• The following list provides a 'knowledge share base' working to collaborate and promote the benefits of Hyperbaric Oxygen Therapy.

  • Australia is not a leader in this field but lagging behind the rest of the world in relationship to the wider applications of modern Hyperbaric Oxygen Therapy using different 'pressure protocols for different conditions'. 

  • The information provided does not constitute a medical endorsement or recommendation. It is intended for informational purposes only, and no claims, either real or implied, are being made. 

A Dual Role for Hyperbaric Oxygen in Stroke Neuroprotection: Preconditioning of the Brain and Stem Cells

Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida USA. June 2018

HB OTG and Stroke Neuroprotection July 2

Med Gas Res. 2018 Jul 3;8(2):64-66. doi: 10.4103/2045-9912.235129. eCollection 2018 Apr-Jun.

The role of argon in stroke.

Li X1, Zhang ZW1, Wang Z1, Li JQ1, Chen G1.


Stroke, also known as "cerebrovascular accident", is an acute cerebrovascular disease that is caused by a sudden rupture of blood vessels in the brain or obstruction of the blood supply by blockage of blood vessels, thus including hemorrhagic and ischemic strokes. The incidence of ischemic stroke is higher than that of hemorrhagic stroke, and accounts for 80% of the total number of strokes. However, the mortality rate of hemorrhagic stroke is relatively high. Internal carotid artery and vertebral artery occlusion and stenosis can cause ischemic stroke, and especially males over 40 years of age are at a high risk of morbidity. According to the survey, stroke in urban and rural areas has become the first cause of death in China. It is also the leading cause of disability in Chinese adults. In a word, stroke is characterized by high morbidity, high mortality and high disability rates. Studies have shown that many noble gases have the neuroprotective effects. For example, xenon has been extensively studied in various animal models of neurological injury including stroke, hypoxic-ischemic encephalopathy. Compared to xenon, Argon, as a noble gas, is abundant, cheap and widely applicable, and has been also demonstrated to be neuroprotective in many research studies. In a variety of models, ranging from oxygen-glucose deprivation in cell culture to complex models of mid-cerebral artery occlusion, subarachnoid hemorrhage or retinal ischemia-reperfusion injury in animals. Argon administration after individual injury demonstrated favorable effects, particularly increased cell survival and even improved neuronal function. Therefore the neuroprotective effects of argon may be of possible clinical use for opening a potential therapeutic window in stroke. It is important to illuminate the mechanisms of argon in nerve function and to explore the best use of this gas in stroke treatment.

A Dual Role for Hyperbaric Oxygen in Stroke Neuroprotection: Preconditioning of the Brain and Stem Cells.

Cond Med 2018 Jun;1(4):151-166

Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida 

Stroke continues to be an extremely prevalent disease and poses a great challenge in developing safe and effective therapeutic options. Hyperbaric oxygen therapy (HBOT) has demonstrated significant pre-clinical effectiveness for the treatment of acute ischemic stroke, and limited potential in treating chronic neurological deficits. Reported benefits include reductions in oxidative stress, inflammation, neural apoptosis, and improved physiological metrics such as edema and oxygen perfusion, all of which contribute to improved functional recovery. This pre-clinical evidence has failed to translate into an effective evidence-based therapy, however, due in large part to significant inconsistencies in treatment protocols and design of clinical studies. While the medical community works to standardize clinical protocols in an effort to advance HBOT for acute stroke, pre-clinical investigations continue to probe novel applications of HBOT in an effort to optimize stroke neuroprotection. One such promising strategy is HBOT preconditioning. Based upon the premise of mild oxidative stress priming the brain for tolerating the full-blown oxidative stress inherent in stroke, HBOT preconditioning has displayed extensive efficacy. Here, we first review the pre-clinical and clinical evidence supporting HBOT delivery following ischemic stroke and then discuss the scientific basis for HBOT preconditioning as a neuroprotective strategy. Finally, we propose the innovative concept of stem cell preconditioning, in tandem with brain preconditioning, as a promising regenerative pathway for maximizing the application of HBOT for ischemic stroke treatment.

The potential long-term neurological improvement of early hyperbaric oxygen therapy on hemorrhagic stroke in the diabetics.

Diabetes Res Clin Pract 2018 Feb 3. Epub 2018 Feb 3.

Department of brain surgery, Ningbo Zhenhai People Hospital (Ningbo Seventh Hospital), Zhejiang 315202, China. Electronic address:

  • February 2018

Aims: Although Hyperbaric oxygen therapy (HyperBOT) attract our attention successfully these days, it is still full of controversy on the treatment of acute stroke. The aim of this study is to assess the potential long-term neurological consequences and safety of using HyperBOT on intracerebral hemorrhage (ICH) in the diabetics.

Methods: In this prospective, randomized controlled trial, 79 diabetes patients suffering from acute ICH were randomized to treat for 60 minutes in a monoplace hyperbaric chamber pressurized with pure oxygen to 2.5-atm absolute (ATA) in the HyperBOT group or 1.5 ATA in the normobaric oxygen therapy (NormBOT) group, which was performed as control. Both short-term and long-term neurological consequences were studied and compared in each group on National Institutes of Health Stroke Scale [NIHSS], Barthel Index, modified Rankin Scale [mRS] and Glasgow Outcome Scale [GOS]. The related complications or side-events of all patients were recorded as well at the final follow-up of six months after onset.

Results: No distinct difference was observed between each group at one month follow-up. However, in the long-term follow-up of six months, a higher frequency of patients in the HyperBOT group resulted into good outcome with a relative high neurological consequence compared with the NormBOT group (Barthel Index: 85.1% versus 65.6%, P= 0.080; mRS: 89.4% versus 68.8%, P= 0.045; GOS: 83.0% versus 62.5%, P= 0.073; NIHSS: 80.9% versus 56.2%, P= 0.035).

Conclusions: Early HyperBOT was found to be safe and effective with regards to the long-term neurological outcome of diabetic patients suffering from ICH.

OXYMED Comment: note 1.5 ATA is not a  "control" - it is a therapeutic pressure as published by Dr Paul Harch.

Hyperbaric Oxygen Therapy in Experimental and Clinical Stroke Rehabilitation. 

Abstract: Zhai WW, Sun L, Yu ZQ, Chen G (Aug 11 2016) Med Gas Res 6(2):111-118. 

Mechanisms Associated With HBOT and Stroke Treatment:

In recent years, studies (Singhal, 2007) have illustrated that HBOT may also accomplish neuroprotective effects in stroke via a variety of complex molecular, biochemical and hemodynamic mechanisms:

  1. HBOT is capable of enhancing the arterial partial pressure of oxygen, improving oxygen delivery and increasing oxygen supply for brain tissue;

  2. HBOT stabilizes the blood-brain barrier (BBB) and reduce cerebral edema (Chen et al., 2011b);

  3. HBOT ameliorates cerebral microcirculation and improve brain metabolism to create sufficient energy, preserve cellular ion homeostasis (Zhang et al., 2005);

  4. HBOT decreases the intracranial pressure via modulating cerebral blood flow and brain edema reduction;

  5. HBOT alleviates post-stroke neuroinflammation;

  6. HBOT inhibits post-stroke cell apoptosis and necrosis;

  7. HBOT improves the microcirculation of anoxic area and reduce cerebral hypoxia-ischemia (Siesjo, 1988);

  8. Appropriate and timely application of HBOT will alleviate oxidative stress and suppress the ischemiareperfusion injury which is generally recognized as one of the core pathophysiology in stroke injury (Sanchez, 2013);

  9. Furthermore, it has been demonstrated that when HBOT is used to treat patients with aneurysmal subarachnoid hemorrhage (SAH), it may attenuate cerebral vascular spasm induced by SAH (Ostrowski and Zhang, 2011);

  10. HBOT is also confirmed favorable to neurogenesis and angiogenesis.

Summary Effects of Hyperbaric Oxygen Therapy in Stroke Rehabilitation. (p113-115)

  1. HBOT can decrease infarction size and reperfusion injury. Early HBOT in rats with permanent middle cerebral artery occlusion (MCAO) has neuroprotective effects, possibly via the inhibition of phospho-protein kinase Calpha (PKC-α) and tumor necrosis factor-alpha (TNF-α). It was observed that the brain infarction area and edema decreased with the expression of TNF-α and PKC-α in the ischemic penumbra tissue down-regulated in the HBOT group which was immediately given HBOT after MCAO model successfully made (Yu et al., 2015).

  2. In a mouse MCAO model, a single session of HBOT immediately applied in MCAO followed by 24 hours’ reperfusion may significantly reduce cerebral edema and brain damage via improvement of the ischemic area perfusion. In addition, the protection effect provided by HBOT was more robust than that provided by toll-like receptor 4 knockout (Dharmasaroja, 2016; Pushkov et al., 2016). However, another study of Rink et al. (2010) surprisingly showed HBOT may increase ease MCAO damage in rats model, different with most investigators that hold HBOT as a safe and effective option on the whole, even though controversial.

  3. HBOT preconditioning (HBO-PC) that means pretreating with hyperbaric oxygen has been shown to be neuroprotective via stabilizing blood-brain barrier permeability and decreasing oxidative stress in animal stroke models. Li et al. (2009) divided the experimental rats into three groups: control group with no treatment, transient MCAO group with clipping unilateral internal carotid artery for 90 minutes, HBO-PC group with four treatment sessions of HBOT at 2.5 ATA per day, once for 1 hour, for 2 days. Finally, they found the rats post HBO-PC showed infarct size reduction by triphenyltetrazolium chloride staining, decreased expression of caspase 9 and 3 as well as increased expression of Bax/Bcl-2 by western-blot assay. Soejima et al. (2013) concluded that HBO-PC can attenuate hyperglycemia-enhanced hemorrhagic transformation after ischemic stroke and reduce hemorrhagic volume and other beneficial effects: decrease infarction size and BBB disruption, improve neurological deficits, down-regulate the expression of hypoxia-inducible factor-1α (HIF-1α), and reduce the activity of matrix metalloproteinases (MMP)-2 and MMP-9. They also found HBOT might decrease poststroke hemorrhagic transformation through increasing peroxisome proliferator activated receptor-γ (PPARγ) in hyperglycemia rats (Soejima et al., 2012, 2013; Bian et al., 2015). Additionally, HBO-PC and HBOT during ischemia was manifested to have neuroprotective effect by the suppression of the increased glutamate and hydroxyl radical level besides modulating energy metabolism in the penumbral area (Yang et al., 2010; Gao-Yu et al., 2011; Bian et al., 2015).

  4. In our review (Ploughman et al., 2015), several studies indicated the post-stroke dendritic branching and synaptogenesis probably represent neuroplasticity implicated in neurological recovery. It has been illustrated that delayed HBOT which begins at 7 days after MCAO and lasts for 42 days can provide certain benefits for neurogenesis and neuroprotection including motor sensory recovery, but the promotion may be reversed by inhibition of reactive oxygen species (ROS) and HIF1α. That is to say, if ROS and HIF-1α are inhibited experimentally prior to the treatment of HBOT, the beneficial effects of delayed HBOT will finally decrease. Thereby, it is deduced that delayed HBOT as an alternative treatment could enhance endogenous neurogenesis and improve the long-term prognosis of stroke survivors (Hu et al., 2014).

  5. In an experimental study in rats related to pre-ischemic HBOT and post-ischemic aminoguanidine (AG), all the rats were equally divided into four groups (n = 7): control group, HBOT group, HBO + AG group, and AG group. The infarction rate was measured at 3 days after MCAO, the investigators found: 22.2 ± 3.1% in control group, 16.1 ± 2.7% in HBOT group, 14.4 ± 3.3% in AG group, and 15.2 ± 1.9% in HBO + AG group. As a result, they came to the conclusion that in permanent MCAO model of rats, AG and HBOT have a protective effect on the infarct rate, but no additive effect (Harman et al., 2012).

  6. However, the results of an in vitro study showed that an increase of oxygen partial pressure and exposure time resulted in elevated free radical, enhanced viscosity of the whole blood and lipid peroxidation in erythrocyte, but attenuated erythrocyte deformability (Chen et al., 2011a). Another finding in ischemia/reperfusion rat models showed that HBOT enlarged the infarct ratio via blocking autophagy by ROS generation and activation of extracellular signalregulated kinase 1/2 (Lu et al., 2014). The results shown above indicate that not all the effects of HBOT are directly beneficial and some effects are still under debate.

  7. In the present study, cyclooxygenase-2 (COX-2) in cerebral tissues is indicated as a critical component of post-stoke neuroinflammation, and HBO-PC has the capability of protecting brain from global ischemia injury. In the transient global cerebral ischemic rat model, Cheng et al. (2011) showed that HBO-PC leaded to an inhibition of COX-2 expression, improved neurofunctional performance, and even decreased the incidence of seizures and mortality, while these beneficial effects of HBO-PC were weakened by COX-2 selective inhibitor pretreatment. It was concluded that HBO-PC may provide brain protection against global ischemia via the suppression of COX-2. Thereby, COX-2 probably acts as a mediator of HBO-PC within the transient ischemic brain tissue.

  8. We reviewed a research referring to the early functional outcome and BBB integrity after co-administered HBOT and thrombolysis treatment using tissue-plasminogen activator (tPA) in the early phase of experimental stroke (Michalski et al., 2011b, 2012; Hafez et al., 2014). In summary, thrombolysis tended to increase BBB permeability while HBOT tended to stabilize BBB but surprisingly failed to improve the early neurofunction as hypothesis. Treatment applied both HBOT and tPA improved early functional outcome but BBB permeability was found to be increased to a certain degree than HBOT alone, potentially owing to enhanced reperfusion in the infarct area and increased BBB permeability and MMP-2 activation via tPA. In another report addressing long-term neurofunctional outcome, combined treatment of tPA and HBOT in early phase of stroke even leaded to delayed brain damage and resulted in neurological deterioration in the long-term follow-up phase (Michalski et al., 2009). As above, simultaneous treatment with hyperoxia and thrombolysis may result in unfavorable therapeutic effects out of our expectation. So further studies are warranted to identify the effect of this combined treatment at molecular level and avoid unfavorable courses of combined treatment in acute stroke.

  9. In addition to decreasing infarction volume and ischemiareperfusion injury, neuronal repair after stroke is also crucial. Investigators have demonstrated that HBOT can stimulate the expression of neurotrophic factors, promote neurogenesis and gliosis. Bone marrow stem cell (BMSC) transplantation, which is important in regenerative therapy, has been demonstrated favorable to improve the outcomes of many neuronal diseases. In cases of animal stroke, the mobilization and migration of BMSCs in brain are also found enhanced by long-course HBOT (Lee et al., 2013). These beneficial effects described above could potentially contribute to neuronal repair after stroke injury.

  10. Thrombolysis potentially improves the risk of post-thrombolytic intracerebral hemorrhage by 6-fold in clinical trials related to cerebral infarction (Hacke et al., 2004). In a MCAO model treated with thrombolysis, HBOT tended to decrease the secondary hemorrhage and reduce the infarct volume if reperfusion was successful (Sun et al., 2010).

  11. HBOT can enhance the efficiency of some neuroprotective drugs and provide additive neuroprotection against ischemia-induced neurodegeneration,  for example, when combine HBOT and the c-Jun N-terminal kinases inhibitor XG-102, the infarct size caused by MCAO was diminished by 78%, while XG-102 and HBOT alone only 43% and 63% (Liu et al., 2010). Moreover, the combination also reduced brain edema and improved neurological outcome more robust than each alone. Nevertheless, not every combined treatment will provide additional benefit, such as combination of HBOT and second generation perfluorochemicals (Schneider et al., 2014), it does not tend to show significantly smaller necrosis than HBOT only.

  12. Hemorrhagic stroke which is more fatal and complex generally involves SAH and intracerebral hemorrhage (ICH) (Pandey and Xi, 2014). Effect of HBOT in hemorrhagic stroke was also studied in animals, mainly involving the suppression of brain edema, neuroinflammation, cerebral vasospasm and the promotion of both angiogenesis and neurogenesis (Peng et al., 2014; Xiong and Yang, 2015; Yang et al., 2015; Zhou et al., 2015). The associated molecular mechanism is basically consistent with that in ischemic stroke.

Summary of Clinical Studies in Stroke & Brain Repair

The first reported clinical application of HBOT and stroke was performed about half a century ago, shortly after the first experimental study in animal. To date, HBOT has been broadly and commonly used as an optional treatment for both ischemic and hemorrhagic stroke (Figure 2), although lack of uniform therapeutic standard, such as time window of treatment and optimal dose (oxygen pressure level).


In recent years, more and more new clinical trials have provided evidence base for HBOT induced cerebral plasticity which can lead to brain function recovery and significant life quality improvement for post-stroke patient. Nevertheless, most clinical studies still lack of standard outcome measurement and negative control. To the best of our knowledge, only three well-designed randomized controlled trials have been published (Anderson et al., 1991; Nighoghossian et al., 1995; Rusyniak et al., 2003), but the discrepancy among the conclusions leaves the final efficacy in human stroke treatment still unclear.


To better understand the current application of HBOT, several latest clinical studies are systematically summarized and analyzed, as shown below:

  1. HBOT exerts therapeutic effects on cognitive recovery from stroke, even at late chronic stage. In a retrospective clinical trial conducted by Ploughman et al. (2015), they analyzed the data of 91 patients suffering memory impairments due to either hemorrhagic or ischemic stroke. All the subjects were in 3-180 months after the initial episode. The HBOT protocol administered in the participants was set at 2.0 ATA, 40-60 sessions per day, 90 minutes each, 5 days per week. Before and after the therapy, the memory function was both measured by a specific test and compared with the brain metabolic changes assessed by single-photon emission computed tomography. Finally, the results illustrate statistically significant memory improvements in almost all the patients and the improvements was in good agreement with an improvement in brain metabolic state, mainly in the temporal lobe.  Recently, another retrospective analysis of chronic cognitive impairments caused by cardiac arrest has shown a result, reconfirmed the therapeutic effect on cognitive functions and the well correlated brain metabolic changes in relevant areas (Hadanny et al., 2015). Hence in the future, HBOT might play as a considerable effective treatment for more and more patients with post-stroke memory impairment.

  2. HBOT is known capable to modulate vasoreactivity and cerebral blood flow (CBF). The response of regional CBF to HBOT in human was firstly investigated and confirmed in 2013. When HBOT at a pressure of 2.5 ATA and a perfusion tracer was used in healthy subjects observing CBF distribution, an increased regional CBF distribution mainly on the dominant hemisphere was observed in sensory-motor area, premotor, posterior cingulate and visual cortices, middle/ inferior temporal gyrus, superior frontal gyrus, angular gyrus and cerebellum (Micarelli et al., 2013). The findings in this research unfold a possible underlying mechanism of HBOT related beneficial effects on the cognitive and motor improvement in stroke patients.

  3. A regression statistical analysis on the basis of the Heyman 1966 HBOT study focused on treatment time window and time in chamber as well as dose of HBOT. In conclusion, only time window post stroke affects the recovery efficacy significantly and the chance of recovery is decreased over time. As a result, the most promising time window for HBOT efficacy in acute stroke is within the first 3 hours. In addition, the earlier the time window, the better the HBOT efficacy (McCormick et al., 2011).

  4. Stroke induced by iatrogenic cerebral air embolism can occur in a lot of invasive therapy, such as catheter insertion and removal, laparoscopic surgery, cardiac surgery, but a potential fatal complication is uncommon. In our review, there are two articles associated to HBOT in this condition. They both retrospectively reviewed the outcome and some factors related to the response to HBOT, appraised the evidence base for the use of it in this setting. A large proportion of the subjects achieved a favorable outcome-full recovery or neurological improvement to varying degrees. The multivariate analysis further indicated HBOT within 6 hours from event increased the therapeutic effect whereas the infarct and edema shown on brain CT or MRI will reduce the benefit from HBOT. So far, HBOT is the only definitive treatment for gas embolism caused stroke with acute neurologic deficits, so timely administration of HBOT appears to be essential to the patients’ function recovery.

  5. As shown above, early HBOT in acute stroke need to be applied within the time window of 3 to 6 hours, but if patients arrive too late, whether HBOT should be used? It has been suggest that delayed but repeated HBOT can also provide salvage of brain cells and promotion of neurofunction. As described in a case report, a patient with acute infarction on the corona radiate was admitted to hospital more than 5 hours after symptom onset (> 4.5 hours), so intravenous thrombolysis could not be performed. However, on the  3rd day, a daily HBOT at 2.0 ATA was preferred and continuously administered for 2 weeks. At last, prominent neurofunctional improvement was demonstrated by several clinical parameters, correlated with the regional CBF and penumbra amelioration noted in image tests (Chen et al., 2011b).

  6. Post-stroke depression frequently affects the quality of life and functional recovery of the patients. Fortunately, HBOT combined with antidepressants has been declared to have a supplementary beneficial effect. In a prospective clinical trial, the combination of HBOT and fluoxetine resulted in significantly higher efficacy than HBOT or fluoxetine alone (Yan et al., 2015). Further investigation is needed to verify the effect of this combination therapy.

  7. The correlation between HBOT and clinical outcome in patients with postoperative intracranial aneurysm has also been investigated. Early HBOT initiated within 1-3 days post-operation has been proved to be a valuable neuroprotective therapy, mainly via ameliorating cerebral vasospasm and ischemia (Ostrowski and Zhang, 2011; Tang et al., 2011).

  8. Clinical trials concerning HBOT in ICH are scarcely reported, although they have been widely used in this field. Our experience indicates that HBOT should be applied as early as possible if the patient is in stable condition, and it may provide an additional chance for the neurological deficits caused by ICH.


Adverse Effects of Hyperbaric Oxygen Therapy

  1. HBOT is considered safe and adverse effects are rarely seen in patients treated in pressures below 3.0 ATA.

  2. However, extreme hyperbaric condition or excess duration may result in oxygen toxicity, mainly including central nervous system toxicity, pulmonary injury, middle ear barotrauma, and retinopathy of prematurity (Calvert et al., 2004).

  3. Elevated pressures (5.0 ATA) can increase the risk of agitation and seizures substantially (Chavko et al., 2001).

  4. HBOT at 4.0 ATA or higher will aggravate oxidative stress in brain tissue, probably via the upregulation of lipid peroxidation and ROS and other free radicals.

  5. Thus, the guideline for HBOT recommended the maximum therapeutic pressure no greater than 3.0 ATA (Matchett et al., 2009).​

What Happens With Stroke

  • Most victims of stroke have years of progressive vascular insufficiency leading to a catastrophic event. Those that survive have a long road ahead. Stroke recovery is slow and many do not survive past 3-5 years due to 'secondary cascade complications'.

  • The event of stroke causes widespread hypoxic damage which can be measured on MRI - often referred to as 'encephalomalacia' which leads to progressive 'softening and liquefaction' of the brain. Google search this term for additional information. The MRI has a typical 'watershed' that delineates the area affected by stroke. However many stroke survivors with further MRI years later demonstrate expansion of the original watershed. This is due to Hypoxic Induced Apoptosis. Hypoxia fosters progressive neurodegeneration compounded by 'learned non-use'.

  • The difficulty in treating stroke is the fact that 'drugs' require Oxygen as a catalyst to penetrate the target region. This is exactly how Hyperbaric Oxygenation provides benefit for stroke victims

  • We often describe the impact of Hyperbaric Oxygenation is like 'getting more fizz into a flat can of coke'! The objective of Hyperbaric Oxygenation is to get more Oxygen (fizz) into the hypoxic damaged nerve cell and neural tracts accelerating recovery and preventing further destructive spread due to hypoxic induced apoptosis.

OXYMED NeuroRecovery

 * OXYMED is like a neuro-recovery boot camp; we make no apology for 'politely pushing the patient'  the objective is to penetrate the deeper neurovascular structures (penumbra), unlock dormant pathways and promote functional changes. OXYMED provides HBOT at pressures ranging between 1.5-2.4 ATA using 100% O2. HBOT is individualized to the patient. These treatment recommendations are in accord with the International Hyperbaric Medicine Foundation (IHMF) 2016.

 ** Hyperbaric Oxygen Therapy is combined with TNF blocker therapies including Cerebryolysin which may enhance the efficacy of individual and combination effects of treatment for neurologic patients. 

 - Elevated pro-inflammatory markers Cytokines (IL1, IL6, IL7, IL8) and TNFα, GlycA, S100B are linked with chronic and progressive neurodegenerative disease including stroke.


OXYMED Case Study - Mr GP age 64 - Right Middle Cerebral Artery Stroke

Cytokine Pre-HBO and Post-HBO. Note pre HBO elevation of Il1, Il7, IL8, TNFa.

Hyperbaric Oxygen Therapy Induces Neuroplasticity in Chronic Stroke Victims

A prospective, randomized, controlled trial including 74 patients (15 were excluded). All participants suffered a stroke 6–36 months prior to inclusion and had at least one motor dysfunction. After inclusion, patients were randomly assigned to "treated" or "cross" groups. Brain activity was assessed by SPECT imaging; neurologic functions were evaluated by NIHSS, ADL, and life quality.

Patients in the treated group were evaluated twice: at baseline and after 40 HBOT sessions. Patients in the cross group were evaluated three times: at baseline, after a 2-month control period of no treatment, and after subsequent 2-months of 40 HBOT sessions.

HBOT protocol: Two months of 40 sessions (60-hours), 5 days/ week, 90 minutes each, 100% oxygen at 2 ATA.

We found that the neurological functions and life quality of all patients in both groups were significantly improved following the HBOT sessions while no improvement was found during the control period of the patients in the cross group. Results of SPECT imaging were well correlated with clinical improvement. Elevated brain activity was detected mostly in regions of live cells (as confirmed by CT) with low activity (based on SPECT) – regions of noticeable discrepancy between anatomy and physiology. Conclusions: The results indicate that HBOT can lead to significant neurological improvements in post stroke patients even at chronic late stages. The observed clinical improvements imply that neuroplasticity can still be activated long after damage onset in regions where there is a brain SPECT/CT (anatomy/physiology) mismatch.

Hyperbaric Oxygen Improves Post Concussion Syndrome Years After Traumatic Brain Injury (TBI)

Citation: Boussi-Gross R, Golan H, Fishlev G, Bechor Y, Volkov O, et al. (2013) Hyperbaric Oxygen Therapy Can Improve Post Concussion Syndrome Years after Mild Traumatic Brain Injury - Randomized Prospective Trial. PLoS ONE 8(11): e79995. doi:10.1371/journal.pone.0079995. Published November 15, 2013

Traumatic brain injury (TBI) is the leading cause of death and disability in the US. Approximately 70-90% of the TBI cases are classified as mild, and up to 25% of them will not recover and suffer chronic neurocognitive impairments. The main pathology in these cases involves diffuse brain injuries, which are hard to detect by anatomical imaging yet noticeable in metabolic imaging.

The current study tested the effectiveness of Hyperbaric Oxygen Therapy (HBOT) in improving brain function and quality of life in mTBI patients suffering chronic neurocognitive impairments.

Methods and Findings: The trial population included 56 mTBI patients 1–5 years after injury with prolonged postconcussion syndrome (PCS). The HBOT effect was evaluated by means of prospective, randomized, crossover controlled trial: the patients were randomly assigned to treated or crossover groups. Patients in the treated group were evaluated at baseline and following 40 HBOT (60-minute) sessions; patients in the crossover group were evaluated three times: at baseline, following a 2-month control period of no treatment, and following subsequent 2-months of 40 HBOT sessions.

The HBOT protocol included 40 treatment sessions (5 days/week), 60 minutes each, with 100% oxygen at 1.5 ATA. ‘‘Mindstreams’’ was used for cognitive evaluations, quality of life (QOL) was evaluated by the EQ-5D, and changes in brain activity were assessed by SPECT imaging. Significant improvements were demonstrated in cognitive function and QOL in both groups following HBOT but no significant improvement was observed following the control period. SPECT imaging revealed elevated brain activity in good agreement with the cognitive improvements.


Conclusions: HBOT can induce neuroplasticity leading to repair of chronically impaired brain functions and improved quality of life in mTBI patients with prolonged PCS at late chronic stage.

Page 11 - Linking elevated oxygen, metabolism and brain activity to neuroplasticity

  • The changes in SPECT images after treatment indicate that HBOT led to reactivation of neuronal activity in stunned areas that seemed normal under CT and MRI imaging.

  • While SPECT imaging has a limited spatial resolution (compared, for example, to fMRI, the changes in activity were sufficiently robust to be clearly detected by the SPECT images. Recently, Kan et al. [57] discussed the need for potent interventions, such as elevated tissue oxygen, capable of repairing microenvironment alterations after mTBI (e.g impairments in vascular changes, in cerebral blood flow and in perfusion), leading to reduced oxygen availability followed by reduced metabolism, which in turn leads to reduced neuronal activity, loss of synapses and tampered neuronal connectivity.

  • The observed reactivation of neuronal activity in the stunned areas found here, along with similar results in post-stroke patients [3], imply that increasing the plasma oxygen concentration with hyperbaric oxygenation is a potent means of delivering to the brain sufficient oxygen for tissue repair. HBOT might initiate a cellular and vascular repair mechanism and improve cerebral vascular flow [34,58,59,60]. More specifically, HBOT induces regeneration of axonal white matter [61,62,63,64, has positive effect upon the myelinization and maturation of injured neural fibers [65], and can stimulate axonal growth and increase the ability of neurons to function and communicate with each other [66].

  • In addition, HBOT was found to have a role in initiation and/or facilitation of angiogenesis and cell proliferation processes needed for axonal regeneration [67]. At the cellular level, HBOT can improve cellular metabolism, reduce apoptosis, alleviate oxidative stress and increase levels of neurotrophins and nitric oxide through enhancement of mitochondrial function (in both neurons and glial cells). Moreover, the effects of HBOT on neurons can be mediated indirectly by glial cells, including astrocytes [23].

  • HBOT may promote the neurogenesis of endogenous neural stem cells [24]. With regard to secondary injury mechanisms in mTBI, HBOT can initiate vascular repair mechanism and improve cerebral vascular flow [58,59,68,69], promote blood brain barrier integrity and reduce inflammatory reactions [28] as well as brain edema [20,21,22,26,34,70].

  • A drawback to the above-mentioned findings is that the different effects have been tested at different experimental setups and while utilizing different protocols of HBOT.

  • However, it is well noticed that there is at least one common denominator to all repair/regeneration mechanisms: Figure 6. Assessments of the mean relative changes and standard errors in quality of life measurements. The changes are shown for the crossover group following control period (green bars) and following HBOT (blue bars), and for the treated group following HBOT (red bars). Note that, according to the questionnaire structure, in the EQ-5D measurement improvement is reflected as score decrease, hence the negative values of change they are all energy/oxygen dependent. It might be possible that HBOT enables the metabolic change simply by supplying the missing energy/oxygen needed for those regeneration processes.

Neurosci Lett. 2017 Feb 22. pii: S0304-3940(17)30175-1. doi: 10.1016/j.neulet.2017.02.059. [Epub ahead of print]

Early hyperbaric oxygen therapy may improve the long term neurological consequences of diabetic patients suffering from hemorrhagic stroke.

Xu Q1, Wei YT1, Fan SB1, Wang L1, Zhou XP1.

Author information



Hyperbaric oxygen therapy (HBOT) is still a controversial alternative strategy for acute stroke. This study was conducted to evaluate the potential long-term efficacy and safety of using HBOT in diabetes patients with intracerebral hemorrhage (ICH).


In this randomized, prospective, normobaric oxygen therapy (NBOT)-controlled pilot study, 79 diabetes patients suffering from acute ICH were randomized to treat for 60minutes in a monoplace hyperbaric chamber pressurized with 100% O2 to 2.5-atm absolute (ATA) in the HBOT group or 1.5 ATA in the NBOT group. The primary outcomes included percentage of patients with improvement at one month and six months after onset (National Institutes of Health Stroke Scale [NIHSS], Barthel Index, modified Rankin Scale [mRS], Glasgow Outcome Scale [GOS]). The complications of all patients were recorded as well at the final follow-up of six months after onset.


Baseline characteristics were similar in both groups. There were no statistical differences between two groups at one month. However, in the long-term follow-up of six months, a larger percentage of patients in the HBOT group had a good outcome defined by their stroke scores compared with the HBOT group (Barthel Index: 85.1% versus 65.6%, P=0.080; mRS: 89.4% versus 68.8%, P=0.045; GOS: 83.0% versus 62.5%, P=0.073; NIHSS: 80.9% versus 56.2%, P=0.035).


In this study, early HBOT was found to be safe and effective with regards to the long term neurological consequences of diabetic patients suffering from ICH.

Med Sci Monit. 2016 Jan 26;22:284-8.

Hyperbaric Oxygen Alleviates Secondary Brain Injury After Trauma Through Inhibition of TLR4/NF-κB Signaling Pathway

Meng XE1, Zhang Y1, Li N1, Fan DF1, Yang C1, Li H1, Guo DZ1, Pan SY1.

Author information

  • 1Department of Hyperbaric Oxygen, Navy General Hospital, Beijing, China (mainland).


BACKGROUND The aim of this study was to investigate the efficacy of hyperbaric oxygen in secondary brain injury after trauma and its mechanism in a rat model.

MATERIAL AND METHODS A rat model of TBI was constructed using the modified Feeney's free-fall method, and 60 SD rats were randomly divided into three groups - the sham group, the untreated traumatic brain injury (TBI) group, and the hyperbaric oxygen-treated TBI group. The neurological function of the rats was evaluated 12 and 24 hours after TBI modeling; the expression levels of TLR4, IκB, p65, and cleaved caspase-3 in the peri-trauma cortex were determined by Western blot; levels of TNF-α, IL-6, and IL-1β were determined by ELISA; and apoptosis of the neurons was evaluated by TUNEL assay 24 hours after TBI modeling.

RESULTS Hyperbaric oxygen therapy significantly inhibited the activation of the TLR4/NF-κB signaling pathway, reduced the expression of cleaved caspase-3, TNF-α, IL-6 and IL-1β (P<0.05), reduced apoptosis of the neurons and improved the neurological function of the rats (P<0.05).

CONCLUSIONS Hyperbaric oxygen therapy protects the neurons after traumatic injury, possibly through inhibition of the TLR4/NF-κB signaling pathway.


Med Gas Res. 2016 Dec 30;6(4):232-236. doi: 10.4103/2045-9912.196907.

Hyperbaric oxygen therapy and preconditioning for ischemic and hemorrhagic stroke.

Hu SL1, Feng H2, Xi GH3.

Author information


To date, the therapeutic methods for ischemic and hemorrhagic stroke are still limited. The lack of oxygen supply is critical for brain injury following stroke. Hyperbaric oxygen (HBO), an approach through a process in which patients breathe in 100% pure oxygen at over 101 kPa, has been shown to facilitate oxygen delivery and increase oxygen supply. Hence, HBO possesses the potentials to produce beneficial effects on stroke. Actually, accumulated basic and clinical evidences have demonstrated that HBO therapy and preconditioning could induce neuroprotective functions via different mechanisms. Nevertheless, the lack of clinical translational study limits the application of HBO. More translational studies and clinical trials are needed in the future to develop effective HBO protocols.

Undersea Hyperb Med. 2015 Jul-Aug;42(4):333-51

Clinical results in brain injury trials using HBO2 therapy: Another perspective

Figueroa XA, Wright JK.


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.


J Formos Med Assoc. 2014 Sep;113(9):620-8. doi: 10.1016/j.jfma.2014.03.012. Epub 2014 Apr 29.

Repetitive hyperbaric oxygen therapy provides better effects on brain inflammation and oxidative damage in rats with focal cerebral ischemia

Chen LF1, Tian YF2, Lin CH3, Huang LY4, Niu KC4, Lin MT5.

Author information

  • 1Nursing Department, Cheng Kung University Hospital and Department of Nursing, Chang Jung University, Tainan, Taiwan.

  • 2Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan; Department of Health and Nutrition, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan. Electronic address:

  • 3Department of Nursing, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan; Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan.

  • 4Department of Hyperbaric Oxygen, Chi Mei Medical Center, Tainan, Taiwan.

  • 5Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan. Electronic address:



Repetitive hyperbaric oxygen (HBO2) therapy may cause excessive generation of reactive oxygen species. This study assessed whether repetitive or 2-4-day trials of HBO2 therapy (2 treatments daily for 2-4 consecutive days) provides better effects in reducing brain inflammation and oxidative stress caused by middle cerebral artery occlusion (MCAO) in rats than did a 1-day trial of HBO2 therapy (2 treatments for 1 day).


Rats were randomly divided into four groups: sham; MCAO without HBO2 treatment; MCAO treated with 1-day trial of HBO2; and MCAO treated with 2-4-day trials of HBO2. One treatment of HBO2 (100% O2 at 253 kPa) lasted for 1 hour in a hyperbaric chamber.


Therapy with the 2-4-day trials of HBO2 significantly and dose-dependently attenuated the MCAO-induced cerebral infarction and neurological deficits more than the 1-day trial of HBO2 therapy.

  • The beneficial effects of repetitive HBO2 therapy were associated with: (1) reduced inflammatory status in ischemic brain tissues (evidenced by decreased levels of tumor necrosis factor-α, interleukin-1β, and myeloperoxidase activity); (2) decreased oxidative damage in ischemic brain tissues (evidenced by decreased levels of reactive oxygen and nitrogen species, lipid peroxidation, and enzymatic pro-oxidants, but increased levels of enzymatic antioxidant defenses); and (3) increased production of an anti-inflammatory cytokine, interleukin-10.



The results provide the apparently contradictory finding that heightened oxygen tension reduced oxidative stress (and inflammation), which was reflected by increased antioxidant and decreased oxidant contents under focal cerebral ischemia.


Neuroscience. 2013 Nov 27. pii: S0306-4522(13)00983-4. doi: 10.1016/j.neuroscience.2013.11.036. [Epub ahead of print]

Interleukin-10 mediates the neuroprotection of hyperbaric oxygen therapy against traumatic brain injury in mice

Chen X1, Duan XS1, Xu LJ1, Zhao JJ2, She ZF1, Chen WW1, Zheng ZJ1, Jiang GD3.

Author information

  • 1Department of Hyperbaric Oxygen, The 113th Hospital of PLA, Ningbo, Zhejiang, China.

  • 2Department of Neurology, The 305th Hospital of PLA, Beijing, China.

  • 3Department of Hyperbaric Oxygen, The 113th Hospital of PLA, Ningbo, Zhejiang, China. Electronic address:


The aim of present study was to elucidate the role of Interleukin-10 (IL-10) in the neuroprotection of hyperbaric oxygen (HBO) against traumatic brain injury (TBI) in mice. The TBI in mice was induced by controlled cortical impact (CCI). HBO was given for 1h at 2.0 ATA in 100% O2.

HBO enhanced the serumal and cerebral IL-10 protein levels in both sham-operated and TBI mice. HBO therapy after TBI reduced lesion volume, attenuated cerebral edema, improved neurological status including motor and cognitive function, inhibited apoptosis evidenced by decreased ratio of cleaved caspase-3 (C3) to pro-C3 and Bax expression and increased bcl-2 expression, and attenuated inflammation marked by reduced expression of IL-1β, IL-6, macrophage inflammatory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1) and activity of matrix metalloproteinase-9 (MMP9).

In addition, HBO after TBI improved the blood-brain barrier, and upregulated the expression of tight junction proteins including zonula occludens-1 (ZO-1) and claudin-5.

  • IL-10 deficiency aggravated TBI-induced damage in the brain and abrogated the beneficial effects of HBO on neuroinflammation, apoptosis, and edema after TBI. IL-10 deficiency itself had no significant effect on brain water content and neurological status. In conclusion, IL-10 played an important role in the neuroprotection of HBO therapy against TBI in mice.


J Surg Res. 2013 Oct;184(2):1076-84. doi: 10.1016/j.jss.2013.04.070. Epub 2013 May 21.

Microglial activation induced by traumatic brain injury is suppressed by postinjury treatment with hyperbaric oxygen therapy

Lim SW, Wang CC, Wang YH, Chio CC, Niu KC, Kuo JR.

Author information

  • Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan. Electronic address:



The mechanisms underlying the protective effects of hyperbaric oxygen (HBO) therapy on traumatic brain injury (TBI) are unclear. TBI initiates a neuroinflammatory cascade characterized by activation of microglia and increased production of proinflammatory cytokines. In this study, we attempted to ascertain whether the occurrence of neuroinflammation exhibited during TBI can be reduced by HBO.


TBI was produced by the fluid percussion technique in rats. HBO (100% O2 at 2.0 absolute atmospheres) was then used at 1 h (HBO I) or 8 h (HBO II) after TBI. Neurobehavior was evaluated by the inclined plane test on the 72 h after TBI and then the rats were killed. The infarction area was evaluated by Triphenyltetrazolium chloride. Immunofluorescence staining was used to evaluate neuronal apoptosis (TUNEL + NeuN), microglial cell aggregation count (OX42 + DAPI), and tumor necrosis factor-alpha (TNF-α) expression in microglia cell (OX42 + TNF-α).


The maximum grasp angle in the inclined plane test and cerebral infarction of the rats after TBI were significantly attenuated by HBO therapy regardless of whether the rats were treated with HBO 1 or 8 h after TBI compared with the controls. TBI-induced microglial activation, TNF-α expression, and neuronal apoptosis were also significantly reduced by HBO therapy.


Our results demonstrate that treatment of TBI during the acute phase of injury can attenuate microgliosis and proinflammatory cytokine TNF-α expression resulting in a neuroprotective effect. Even treating TBI with HBO after 8 h had a therapeutic effect.


Undersea Hyperb Med. 2013 Mar-Apr;40(2):165-93

A prospective trial of hyperbaric oxygen for chronic sequelae after brain injury (HYBOBI)

Churchill S, Weaver LK, Deru K, Russo AA, Handrahan D, Orrison WW Jr, Foley JF, Elwell HA.


LDS Hospital, Salt Lake City, Utah; Intermountain Medical Center, Murray, Utah, USA.


Some practitioners advocate hyperbaric oxygen (HBO2) for sequelae following brain injury. This study assessed recruitment, tolerance and safety in preparation for a randomized clinical trial. Design: Prospective, open-label feasibility study.


Hyperbaric medicine department of a tertiary academic hospital. Participants: Participatory adult outpatients with problems from stroke (n=22), anoxia (13) or trauma (28) that occurred at least 12 months before enrollment, without contraindications to HBO2. Sixty-three participants enrolled in the study (21 females,42 males). Age was 45 +/- 16 years (18-76) and time from injury was 6.9 +/- 7.1 years (1.0-29.3). Fifty-three completed the study intervention, and 55 completed the assessment battery.


Participants underwent 60 daily HBO2 sessions (1.5 atm abs, 100% oxygen, 60 minutes). Assessments were conducted at baseline, after the HBO2 course, and six months later. Main outcome measurements: The prime outcome was feasibility. To estimate the immediate and long-term effects of HBO2, we assessed neuropsychological measures, questionnaires, neurologic exam and physical functioning measures. Some participants also had pre- and post-HBO2 speech evaluation (n=27) and neuroimaging (n=17).


The study met our a prior definition for feasibility for recruitment, but 44% required additional time to complete the 60 sessions (up to 105 days). HBO2-related adverse events were rare and not serious. Although many participants reported improvement in symptoms (51% memory, 51% attention/concentration, 48% balance/coordination, 45% endurance, 20% sleep) post-HBO2, and 93% reported that they would participate in the study again, no standardized testing showed clinically important improvement. In the small subset of those undergoing neuroimaging, apparent improvement was observed in auditory functional MRI (8/13), MR spectroscopy (9/17) and brain perfusionby CT angiography (5/9).


Conducting an HBO2 clinical trial in this population was feasible. Although many participants reported improvement, the lack of concurrent controls limits the strength of inferences from this trial, especially considering lack of change in standardized testing. The clinical relevance of neuroimaging changes is unknown. The findings of this study may indicate a need for caution when considering the broad application of HBO2 more than one year after brain injury due to stroke, severe TBI and anoxia, until there is more compelling evidence from carefully designed sham-controlled, blinded clinical trials.


Neuropsychiatr Dis Treat. 2010 Dec 6;6:785-9. doi: 10.2147/NDT.S16071.

Hyperbaric oxygen ameliorates worsening signs and symptoms of post-traumatic stress disorder

Eovaldi B, Zanetti C.


Department of Medicine, Chicago College of Osteopathic Medicine, Chicago, IL, USA.


Hyperbaric oxygen therapy at 2.4 atmospheric pressure absolutes for 90 minutes per day ameliorated the signs and symptoms of agitation, confusion, and emotional distress in a 27-year-old male seven days following a traumatic accident.

Hyperbaric oxygen was used to treat the patient's crush injury and underlying nondisplaced pelvic fractures which were sustained in a bicycle versus automobile traffic accident. Its effect on the patient's neuropsychiatric symptoms was surprising and obvious immediately following the initial hyperbaric oxygen treatment.

Complete cognitive and psychiatric recovery was achieved by the seventh and final hyperbaric oxygen treatment. We propose that hyperbaric oxygen was effective in improving the patient's neuropsychiatric symptoms by reducing cerebral oxidative stress, inflammation, vasogenic edema, and hippocampal neuronal apoptosis.

Further investigation into the use of hyperbaric oxygen as a novel therapy for the secondary prevention of post-traumatic stress disorder that often accompanies post-concussive syndrome may be warranted. We acknowledge that hyperbaric oxygen therapy has been shown to have a strong placebo effect on neurologic and psychiatric diseases.

J Neurotrauma 2013 Jun 3. [Epub ahead of print]

The Therapeutic Role of Interleukin-10 after Spinal Cord Injury


University of Wisconsin , Neurological Surgery, 600 Highland Avenue, Madison, Wisconsin, United States, 53792, 608-265-8800 ;


Spinal cord injury (SCI) is a devastating condition affecting 270,000 people in the United States. A potential treatment for decreasing the secondary inflammation, excitotoxic damage, and neuronal apoptosis associated with SCI is the anti-inflammatory cytokine interleukin-10.

  • The best characterized effects of IL-10 are anti-inflammatory-it down-regulates pro-inflammatory species IL-1β, IL-2, IL-6, tumor necrosis factor-α, interferon-γ, matrix metalloproteinase-9, nitric oxide synthase, myeloperoxidase, and reactive oxygen species. Pro-apoptotic factors cytochrome c, caspase 3, and Bax are down-regulated by IL-10, whereas anti-apoptotic factors Bcl-2 and Bcl-xl are up-regulated by IL-10.


  • IL-10 also provides trophic support to neurons through the IL-10 receptor. Increased tissue sparing, functional recovery, and neuroprotection are seen with an immediate post-SCI systemic administration of IL-10. Treatment of SCI with IL-10 has been used successfully in combination with Schwann cell and olfactory glial cell grafts as well as methylprednisolone.


Minocycline, tetramethylpyrazine, and hyperbaric oxygen treatment all increase IL-10 levels in a SCI models and result in increased tissue sparing and functional recovery. A chronic systemic administration of IL-10 does not appear to be beneficial to SCI recovery and causes increased susceptibility to septicemia, pneumonia, and peripheral neuropathy. However, a localized up-regulation of IL-10 has been shown to be beneficial and can be achieved by herpes simplex virus gene therapy, injection of poliovirus replicons, or surgical placement of a slow-release compound. IL-10 shows promise as a treatment for SCI, although research on local IL-10 delivery timeline and dosage needs to be expanded upon.



J Pain. 2013 May 14. pii: S1526-5900(13)00839-0. doi: 10.1016/j.jpain.2013.02.003. [Epub ahead of print]

Repetitive Hyperbaric Oxygen Treatment Attenuates Complete Freund's Adjuvant-Induced Pain and Reduces Glia-Mediated Neuroinflammation in the Spinal Cord.


Institute of Nautical Medicine, Jiangsu Key laboratory of Neuroregeneration, Nantong University, Nantong, China.


Hyperbaric oxygen (HBO) therapy is reported to attenuate pain in both clinical pain conditions and animal pain models, but the underlying mechanism remains to be investigated. Here, we show that 7 daily 60-minute HBO (100% oxygen, 2 atmosphere absolute) treatments effectively and persistently inhibited heat hyperalgesia, mechanical allodynia, and paw edema induced by peripheral injection of complete Freund's adjuvant (CFA). Five daily 60-minute HBO treatments also produced a prolonged reversal effect of the ongoing inflammatory pain.

Furthermore, such an HBO treatment reduced CFA-induced activation of glial cells, phosphorylation of mitogen-activated protein kinases, and production of a variety of proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin-1 beta [IL-1β], and interleukin-6 [IL-6]) and chemokines (monocyte chemoattractant protein-1 [MCP-1], keratinocyte-derived chemokine [KC], and IFN-gamma-inducible protein 10 [IP-10]) in the spinal cord. HBO treatment also decreased lipopolysaccharide-induced mRNA expression of these cytokines and chemokines in primary cultures of astrocytes and microglia.

In addition, the mRNA expressions of IL-1β, IL-6, MCP-1, KC, and IP-10 in the inflamed paw skin were decreased by HBO. Taken together, these data suggest that HBO treatment is an effective therapy for inflammatory pain in animals. The inhibition of the neuroinflammation that is mediated by glial cells and inflammatory mediators may, at least in part, contribute to the antinociceptive effect of HBO therapy.

PERSPECTIVE: Our results suggest that repetitive HBO treatment attenuates CFA-induced pain and reduces glial activation and inflammatory mediators' production. These findings provide the evidence of the antinociception effect of HBO on inflammatory pain and characterize some of the underlying mechanisms.


J Neurosurg 2013 Jun;118(6):1317-28. doi: 10.3171/2013.2.JNS121468. Epub 2013 Mar 19.

A prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury.

Rockswold SB, Rockswold GL, Zaun DA, Liu J.


Department of Physical Medicine and Rehabilitation.


Object Preclinical and clinical investigations indicate that the positive effect of hyperbaric oxygen (HBO2) for severe traumatic brain injury (TBI) occurs after rather than during treatment. The brain appears better able to use baseline O2 levels following HBO2 treatments. In this study, the authors evaluate the combination of HBO2 and normobaric hyperoxia (NBH) as a single treatment. Methods Forty-two patients who sustained severe TBI (mean Glasgow Coma Scale [GCS] score 5.7) were prospectively randomized within 24 hours of injury to either: 1) combined HBO2/NBH (60 minutes of HBO2 at 1.5 atmospheres absolute [ATA] followed by NBH, 3 hours of 100% fraction of inspired oxygen [FiO2] at 1.0 ATA) or 2) control, standard care. Treatments occurred once every 24 hours for 3 consecutive days. Intracranial pressure, surrogate markers for cerebral metabolism, and O2 toxicity were monitored. Clinical outcome was assessed at 6 months using the sliding dichotomized Glasgow Outcome Scale (GOS) score. Mixed-effects linear modeling was used to statistically test differences between the treatment and control groups. Functional outcome and mortality rates were compared using chi-square tests. Results There were no significant differences in demographic characteristics between the 2 groups. In comparison with values in the control group, brain tissue partial pressure of O2 (PO2) levels were significantly increased during and following combined HBO2/NBH treatments in both the noninjured and pericontusional brain (p < 0.0001). Microdialysate lactate/pyruvate ratios were significantly decreased in the noninjured brain in the combined HBO2/NBH group as compared with controls (p < 0.0078). The combined HBO2/NBH group's intracranial pressure values were significantly lower than those of the control group during treatment, and the improvement continued until the next treatment session (p < 0.0006). The combined HBO2/NBH group's levels of microdialysate glycerol were significantly lower than those of the control group in both noninjured and pericontusional brain (p < 0.001). The combined HBO2/NBH group's level of CSF F2-isoprostane was decreased at 6 hours after treatment as compared with that of controls, but the difference did not quite reach statistical significance (p = 0.0692). There was an absolute 26% reduction in mortality for the combined HBO2/NBH group (p = 0.048) and an absolute 36% improvement in favorable outcome using the sliding dichotomized GOS (p = 0.024) as compared with the control group.

Conclusions In this Phase II clinical trial, in comparison with standard care (control treatment) combined HBO2/NBH treatments significantly improved markers of oxidative metabolism in relatively uninjured brain as well as pericontusional tissue, reduced intracranial hypertension, and demonstrated improvement in markers of cerebral toxicity. There was significant reduction in mortality and improved favorable outcome as measured by GOS. The combination of HBO2 and NBH therapy appears to have potential therapeutic efficacy as compared with the 2 treatments in isolation. Clinical trial registration no.: NCT00170352 ( ).


Med Gas Res 2011 Sep 6;1(1):21. doi: 10.1186/2045-9912-1-21.

Hyperbaric oxygen therapy for traumatic brain injury.

Department of Biophysics & Bioengineering, Loma Linda University, Griggs Hall, Room 227, 11065 Campus St,, Loma Linda, California, 92354, USA.


Traumatic brain injury (TBI) is a major public health issue. The complexity of TBI has precluded the use of effective therapies. Hyperbaric oxygen therapy (HBOT) has been shown to be neuroprotective in multiple neurological disorders, but its efficacy in the management of TBI remains controversial. This review focuses on HBOT applications within the context of experimental and clinical TBI. We also discuss its potential neuroprotective mechanisms. Early or delayed multiple sessions of low atmospheric pressure HBOT can reduce intracranial pressure, improve mortality, as well as promote neurobehavioral recovery. The complimentary, synergistic actions of HBOT include improved tissue oxygenation and cellular metabolism, anti-apoptotic, and anti-inflammatory mechanisms. Thus HBOT may serve as a promising neuroprotective strategy that when combined with other therapeutic targets for TBI patients which could improve long-term outcomes.


Brain Inj. 2012;26(10):1273-84. Epub 2012 May 9.

Hyperbaric oxygenation improves locomotor ability by enhancing neuroplastic responses after cortical ablation in rats.

Institute of Medical Physiology 'Richard Burian', School of Medicine, University of Belgrade, Serbia.


To investigate whether hyperbaric oxygenation (HBO) can improve the recovery of motor functions in rats after suction ablation of the right sensorimotor cortex.

The experimental paradigm implies the following groups: Control animals (C), Control + HBO (CHBO), Sham controls (S), Sham control + HBO (SHBO), Lesion group (L), right sensorimotor cortex was removed by suction, Lesion + HBO (LHBO). Hyperbaric protocol: pressure applied 2.5 atmospheres absolute, for 60 minutes, once a day for 10 days. A beam walking test and grip strength meter were used to evaluate the recovery of motor functions. Expression profiles of growth-associated protein 43 (GAP43) and synaptophysin (SYP) were detected using immunohistochemistry.

The LHBO group achieved statistically superior scores in the beam walking test compared to the L group. Additionally, the recovery of muscle strength of the affected hindpaw was significantly enhanced after HBO treatment. Hyperbaric oxygenation induced over-expression of GAP43 and SYP in the neurons surrounding the lesion site.

Data presented suggest that hyperbaric oxygen therapy can intensify neuroplastic responses by promoting axonal sprouting and synapse remodelling, which contributes to the recovery of locomotor performances in rats. This provides the perspective for implementation of HBO in clinical strategies for treating traumatic brain injuries.


J Trauma Acute Care Surg. 2012 Mar;72(3):650-9.

Attenuating inflammation but stimulating both angiogenesis and neurogenesis using hyperbaric oxygen in rats with traumatic brain injury.

Department of Biotechnology, Southern Taiwan University, Tainan, Taiwan.

Erratum in J Trauma Acute Care Surg. 2012 Jul;73(1):295-6.


Inflammation, angiogenesis, neurogenesis, and gliosis are involved in traumatic brain injury (TBI). Several studies provide evidence supporting the neuroprotective effect of hyperbaric oxygen (HBO2) therapy in TBI. The aim of this study was to ascertain whether inflammation, angiogenesis, neurogenesis, and gliosis during TBI are affected by HBO2 therapy.

Rats were randomly divided into three groups: TBI + NBA (normobaric air: 21% O2 at 1 absolute atmospheres), TBI + HBO2, and Sham operation + NBA. TBI + HBO2 rats received 100% O2 at 2.0 absolute atmospheres for 1 hr/d for three consecutive days. Behavioral tests and biochemical and histologic evaluations were done 4 days after TBI onset.

TBI + NBA rats displayed: (1) motor and cognitive dysfunction; (2) cerebral infarction and apoptosis; (3) activated inflammation (evidenced by increased brain myeloperoxidase activity and higher serum levels of tumor necrosis factor-α); (4) neuronal loss (evidenced by fewer NeuN-positive cells); and (5) gliosis (evidenced by more glial fibrillary protein-positive cells).

  • In TBI + HBO2 rats, HBO2 therapy significantly reduced TBI-induced motor and cognitive dysfunction, cerebral infarction and apoptosis, activated inflammation, neuronal loss, and gliosis. In addition, HBO2 therapy stimulated angiogenesis (evidenced by more bromodeoxyuridine-positive endothelial and vascular endothelial growth factor-positive cells), neurogenesis (evidenced by more bromodeoxyuridine-NeuN double-positive and glial cells-derived neurotrophic factor-positive cells), and overproduction of interleukin-10 (an anti-inflammatory cytokine).

Collectively, these results suggest that HBO2 therapy may improve outcomes of TBI in rats by inhibiting activated inflammation and gliosis while stimulating both angiogenesis and neurogenesis in the early stage.


Neuroprotective Effects of Hyperbaric Oxygen Treatment in Traumatic Brain Injury of Rat.

Wang G, Jiang Z. Institute of Nautical Medicine, Department of Neuropharmacology, Department of Neuropharmacology, Institute of Nautical Medicine, Nantong University, 19 Qixiu Road, Chongchuan District, Nantong, Jiangsu 226001, China, Nantong, China, 226001, 86-513-85051799, 86-513-85051796; J Neurotrauma. 2010 Jun 23. [Epub ahead of print]

Abstract: This study was designed to evaluate the potential benefits of hyperbaric Oxygen (HBO) in the treatment of traumatic brain injury (TBI). The right cerebral cortex of rats was injured by the impact of a 20 g object dropped from a standard predetermined height. Rats received HBO treatment at 3 ATA for 60 min after TBI. Neurological behavior score, brain water content, morphological changes in the hippocampus, and cell apoptosis in brain tissue surrounding the primary injury were examined to reflect the brain damage severity. Three and six hours after TBI, HBO-treated rats displayed a significant reduction of brain damage. However, 12 h after TBI, the efficacy of HBO treatment was considerably attenuated. Furthermore, 24 h, 48 h and 72 h after TBI, the HBO treatment did not show notable effects. In contrast, multiple HBO treatments (3 or 5 times totally), even started from 48 h after TBI, remarkably reduced the neurology deficit score and the loss of neuronal number in the hippocampus. Although multiple treatments started from 48 h significantly improved the neurological behaviors and reduced the brain injury, the overall benefic effects were substantially weaker than the ones observed after single treatment from 6 h.

These results suggest that: 1) HBO treatment could alleviate brain damage after TBI. 2) Single treatment of HBO has a time limitation of 12 h post-TBI. 3) Multiple HBO treatments have the possibility to extend the post-TBI delivery time-window. Therefore, our results clearly suggest the validity of HBO therapy for the treatment of TBI.


Undersea Hyperb Med 2012 Nov-Dec;39(6):1075-82.

Hyperbaric side effects in a traumatic brain injury randomized clinical trial.

Wolf EG, Prye J, Michaelson R, Brower G, Profenna L, Boneta O.


USAF School of Aerospace Medicine, Hyperbaric Medicine Department, Lackland AFB, Texas, USA.



To catalog the side effects of 2.4 atmospheres absolute (atm abs) hyperbaric oxygen (HBO2) vs. sham on post-concussion symptoms in military service members with combat-related, mild traumatic brain injury (TBI).


Fifty subjects diagnosed with TBI were randomized to either a sham (1.3 atm abs breathing air) or treatment (2.4 atm abs breathing 100% oxygen) hyperbaric profile. Forty-eight subjects completed 30 exposures. Medical events during hyperbaric exposures were separately annotated by medical staff and chamber operators. After the blind was broken, events were segregated into the exposure groups.


These side effects were observed as rate (sham/treatment): ear block (ear barotrauma) 5.51% (1.09%/5.91%), sinus squeeze 0.14% (0.0%/0.27%), and confinement anxiety 0.27% (0.27%/0.27%). Other conditions that occurred included: headache 0.61% (0.68%/0.54%); nausea 0.2% (0.14%/0.27%); numbness 0.07% (0%/0.13%); heartburn 0.07% (0.14%/0%); musculoskeletal chest pain 0.07% (0%/0.13%); latex allergy 0.07% (0.14%/0%); and hypertension 0.07% (0.14%/0%).


This study demonstrated no major adverse events, such as pulmonary barotraumas, pulmonary edema or seizure. Given the infrequent, mild side effect profile, the authors feel the study demonstrated that hyperbaric oxygen therapy (HBO2T) was safe at a relatively high treatment pressure in TBI subjects, and these data can be used to evaluate the risk/ benefit calculation when deciding to utilize HBO2T for treatment of various diseases in the TBI population.


J Surg Res. 2013 May 21. pii: S0022-4804(13)00442-3. doi: 10.1016/j.jss.2013.04.070. [Epub ahead of print]

Microglial activation induced by traumatic brain injury is suppressed by postinjury treatment with hyperbaric oxygen therapy.

Lim SW, Wang CC, Wang YH, Chio CC, Niu KC, Kuo JR.


Department of Neurosurgery, Chi-Mei Medical Center, Tainan, Taiwan. Electronic address:



The mechanisms underlying the protective effects of hyperbaric oxygen (HBO) therapy on traumatic brain injury (TBI) are unclear. TBI initiates a neuroinflammatory cascade characterized by activation of microglia and increased production of proinflammatory cytokines. In this study, we attempted to ascertain whether the occurrence of neuroinflammation exhibited during TBI can be reduced by HBO.


TBI was produced by the fluid percussion technique in rats. HBO (100% O2 at 2.0 absolute atmospheres) was then used at 1 h (HBO I) or 8 h (HBO II) after TBI. Neurobehavior was evaluated by the inclined plane test on the 72 h after TBI and then the rats were killed. The infarction area was evaluated by Triphenyltetrazolium chloride. Immunofluorescence staining was used to evaluate neuronal apoptosis (TUNEL + NeuN), microglial cell aggregation count (OX42 + DAPI), and tumor necrosis factor-alpha (TNF-α) expression in microglia cell (OX42 + TNF-α).


The maximum grasp angle in the inclined plane test and cerebral infarction of the rats after TBI were significantly attenuated by HBO therapy regardless of whether the rats were treated with HBO 1 or 8 h after TBI compared with the controls. TBI-induced microglial activation, TNF-α expression, and neuronal apoptosis were also significantly reduced by HBO therapy.


Our results demonstrate that HBO treatment of TBI during the acute phase of injury can attenuate microgliosis and proinflammatory cytokine TNF-α expression resulting in a neuroprotective effect. Even treating TBI with HBO after 8 h had a therapeutic effect.


J Neurotrauma. 2012 Jan 1;29(1):168-85. doi: 10.1089/neu.2011.1895. Epub 2011 Nov 22.

A phase I study of low-pressure hyperbaric oxygen therapy for blast-induced post-concussion syndrome and post-traumatic stress disorder.

Harch PG,

Department of Medicine, Section of Emergency and Hyperbaric Medicine, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.


This is a preliminary report on the safety and efficacy of 1.5 ATA hyperbaric oxygen therapy (HBOT) in military subjects with chronic blast-induced mild to moderate traumatic brain injury (TBI)/post-concussion syndrome (PCS) and post-traumatic stress disorder (PTSD). Sixteen military subjects received 40 1.5 ATA/60 min HBOT sessions in 30 days. Symptoms, physical and neurological exams, SPECT brain imaging, and neuropsychological and psychological testing were completed before and within 1 week after treatment. Subjects experienced reversible middle ear barotrauma (5), transient deterioration in symptoms (4), and reversible bronchospasm (1); one subject withdrew. Post-treatment testing demonstrated significant improvement in: symptoms, neurological exam, full-scale IQ (+14.8 points; p<0.001), WMS IV Delayed Memory (p=0.026), WMS-IV Working Memory (p=0.003), Stroop Test (p<0.001), TOVA Impulsivity (p=0.041), TOVA Variability (p=0.045), Grooved Pegboard (p=0.028), PCS symptoms (Rivermead PCSQ: p=0.0002), PTSD symptoms (PCL-M: p<0.001), depression (PHQ-9: p<0.001), anxiety (GAD-7: p=0.007), quality of life (MPQoL: p=0.003), and self-report of percent of normal (p<0.001), SPECT coefficient of variation in all white matter and some gray matter ROIs after the first HBOT, and in half of white matter ROIs after 40 HBOT sessions, and SPECT statistical parametric mapping analysis (diffuse improvements in regional cerebral blood flow after 1 and 40 HBOT sessions). Forty 1.5 ATA HBOT sessions in 1 month was safe in a military cohort with chronic blast-induced PCS and PTSD. Significant improvements occurred in symptoms, abnormal physical exam findings, cognitive testing, and quality-of-life measurements, with concomitant significant improvements in SPECT.


Low pressure hyperbaric oxygen therapy and SPECT brain imaging in the treatment of blast-induced chronic traumatic brain injury (post-concussion syndrome) and post traumatic stress disorder

Paul G Harch*1, Edward F Fogarty2, Paul K Staab1 and Keith Van Meter1. Section of Emergency Medicine, Department of Medicine, Louisiana State University Health Sciences Center, 2021 Perdido St, Room W535, New Orleans, Louisiana, 70112, USA and 2Department of Radiology, University of North Dakota School of Medicine and Health Sciences,


A 25-year-old male military veteran presented with diagnoses of post concussion syndrome and post traumatic stress disorder three years after loss of consciousness from an explosion in combat. The patient underwent single photon emission computed tomography brain blood flow imaging before and after a block of thirty-nine 1.5 atmospheres absolute hyperbaric oxygen treatments. The patient experienced a permanent marked improvement in his post-concussive symptoms, physical exam findings, and brain blood flow. In addition, he experienced a complete resolution of posttraumatic stress disorder symptoms. After treatment he became and has remained employed for eight consecutive months. This case suggests a novel treatment for the combined diagnoses of blast-induced post-concussion syndrome and post-traumatic stress disorder.


Low Pressure Hyperbaric Oxygen Therapy For Traumatic Brain Injury


Traumatic brain injury (TBI) is a major public health issue. The complexity of TBI has precluded the use of effective therapies. Hyperbaric oxygen therapy (HBOT) has been shown to be neuroprotective in multiple neurological disorders, but its efficacy in the management of TBI remains controversial. This review focuses on HBOT applications within the context of experimental and clinical TBI. We also discuss its potential neuroprotective mechanisms. Early or delayed multiple sessions of low atmospheric pressure HBOT can reduce intracranial pressure, improve mortality, as well as promote neurobehavioral recovery. The complimentary, synergistic actions of HBOT include improved tissue oxygenation and cellular metabolism, anti-apoptotic, and anti-inflammatory mechanisms. Thus HBOT may serve as a promising neuroprotective strategy that when combined with other therapeutic targets for TBI patients which could improve long-term outcomes.