Traumatic Brain Injury, Post-concussion Syndrome, Stroke
Hyperbaric oxygen therapy for post concussion symptoms: issues may affect the results.
Med Gas Res. 2015 Aug 25;5:10. doi: 10.1186/s13618-015-0033-3. eCollection 2015.
Hyperbaric oxygen therapy for traumatic brain injury: bench-to-bedside.
Traumatic brain injury (TBI) is a serious public health problem in the United States. Survivors of TBI are often left with significant cognitive, behavioral, and communicative disabilities. So far there is no effective treatment/intervention in the daily clinical practice for TBI patients. The protective effects of hyperbaric oxygen therapy (HBOT) have been proved in stroke; however, its efficiency in TBI remains controversial. In this review, we will summarize the results of HBOT in experimental and clinical TBI, elaborate the mechanisms, and bring out our current understanding and opinions for future studies.
Med Gas Res. 2016 Jul 11;6(2):102-110. Hyperbaric oxygen therapy for traumatic brain injury: bench-to-bedside.
Hyperbaric oxygen: B-level evidence in mild traumatic brain injury clinical trials.
First, to demonstrate that B-level evidence exists for the use of hyperbaric oxygen therapy (HBOT) as an effective treatment in mild to moderate traumatic brain injury/persistent postconcussion syndrome (mTBI/PPCS). Second, to alert readers and researchers that currently used pressurized air controls (≥21% O2, >1.0 ATA) are therapeutically active and cannot be utilized as sham controls without further validation.
Review of published, peer-reviewed articles of HBOT prospective and controlled clinical trials of mTBI/PPCS symptoms.
Published results demonstrate that HBOT is effective in the treatment of mTBI/PPCS symptoms. Doses of oxygen that are applied at ≥21% O2 and at pressures of >1.0 ATA produce improvements from baseline measures. Some of the recently published clinical trials are mischaracterized as sham-controlled clinical trials (i.e., sham = 21% O2/1.2-1.3 ATA), but are best characterized as dose-varying (variation in oxygenconcentration, pressure applied, or both) clinical trials.
Hyperbaric oxygen and hyperbaric air have demonstrated therapeutic effects on mTBI/PPCS symptoms and can alleviate posttraumatic stress disorder symptoms secondary to a brain injury in 5 out of 5 peer-reviewed clinical trials. The current use of pressurized air (1.2-1.3 ATA) as a placebo or sham in clinical trials biases the results due to biological activity that favors healing.
Neurology. 2016 Sep 27;87(13):1400-6. doi: 10.1212/WNL.0000000000003146. Epub 2016 Aug 31.
Neuroprotection of hyperbaric oxygen therapy in sub-acute traumatic brain injury: not by immediately improving cerebral oxygen saturation and oxygen partial pressure.
Although hyperbaric oxygen (HBO) therapy can promote the recovery of neural function in patients who have suffered traumatic brain injury (TBI), the underlying mechanism is unclear. We hypothesized that hyperbaric oxygen treatment plays a neuroprotective role in TBI by increasing regional transcranial oxygen saturation (rSO2) and oxygen partial pressure (PaO2). To test this idea, we compared two groups: a control group with 20 healthy people and a treatment group with 40 TBI patients. The 40 patients were given 100% oxygen of HBO for 90 minutes. Changes in rSO2 were measured. The controls were also examined for rSO2 and PaO2, but received no treatment. rSO2 levels in the patients did not differ significantly after treatment, but levels before and after treatment were significantly lower than those in the control group. PaO2 levels were significantly decreased after the 30-minute HBO treatment. Our findings suggest that there is a disorder of oxygen metabolism in patients with sub-acute TBI. HBO does not immediately affect cerebral oxygen metabolism, and the underlying mechanism still needs to be studied in depth.
Neural Regen Res. 2016 Sep;11(9):1445-1449.
The Effectiveness of Hyperbaric Oxygen Therapy as a Treatment for Postconcussion Symptoms.
Concussions are a prevalent topic in medicine. Concussion symptoms include headaches, dizziness, nausea, neuropsychiatric symptoms, and cognitive impairments, the persistence of these referred to as postconcussion syndrome. The use of hyperbaric oxygen therapy (HBOT) has been proposed and evaluated as an additional treatment of these symptoms. Using HBOT is an innovative approach that has been considered by many, but has received both criticism and acceptance.
Is hyperbaric oxygen therapy treatment an effective means of reducing symptoms for individuals suffering from postconcussion syndrome (persistence of symptoms for > 3 months)? Summary of Search: The literature was searched for studies that were relevant to the clinical question. Literature provided 5 level 1 studies that were relevant enough to be considered.
Clinical Bottom Line
Based on the research that is available, we conclude that there is more evidence to refute the use of HBOT for postconcussion syndrome than to support it. Strength of recommendation: Four studies disprove the use of HBOT. One study supported the use of HBOT. These 5 studies are the same level of evidence (level 1), and provide significant findings in their studies. The strength of this recommendation is a B according to the Centre for Evidence-Based Medicine.
J Sport Rehabil. 2016 Nov 11:1-14. [Epub ahead of print]
The researchers include sham studies which used active hyperbaric oxygen at 1.2-1.3 ATAs as sham in order to disprove the efficacy of HBOT for post concussion syndrome. Recent researchers have pointed out the fallibility of including an active HBOT treatment as the sham and comparing it to HBOT at higher ATAs. Studies using shams with active HBOT (1.2-1.3) should be carefully evaluated and omitted from consideration in future evaluation of HBOT efficacy.
Is Hyperbaric Oxygen Therapy Effective for Traumatic Brain Injury? A Rapid Evidence Assessment of the Literature and Recommendations for the Field.
This systematic review examines the efficacy of hyperbaric oxygen(HBO2) for traumatic brain injury (TBI) to make evidence-based recommendations for its application and future research.
A comprehensive search was conducted to identify studies through 2014. Methodological quality was assessed and synthesis and interpretation of relevant data was performed.
Twelve randomized trials were included. All mild TBI studies demonstrated minimal bias and no statistically significant differences between HBO2 and sham arms. Statistically significant improvement occurred over time within both groups. Moderate-to-severe TBI studies were of mixed quality, with majority of results favoring HBO2 compared with “standard care.” The placebo analysis conducted was limited by lack of details.
For mild TBI, results indicate HBO2 is no better than sham treatment. Improvements within both HBO2 and sham groups cannot be ignored. For acute treatment of moderate-to-severe TBI, although methodology appears flawed across some studies, because of the complexity of brain injury, HBO2 may be beneficial as a relatively safe adjunctive therapy if feasible. Further research should be considered to resolve the controversy surrounding this field, but only if methodological flaws are avoided and bias minimized.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
J Head Trauma Rehabil. 2016 Sep 6. [Epub ahead of print]
COMMENTARY: This review is another illustration of the confusion in research regarding sham controls using therapeutic ATAs at lower levels verses so-called “intervention HBOT” at higher ATAs. Both represent HBOT interventions with differing ATAs and therefore the sham cannot be considered an inactive treatment or placebo.
Effects of Hyperbaric Oxygen Therapy on Inflammasome Signaling after Traumatic Brain Injury.
Neuroinflammation plays an important role in secondary tissue damage after traumatic brain injury (TBI). Recently, the inflammasome-mediated inflammatory pathway has been observed in the inflammatory response of TBI. In this study, we investigated the influence of hyperbaric oxygen therapy (HBOT) on inflammasome activation after TBI.
The experimental mice were randomly divided into 4 groups as follows: sham-operated normobaric air (21% O2 at one absolute atmosphere), HBOT only, TBI + normobaric air and TBI + HBOT. Following the evaluation of motor deficits and brainedema, the expression of inflammasome components and effectors was measured by qRT-PCR and Western blotting. Moreover, alterations in IL-1β, IL-18 and high-mobility group box 1 (HMGB1) were calculated by enzyme-linked immunosorbent assay at each time point after injury.
HBOT improved motor score and reduced brain edema. Furthermore, it suppressed protein expression of inflammasome components and reduced the levels of IL-1β and IL-18, accompanied by the reduction of HMGB1 in brain tissues and serum.
These results suggest that HBOT may alleviate the inflammatory response after TBI by inhibiting the activation of inflammasome signaling.
Neuroimmunomodulation. 2016;23(2):122-9. doi: 10.1159/000445689. Epub 2016 May 24.
Hyperbaric oxygen therapy for the treatment of traumatic brain injury: a meta-analysis.
Compelling evidence suggests the advantage of hyperbaric oxygen therapy (HBOT) in traumatic brain injury. The present meta-analysis evaluated the outcomes of HBOT in patients with traumatic brain injury (TBI). Prospective studies comparing hyperbaric oxygen therapy vs. control in patients with mild (GCS 13-15) to severe (GCS 3-8) TBI were hand-searched from medical databases using the terms “hyperbaric oxygen therapy, traumatic brain injury, and post-concussion syndrome”. Glasgow coma scale (GCS) was the primary outcome, while Glasgow outcome score (GOS), overall mortality, and changes in post-traumatic stress disorder (PTSD) score, constituted the secondary outcomes. The results of eight studies (average age of patients, 23-41 years) reveal a higher post-treatment GCS score in the HBOT group (pooled difference in means = 3.13, 95 % CI 2.34-3.92, P < 0.001), in addition to greater improvement in GOS and lower mortality, as compared to the control group. However, no significant change in the PTSD score was observed. Patients undergoing hyperbaric therapy achieved significant improvement in the GCS and GOS with a lower overall mortality, suggesting its utility as a standard intensive care regimen in traumatic brain injury.
Neurol Sci. 2016 May;37(5):693-701. doi: 10.1007/s10072-015-2460-2. Epub 2016 Jan 8.
Hyperbaric oxygen may induce angiogenesis in patients suffering from prolonged post-concussion syndrome due to traumatic brain injury.
Recent clinical studies present convincing evidence that hyperbaric oxygen therapy (HBOT) may be the coveted neurotherapeutic method for brain repair. One of the most interesting ways in which HBOT can induce neuroplasticity is angiogenesis. The objective in this study was to assess the neurotherapeutic effect of HBOT in post TBI patients using brain perfusion imaging and clinical cognitive functions.
Retrospective analysis of patients suffering from chronic neuro-cognitive impairment from TBI treated with HBOT. The HBOT protocol included 60 daily HBOT sessions, 5 days per week. All patients had pre and post HBOT objective computerized cognitive tests (NeuroTrax) and brain perfusion MRI.
Ten post-TBI patients were treated with HBOT with mean of 10.3±3.2 years after their injury. After HBOT, whole-brain perfusion analysis showed significantly increased cerebral blood flow and cerebral blood volume. Clinically, HBOT induced significant improvement in the global cognitive scores (p = 0.007). The most prominent improvements were seen in information processing speed, visual spatial processing and motor skills indices.
HBOT may induce cerebral angiogenesis, which improves perfusion to the chronic damage brain tissue even months to years after the injury.
Restor Neurol Neurosci. 2015;33(6):943-51. doi: 10.3233/RNN-150585.
Hyperbaric oxygen can induce neuroplasticity and improve cognitive functions of patients suffering from anoxic brain damage.
Cognitive impairment may occur in 42-50% of cardiac arrest survivors. Hyperbaric oxygen therapy (HBO2) has recently been shown to have neurotherapeutic effects in patients suffering from chronic cognitive impairments (CCI) consequent to stroke and mild traumatic brain injury.The objective of this study was to assess the neurotherapeutic effect of HBO2 in patients suffering from CCI due to cardiac arrest.
Retrospective analysis of patients with CCI caused by cardiac arrest, treated with 60 daily sessions of HBO2. Evaluation included objective computerized cognitive tests (NeuroTrax), Activity of Daily Living (ADL) and Quality of life questionnaires. The results of these tests were compared with changes in brain activity as assessed by single photon emission computed tomography (SPECT) brain imaging.
The study included 11 cases of CCI patients. Patients were treated with HBO2, 0.5-7.5 years (mean 2.6 ± 0.6 years) after the cardiac arrest. HBO2 was found to induce modest, but statistically significant improvement in memory, attention and executive function (mean scores) of 12% , 20% and 24% respectively. The clinical improvements were found to be well correlated with increased brain activity in relevant brain areas as assessed by computerized analysis of the SPECT imaging.
Although further research is needed, the results demonstrate the beneficial effects of HBO2 on CCI in patients after cardiac arrest, even months to years after the acute event.
Restor Neurol Neurosci. 2015;33(4):471-86. doi: 10.3233/RNN-150517.
Clinical results in brain injury trials using HBO2 therapy: Another perspective.
The current debate surrounding the use of hyperbaric oxygen (HBO2) for neurological indications, specifically mild to moderate chronic traumatic brain injury (mTBI) and post-concussion syndrome (PCS), is mired in confusion due to the use of non-validated controls and an unfamiliarity by many practitioners of HBO2 therapy with the experimental literature. In the past 40 years, the use of an air sham (21% oxygen, 1.14-1.5 atmospheres absolute/atm abs) in clinical and animal studies, instead of observational or crossover controls, has led to false acceptance of the null hypothesis (declaring no effect when one is present), due to the biological activity of these “sham” controls. The recent Department of Defense/Veterans Administration (DoD/VA) sponsored trials, previous published reports on the use of HBO2 therapy on stroke and mTBI and preliminary reports from the HOPPS Army trial, have helped to highlight the biological activity of pressurized air, validate the development of a convincing control for future studies and demonstrate the effectiveness of a hyperbaric intervention for mTBI/ PCS. Approval of HBO2 for neurological indications, especially for mTBI/PCS, should be granted at the federal, state and certifying body levels as a safe and viable treatment for recovery in the post-acute phase. Undersea Hyperb Med. 2015 Jul-Aug;42(4):333-51. https://www.ncbi.nlm.nih.gov/pubmed/26403018
Cognitive function in a traumatic brain injury hyperbaric oxygenrandomized trial.
Determine changes in cognition and post-traumatic stress disorder (PTSD) symptoms in subjects with traumatic brain injury (TBI) exposed to 2.4 atmospheres absolute (atm abs) breathing 100% oxygen vs. sham (1.3 atm-abs air).*
Fifty randomized subjects completed a total of 30 exposures. A concussion history was taken, then baseline, post-series, and six-week follow-up immediate post-concussion assessment and cognitive testing, Brain-checkers and PTSD Checklist for Military (PCL-M) tests were administered.
No statistically significant differences between groups were noted, but both groups improved. Subgroups analyses, based on concussion history and individual test components, showed improvement in the treatment group vs. the sham. These subgroups included the number of concussive events, time from event to consent, loss of consciousness, visual memory, processing, go–no go, and simple reaction time.
There was no statistically significant difference between a sham and 2.4 atm abs hyperbaric oxygen (HBO2) in cognitive scores from ImPACT and Brain-checkers or composite scores in the PCL-M; however both groups showed improvement. Subgroups with favorable response to treatment are identified. Future studies evaluating HBO2 should consider concussion histories or focus on validating subgroup response to determine HBO2 as a potential adjunctive treatment for persistent symptoms following TBI.
Undersea Hyperb Med. 2015 Jul-Aug;42(4):313-32.
*The researchers used active hyperbaric oxygen at 1.3 ATAs as sham. This study is another illustration of a seriously flawed research methodology. Recent researchers have pointed out the fallibility of including an active HBO treatment as the sham and comparing it to HBO at higher ATAs. It should be note that the researchers demonstrate that both groups show improvement and only point out that there was no statistical difference between the two groups. In fact, HBOT is effective here in both groups.
All the right moves: the need for the timely use of hyperbaric oxygen therapy for treating TBI/CTE/PTSD.
The modern age of hyperbaric medicine began in 1937; however, today few know about hyperbaric oxygen’s effects on the body and medical conditions outside of diving medicine and wound care centers – a serious ethical issue as there are 20 US military veterans committing suicide every day directly related to Traumatic Brain Injury/Post Traumatic Stress Disorder. The problem is not whether hyperbaric oxygen is effective for treating brain injuries, but why the interference in offering this therapy to those who need it.
Up against black-boxed anti-depressants that are not efficacious, it should be a “no-brainer” to use a safe, off-label drug, but in the case of military veterans, every suicide might be seen as a tremendous cost saving to certain technocrats. The unspoken rationale is that if the military were to embrace hyperbaricoxygen as the efficacious therapy that it is then current active troops that have suffered injuries will come forward and seek treatment and benefits for their Traumatic Brain Injuries now that they know there is a viable therapy and in so doing troop strength will be decimated. So, to attempt to delay the acceptance of hyperbaric oxygen the Department of Defense has funded faux-studies claiming low pressure room air to be a placebo or sham, and then proclaiming there is no statistical difference between treatment arms and sham or placebo treatment arms. With few who understand hyperbaric medicine there is almost no one to call them on this subterfuge and prevarication. Many peer-reviewed articles have been published in the last decade that demonstrate hyperbaric oxygen is effective in repairing an injured brain even long after that injury took place. One of the most notable showed that blast-induced brain injured war veterans experienced a 15 point IQ increase (p < 0.001).
Hyperbaric oxygen is an efficacious, benign and humanitarian way to affect brain repair but it has not been adopted because it lacks patent protection and has no large corporate sponsors. It has also met interference because other agendas are present be they the protection of the status quo, myopic budgetary constraints, or perceived liability issues.
Med Gas Res. 2015 May 28;5:7. doi: 10.1186/s13618-015-0028-0. eCollection 2015.
Hyperbaric oxygen in chronic traumatic brain injury: oxygen, pressure, and gene therapy.
Hyperbaric oxygen therapy is a treatment for wounds in any location and of any duration that has been misunderstood for 353 years. Since 2008 it has been applied to the persistent post-concussion syndrome of mild traumatic brain injury by civilian and later military researchers with apparent conflicting results. The civilian studies are positive and the military-funded studies are a mixture of misinterpreted positive data, indeterminate data, and negative data. This has confused the medical, academic, and lay communities. The source of the confusion is a fundamental misunderstanding of the definition, principles, and mechanisms of action of hyperbaric oxygen therapy. This article argues that the traditional definition of hyperbaric oxygen therapy is arbitrary. The article establishes a scientific definition of hyperbaric oxygen therapy as a wound-healing therapy of combined increased atmospheric pressure and pressure of oxygenover ambient atmospheric pressure and pressure of oxygen whose main mechanisms of action are gene-mediated. Hyperbaric oxygen therapy exerts its wound-healing effects by expression and suppression of thousands of genes. The dominant gene actions are upregulation of trophic and anti-inflammatory genes and down-regulation of pro-inflammatory and apoptotic genes. The combination of genes affected depends on the different combinations of total pressure and pressure of oxygen. Understanding that hyperbaric oxygen therapy is a pressure and oxygen dose-dependent gene therapyallows for reconciliation of the conflicting TBI study results as outcomes of different doses of pressure and oxygen.
Med Gas Res. 2015 Jul 14;5:9. doi: 10.1186/s13618-015-0030-6. eCollection 2015.
Effects of hyperbaric oxygen on symptoms and quality of life among service members with persistent postconcussion symptoms: a randomized clinical trial.
Improvement has been anecdotally observed in patients with persistent postconcussion symptoms (PCS) after mild traumatic brain injury following treatment with hyperbaric oxygen (HBO). The effectiveness of HBO as an adjunctive treatment for PCS is unknown to date.
To compare the safety of and to estimate the efficacy for symptomatic outcomes from standard PCS care alone, care supplemented with HBO, or a sham procedure.
DESIGN, SETTING, AND PARTICIPANTS
Multicenter, double-blind, sham-controlled clinical trial of 72 military service members with ongoing symptoms at least 4 months after mild traumatic brain injury enrolled at military hospitals in Colorado, North Carolina, California, and Georgia between April 26, 2011, and August 24, 2012. Assessments occurred before randomization, at the midpoint, and within 1 month after completing the interventions.
Routine PCS care was provided in specialized clinics. In addition, participants were randomized 1:1:1 to 40 HBO sessions administered at 1.5 atmospheres absolute (ATA), 40 sham sessions consisting of room air at 1.2 ATA, or no supplemental chamber procedures. MAIN
OUTCOMES AND MEASURES
The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) served as the primary outcome measure. A change score of at least 2 points on the RPQ-3 subscale (range, 0-12) was defined as clinically significant. Change scores from baseline were calculated for the RPQ-3 and for the total RPQ. Secondary measures included additional patient-reported outcomes and automated neuropsychometric testing.
On average, participants had sustained 3 lifetime mild traumatic brain injuries; the most recent occurred 23 months before enrollment. No differences were observed between groups for improvement of at least 2 points on the RPQ-3 subscale (25% in the no intervention group, 52% in the HBO group, and 33% in the sham group; P = .24). Compared with the no intervention group (mean change score, 0.5; 95% CI, -4.8 to 5.8; P = .91), both groups undergoing supplemental chamber procedures showed improvement in symptoms on the RPQ (mean change score, 5.4; 95% CI, -0.5 to 11.3; P = .008 in the HBO group and 7.0; 95% CI, 1.0-12.9; P = .02 in the sham group). No difference between the HBO group and the sham group was observed (P = .70). Chamber sessions were well tolerated.
CONCLUSIONS AND RELEVANCE
Among service members with persistent PCS, HBO showed no benefits over sham compressions. Both intervention groups demonstrated improved outcomes compared with PCS care alone. This finding suggests that the observed improvements were not oxygen mediated but may reflect nonspecific improvements related to placebo effects.
JAMA Intern Med. 2015 Jan;175(1):43-52. doi: 10.1001/jamainternmed.2014.5479.
The researchers include sham studies which used active hyperbaric oxygen at 1.2 ATAs as sham. Recent researchers have pointed out the fallibility of including an active HBO treatment as sham and comparing it to HBO at higher ATAs. Studies using shams with active HBOT (1.2-1.3) should be carefully evaluated and omitted from consideration in future evaluation of HBOT efficacy.
Improvement of memory impairments in poststroke patients by hyperbaric oxygen therapy.
Several recent studies have shown that hyperbaric oxygen (HBO₂) therapy carry cognitive and motor therapeutic effects for patients with acquired brain injuries. The goal of this study was to address the specific effects of HBO₂ on memory impairments after stroke at late chronic stages.
A retrospective analysis was conducted on data of 91 stroke patients 18 years or older (mean age ∼60 years) who had either ischemic or hemorrhagic stroke 3-180 months before HBO₂ therapy (M = 30-35 months). The HBO₂ protocol included 40 to 60 daily sessions, 5 days per week, 90 min each, 100% oxygen at 2ATA, and memory tests were administered before and after HBO₂ therapy using NeuroTrax’s computerized testing battery. Assessments were based on verbal or nonverbal, immediate or delayed memory measures. The cognitive tests were compared with changes in the brainmetabolic state measured by single-photon emission computed tomography.
Results revealed statistically significant improvements (p < .0005, effect sizes medium to large) in all memory measures after HBO₂ treatments. The clinical improvements were well correlated with improvement in brain metabolism, mainly in temporal areas.
Although further research is needed, the results illustrate the potential of HBO₂ for improving memory impairments in poststroke patients, even years after the acute event.