Traumatic brain injury (TBI) is a major cause of death and disability that disproportionately affects young adults (1). The persistence of symptoms for >3 months following the onset of mild TBI is known as post-concussion syndrome (PCS). The incidence of PCS following the onset of TBI is ~15% after 3 months and 3-5% after 1 year (2). Common post-concussion symptoms include headaches, balance problems, sleep disturbance, fatigue, forgetfulness, poor concentration, irritability and anxiety (3). There are currently few established therapies available to treat patients with persistent PCS.

Hyperbaric oxygenation (HBO) therapy is currently used to treat acute and chronic ischemic injuries. HBO has well established theoretical underpinnings and is able to treat dive-related injuries, soft tissue injuries and carbon monoxide poisoning (4). The results of several studies have provided inconclusive evidence for the efficacy of HBO therapy in treating patients with PCS. Previous studies lacking control groups compared data pre- and post-HBO and found that HBO has a beneficial effect (5,6). However, a selection of prospective randomized trials did not prove the therapeutic effectiveness of HBO in PCS following mild TBI (7,8).

TBI is categorized into two phases: The primary insult and ensuing secondary reaction. A variable degree of irreversible primary damage to the neurological tissue occurs at the onset of injury (9). Secondary pathologies of TBI include ischemia, edema, hypoxia and other biochemical and inflammatory processes (10,11). Local hypoxia and ischemia may lead to the initiation of neuronal cell death. The use of HBO to treat TBI is based on the fact that hypoxia may serve an important role in causing secondary injury (12).

Previous studies in animals have demonstrated that HBO may have beneficial effects on brain injury. HBO limits the growth of cerebral contusions (13), increases the contused hippocampus vascular density (14), decreases the extent of secondary cell death and reactive neuroinflammation (15), preserves mitochondrial integrity and inhibits the mitochondrial apoptotic pathway (16). As an adjunctive treatment for patients with TBI, HBO may reduce the risk of mortality and improve the final Glasgow Coma Scale score (17). However there is little evidence that the prognosis of survivors improves following HBO (18,19).

The present study conducted a systematic review and meta-analysis of the current literature to examine the benefit of HBO therapy in the treatment of patients with PCS. The current available clinical evidence was presented in order to provide a foundation for future research.

The present systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (20) and was registered on the PROSPERO database (crd.york.ac.uk/PROSPERO; registration no. CRD 42016032620).

PCS is a term used to describe the complex and controversial physical, cognitive and emotional symptoms associated with mild brain injury. PCS persists for weeks or months in the majority of patients and <25% of patients may experience prolonged PCS in which symptoms last for >6 months (64). These patients are at high risk of emotional and cognitive dysfunction in which they may be unable to perform ordinary daily activities and maintain work responsibilities, as well as normal social relationships (65,66). Currently, there is limited evidence that multifaceted rehabilitation programs that include psychotherapy improve the management of persistent symptoms in PCS (67). Based on previous studies investigating other neurological conditions, it has been suggested that HBO therapy may be a potential treatment for chronic PCS (5,6,52).

The results of the present systematic review identified no improvement in RPQ score or symptoms of PCS between low and high oxygen dose groups and no significant difference in the improvement of neurobehavioral symptoms between HBO and sham groups. Thus, there is no evidence that HBO therapy is effective at treating patients with PCS. However, HBO therapy is a combination of increased pressure and increased pressure of oxygen above ambient atmospheric pressure and the sham designs used in the studies included in the present review may not have tested an extensive enough range of pressurized air doses (37,57).

The effects of air pressure have been investigated since the early 20th century; however, they have been more actively studied since the 1990s. The majority of studies performed so far have been cell culture experiments (57). A follow-up study by Mulkey et al (68) suggests that neuronal barosensitivity occurs at pressures of 100 mmHg (1.13 ATA). Furthermore, it has been demonstrated that even a small increase in partial pressure to 1.05 ATA at an altitude of 402 m below sea level may induce noticeable physiological effects, such as improved pulmonary function and blood oxygen saturation (69–71). A room air pressure of 1.2 or 1.3 ATA may not be appropriate for sham controls, as this may lead to significant increases in tissue oxygenation (72). Thus, the use of 21% oxygen at 1.14-1.5 ATA in for sham controls in clinical trials as an alternative to observation or crossover controls may lead to false acceptance of the null hypothesis, due to the biological activity that occurs under these conditions (29). Consequently, studies that included a sham group were identified as having high bias (4,7,8,55). The minimum pressure at which patients sense an increase in air pressure is 1.3 ATA. Controlled experiments testing the effects of HBO therapy must therefore ensure that pressure and oxygen concentrations are not above base levels in the control groups to meet the true definition of a sham (73). However, this may result in inherent ethical and logistic difficulties in handling the sham control in HBO trials.

Objective and precise assessment methods are another challenge in evaluating the efficacy of HBO therapy in patients with PCS. To the best of our knowledge, validated outcome measures for intervention trials in PCS have not yet been established. In the majority of the studies included in the present review, outcomes were evaluated using RPQ, PCL or NSI. All of these assessments are well established; however, they are all subjective performance evaluations (58,60–62). The RPQ has several limitations in its implementation and ability to accurately reflect test-taker experience (74). The interpretation and accuracy of the RPQ and other methods varies widely due to self-administration and the confounding variables involved due to its sensitivity to covariates, including subjective patient memory, social desirability, stress, personality factors and the willingness of patients to reveal problems (74). The studies included in the present review relied on self-administration assessments, which is a limitation. SPECT imaging was used in one randomized, crossover controlled trial and revealed elevated brain activity with cognitive improvements following HBO therapy in the treated and crossover groups (56). This is consistent with the results of previous studies (5,6). Although the use of SPECT imaging may not be sensitive enough to detect abnormalities in patients with PCS, it is an objective assessment method that may provide evidence supporting the use of HBO or sham interventions and allows a greater refinement of HBO treatment for patients with PCS.

A study of HBO therapy used to treat sub-acute moderate to severe TBI at 2.0 ATA reported a 9% seizure rate (75). However, serious side effects from HBO therapy are rare in patients with chronic and mild TBI and a previous study demonstrated that patients with TBI treated with HBO do not experience any marked side effects (76). Two trials in the current study reported that adverse events occurred during HBO therapy, which were equally distributed between the HBO and sham groups (8,47) included in the present review. Serious adverse events, including pulmonary barotraumas, pulmonary edema or seizure were not observed.

There are several differences between blast-related and sports-related PCS. Patients with blast mild TBI have usually experienced two episodes of head trauma, often within sec of each other. The magnitude of head acceleration is stronger than that of a sports-related concussion and the entire body is exposed to the blast. Consequently, blast TBI is caused by multiple, interwoven mechanisms of systemic, local and cerebral responses to blast exposure (77). The majority of patients included in the present review were from the military, thus, the results are not representative of patients diagnosed with sports-related concussion.

Previous studies have demonstrated that there is an optimal therapeutic time frame for HBO treatment in neonatal rats with hypoxic-ischemic brain damage (78–80). However, to the best of our knowledge, the optimal timing of treatment for patients with brain injury remains unknown. Efrati and Ben-Jacob (23) suggested that HBO therapy may begin either at the degenerative or regenerative stages and is usually safe 1 month following acute injury. Subset analysis of isolated mild TBI demonstrated a trend toward harm from HBO at 2.4 ATA, suggesting that HBO at 2.4 ATA may actually have a negative impact on isolated mild TBI symptoms (81), however, the optimal effective doses of pressure and oxygen concentration in HBO therapy remain unclear, as does the optimal duration of treatment. The majority of the results of the studies included in the present review were obtained following 30-40 sessions of HBO therapy. It is hypothesized that additional sessions of HBO therapy may be beneficial (43) however, to the best of our knowledge, no data are available on the upper time limit at which no further improvements occur. The long-term effects of HBO therapy are not well studied. In the studies included in the current review, the time point for outcome assessment was usually <1 week following completion of treatment. One previous study identified that treating blast-related PCS 3 months following compression had no significant effect (53). Thus, further studies are required to develop understanding of the optimal number, duration and long-term effects of treatment sessions and the optimum time frame following injury onset for initiating HBO therapy.

Case reports and phase I clinical trials have demonstrated that HBO is an effective therapy for correctly diagnosed PCS (5,6) however, the results of RCTs included in the current review were not consistent with this. HBO therapy may improve the symptoms of patients with increased levels of oxygen concentration and pressure. The results of the current meta-analysis indicated that increased doses of oxygen had no effect on PCS. The efficacy of pressurization remains elusive, as the symptoms of patients in the HBO and sham groups were improved with no difference in improvements observed between them. It is therefore essential to develop a sham that controls for pressurization or oxygen concentration separately in RCTs.

Although it remains unknown whether the symptoms of PCS improve following HBO therapy, it has been demonstrated that HBO therapy does not cause any serious side effects; thus, it has been recommended that patients with PCS should undergo HBO therapy, until future studies are completed. However, it should be noted that HBO treatment is costly and potentially dangerous thus, its use must be evidence-based (82). The use of genuine sham controls in studies on HBO therapy is not feasible or cost effective and the optimal therapeutic window and oxygen dose of HBO therapy remain unknown. Therefore future studies should be conducted on a large scale or in cohorts to produce more useful results. The approval of HBO therapy on a tentative basis would allow for studies to be conducted on a large patient population.

There were several limitations of the current meta-analysis. Although a comprehensive search of six databases was conducted, only four studies consisting of 238 patients in total were included in the present systematic review. The small number of included studies limited the statistical power of detection. Additionally, the sample set of patients used is not representative of patients with sport-related PCS due to the small number of studies included, which primarily included members of the military that had experienced blast-induced PCS. A comparison of all groups was not conducted due to the heterogeneity between different trials. In addition, the study design of the sham group may lead to high bias. Therefore, more rigorous reviews are required to assess the effects and safety of HBO therapy in patients with PCS.

In conclusion, the present systematic review demonstrated that HBO therapy was not associated with significant improvements in patients with PCS. Large scale observation or cohort studies are required to provide information for the design and execution of a large clinical trial consisting of proper treatment, control and sham groups. This future trial may subsequently provide the evidence required for the efficacy of HBO therapy in the treatment of patients with PCS.