls in traumatic brain injury patients
Nine studies were pooled in the meta-analysis and brain metabolism, cognitive function, and outcome were taken into consideration. Results showed that HBO treatment significantly improved the Glasgow outcome scale (GOS) score and reduced overall mortality in patients with severe TBI compared with controls. In patients with mild TBI, HBO showed function alleviating the cognitive disorder after trauma, including memory, executive function, attention, and information processing speed. Studies analyzing cognitive function showed low heterogeneity with no bias, while the outcome of studies for analyzing brain metabolism had large heterogeneity but no obvious publication bias [Figure 5], [Figure 6] and [Table 7].
|Figure 5: Forest plots and Begg's funnel plots of studies comparing hyperbaric oxygen treatment with controls in patients with traumatic brain injury. (a) Forest plot and Begg's funnel plots conducted using Glasgow outcome scale improvement rate. (b) Forest plot and Begg's funnel plots conducted using mortality. (c) Forest plot and Begg's funnel plots conducted using intracranial pressure. (d) Forest plot and Begg's funnel plots conducted using brain tissue oxygen pressure|
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|Figure 6: Forest plots and Begg's funnel plots of studies comparing hyperbaric oxygen treatment with controls in patients with traumatic brain injury. (a) Forest plot and Begg's funnel plots conducted using memory. (b) Forest plot and Begg's funnel plots conducted using executive function. (c) Forest plot and Begg's funnel plots conducted using attention. (d) Forest plot and Begg's funnel plots conducted using information processing speed|
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| Discussion|| |
Central nervous injury, including brain injury and spinal cord injury, could result in acroparalysis, paralysis, and even death. Effective treatment to protect nerves from injury and improve overall outcome was always required. Oxygen therapy, due to its availability and safety, had been applied in protection of nervous systems for decades.
Stroke is a leading cause of disability and death in adult and AIS is the main component in it. Brain has low antioxidant defenses and is vulnerable to hypoxia, where improving oxygen supply by oxygen therapy could be a rational treatment. Both NBO and HBO are effective methods to administer high concentrations of oxygen to brain tissue while each of them has advantages. NBO therapy had hemodynamic benefit in acute stroke patients. Singhal et al. conducted high-flow oxygen therapy via facemask for 8 h in patients with acute stroke (<12 h) and found that mean relative diffusion MRI lesion volumes were significantly reduced at 4 h compared with control group  which were consistent with following study. Apart from hemodynamic effect, NBO can also benefit cerebral metabolism and prognosis. NBO improves aerobic metabolism and preserves neuronal integrity in the acute ischemic brain by detecting lactate and N-acetyl-aspartate levels before, during, and after therapy. NBO therapy could result in preferable outcome, such as less mortality and comorbidities in patients experienced severe AIS , However, in Indian population, Padma et al. revealed that NBO did not improve the clinical scores of stroke outcome in patients with AIS. In the present meta-analysis, significant improvement in reperfusion rate was revealed in NBO group compared with control group. NBO therapy appears a promising therapy for short-lasting ischemia and is attractive clinically as it could be started at home in at-risk patients or in the ambulance in subjects suspected of transient ischemic attack/early stroke. On the other hand, several trials had been conducted to explore the effect of HBO in stroke patients. Anderson first administered a double-blind prospective protocol to 39 patients with acute ischemic cerebral infarction, and found no effect of HBO treatment. Subsequent trials had opposite results, which shown a favorable effect on stroke patients.,, On account of small number of patients in each group, the validity of HBO in stroke patients is still to be considered. In the present study, no favorable outcome effect of HBO treatment was observed in stroke patients. Furthermore, recent meta-analysis concerning association between arterial hyperoxia and outcome, more favorable outcome was shown for NBO.,
TBI is the main cause of morbidity and mortality among young people and often result in unfavorable outcome due to damage to the CNS. Apart from the damage to blood vessels and axonal shearing induced by mechanical brain tissue injury, second injury induced by mitochondrial dysfunction, neuronal degeneration, inflammation, BBB dysfunction, and tissue hypoxia could lead brain cell to death after trauma. Among those factors, cerebral hypoxia had been considered a key role in the process and oxygen therapy was a reasonable treatment to normalize aerobic metabolism and increase survival of neural tissue. Tolias et al. performed a prospective study of 52 patients with severe TBI and found the biochemical markers (such as glucose, glutamate, and lactate levels) in the brain in the NBO treatment group had a significant improvement compared with controls. Several studies had similar results., Using positron emission tomography to directly measure the cerebral metabolic rate for oxygen, Diringer found that NBO did not improve brain oxygen metabolism, which was also proved by oxygen-15 positron emission tomography scanning. In the present study, NBO treatment was observed to be able to increase PbO2 and lactate/pyruvate ratio in brain significantly and might play a favorable role in the treatment of TBI patients. Figaji et al. found that hyperoxia increased arterial partial pressure of oxygen (PaO2) as well as PbO2 significantly in TBI patients and the oxygen reactivity index (PbO2: PaO2 ratio) was inversely related to outcome. Together with results of other studies, the baseline metabolic state of the injured brain should be taken into account when applying NBO therapy to patients with TBI. At the same time, recent study revealed that incremental normobaric inspired fraction of oxygen (FiO2) levels were associated with increased cerebral excitotoxicity in patients with severe TBI, independent from PbO2 and other important cerebral and systemic determinants, which suggested us to focusing on the dose of oxygen in the following investigation.
HBO therapy had been shown to be effective in TBI patients in terms of metabolism, oxygen toxicity, ICP, cognition, and quality-of-life, along with significant improvements in single-photon emission computed tomography imaging., Rockswold compared HBO and NBO treatment effects in severe TBI and found that HBO had a more robust posttreatment effect than NBO on oxidative cerebral metabolism and oxygen treatment for severe TBI was not an all or nothing phenomenon but represented a graduated effect. In the following clinical trial, they evaluated the combination of HBO and NBO as a single treatment. Compared with standard care (control treatment), combined HBO/NBO treatments significantly improved markers of oxidative metabolism in both relatively uninjured brain and pericontusional tissue, reduced intracranial hypertension, and demonstrated improvement in markers of cerebral toxicity. Significant reduction in mortality and improved favorable outcome measured by GOS were also observed in this trial, which implied that the combination of HBO and NBO therapy have potential therapeutic efficacy compared with the 2 treatments in isolation. However, there was also evidence that HBO treatment could only improve the Glasgow coma scale score, but had no influence on the quality of life and prognosis. In the present meta-analysis, HBO significantly improved the GOS score and reduced overall mortality in patients with severe TBI as well as alleviated cognitive function in mild TBI patients. With the evidence that no major adverse events occurred in the treatment of HBO, our results together with previous studies indicated that HBO was preferable in the treatment of TBI subjects, even at a relatively high treatment pressure.
Apart from brain injuries, oxygen therapy could also be of benefit in spinal cord injuries. Recent study showed a full neurological recovery of spinal cord injury caused by surgery using immediate HBO therapy and therapeutic hypothermia. Concerning spinal cord injuries, more researches were still in animal models, which showed improvement of local inflammation and reduction of apoptosis after HBO.
Overall, oxygen plays an important role in neuroprotection after different kinds of central nerve system injuries. Due to its easy access and safety to use, oxygen therapy should be well applied in clinical practice. However, as the baseline of patients varied, the most appropriate pressure, duration, and frequency of oxygen treatment should be further explored. At the same time, the sham/control group in clinical trials should be carefully selected, where the problem of null hypothesis existed resulted from the biological activity of these “sham” controls in the past researches.
Financial support and sponsorship
This study was supported by the National Natural Science Foundation of China (81501925).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]