Scientific basis

	• Oxygen breathed at pressure increases dissolved oxygen in plasma to the extent that it can nourish the tissues even in the absence of red blood cells.
	• Improvement of microcirculation.
	• Hyperbaric oxygen, by improving oxygenation of the penumbra that surrounds the area of total ischemia, prevents glycolysis and subsequent intracellular acidosis.

Only a limited amount of oxygen is dissolved in blood at normal atmospheric pressure, but under hyperbaric conditions, it is possible to dissolve sufficient oxygen (ie, 6 vol% in plasma, or 6 times the volume of oxygen dissolved in plasma under pressure) to meet the usual requirements of the body. In this case, oxyhemoglobin will pass unchanged from the arterial to the venous side because the oxygen that is physically dissolved in solution will be utilized more readily than that bound to hemoglobin. The partial pressure of oxygen simply rises linearly with the rise of pressure.

The effect of hyperbaric oxygen on the brain has been studied extensively during the past decade and described in a textbook on this subject (21). Hyperbaric oxygen has a beneficial effect in cerebral ischemia through the following mechanisms:

	• Oxygen breathed at pressure (eg, 2 ATA) produces PaO2 1433 mm Hg (ie, a 10-fold increase in dissolved oxygen in plasma).
	• Hyperbaric oxygen can nourish the tissues even in the absence of red blood cells.
	• Oxygen can diffuse extravascularly. Diffusion is facilitated by the gradient between the high oxygen tension in the patent capillaries and the low tension in the occluded ones. The effectiveness of this mechanism depends on the abundance of capillaries in the tissues. The brain is a vascular tissue; therefore, this mechanism can provide for the oxygenation of the tissues after vascular occlusion.
	• Improvement of microcirculation. The supply of oxygen to the tissues can be facilitated by decreasing the viscosity of the blood and reducing platelet aggregation as well as by increasing red blood cell partial pressure of oxygen.
	• Hypoxia or ischemia disrupts autoregulation of cerebral circulation, and the arterioles may become dilated. Hyperbaric oxygen exerts a vasoconstricting effect to counteract this and, thus, reduces the extravasation of fluid with relief of cerebral edema.
	• Hyperbaric oxygen, by improving oxygenation of the penumbra that surrounds the area of total ischemia, prevents glycolysis and subsequent intracellular acidosis.
	• Relief of hypoxia.
	• Preservation of partially damaged tissue and prevention of further progression of secondary effects of cerebral lesions. Hyperbaric oxygen breaks the vicious cycle of brain damage leading to hypoxia, edema, and brain damage.
	• Improvement of cerebral metabolism.
	• Relief of spasticity in chronic poststroke stage.

Animal experimental evidence. Animal stroke models are considered appropriate for evaluating the effects of hyperbaric oxygenation in acute cerebral infarction. Animal studies for the effect of hyperbaric oxygenation in focal cerebral ischemia and global ischemia or hypoxia are summarized in the Textbook of Hyperbaric Medicine (21). Most of these studies show beneficial effects of hyperbaric oxygen. The pressures required for optimal administration of oxygen are higher in rats than in humans.

In an animal experimental study monitored by MRI, hyperbaric oxygen treatment reversed ischemic lesion size between 3 and 5 hours after ischemia and achieved a long-lasting neuroprotective effect without significant oxidative damage (45). A study that monitored the early in vivo effects of hyperbaric oxygen at 3 atmospheres absolute after transient focal ischemia in Wistar rats using repetitive MRI found that hyperbaric oxygen therapy has an immediate protective on the brain that is superior to normobaric oxygen (54). In another study, hyperbaric oxygen was shown to be highly efficient in reducing infarct volume and improving neurobehavioral outcome in transient middle cerebral artery occlusion within the first 6 hours but was harmful at later time points because of increased infarct volume (30). In permanent middle cerebral artery occlusion, hyperbaric oxygen failed to improve infarct volume and clinical outcome. As shown by measurement of infarct volume by magnetic resonance imaging and 2,3,5-triphenyltetrazolium chloride, hyperbaric oxygen treatment at 2.5 atmospheres absolute demonstrated significant neuroprotection at 5 hours after embolic focal cerebral ischemia that lasted for 168 hours (14).

In a rat model of middle cerebral artery occlusion, hyperbaric oxygen at 2 atmospheres absolute reduced the infarct size compared to models exposed to normobaric oxygen or normobaric air (16). Electron paramagnetic resonance oximetry was found to be an effective method of monitoring cerebral PO2. In an animal experiment, it was shown that early intra-ischemic hyperbaric oxygen treatment reduces the blood-brain barrier disruption, hemorrhagic transformation, and mortality after focal cerebral ischemia, suggesting that this treatment could be used to reduce hemorrhagic conversion in patients with stroke (39). In a mouse model of middle cerebral artery occlusion, measurement of biomarkers of hypoxia such as hypoxia-inducible factor-1 alpha revealed that hyperbaric oxygen improves penumbral oxygenation in focal ischemia (48). Oxygen has been a highly neuroprotective molecule in transient focal cerebral ischemia in rats when applied early, and hyperbaric oxygen was shown to be more effective than normobaric oxygen (10).

Critics of hyperbaric oxygen therapy sometimes express the concern that an increased formation of reactive oxygen species in acute focal cerebral ischemia may be an undesirable side effect. Brief episodes of oxygen therapy do not promote damage inflicted by reactive oxygen species but have a neuroprotective effect. In mice with focal infarction induced by middle cerebral artery occlusion, breathing of 100% normobaric or hyperbaric oxygen at 3 ATA pressure significantly reduced superoxide radicals as compared to air breathing in control animals (49).

Global cerebral ischemia or hypoxia, such as occurs in cardiac arrest, is a somewhat different situation than acute focal cerebral ischemia for the evaluation of hyperbaric oxygen therapy. A study in dogs showed that postischemic hyperbaric oxygen provides histopathological neuroprotection and improves neurologic outcome after cardiac arrest or resuscitation (42). Beneficial effects of hyperbaric oxygen therapy on the ischemic microcirculation suggest an important modification of various cell types within the neurovascular unit (37). On a molecular level, hyperbaric oxygen inhibits hypoxia inducible factor-1alpha, up-regulates Bcl-2, inhibits MMP-9, decreases cyclooxygenase-2 activity, decreases myeloperoxidase activity, and upregulates superoxide dismutase, all of which contribute to neuroprotection in the acutely ischemic brain (31). In animal stroke models, hyperbaric oxygen limits leukocyte accumulation to the infarct site by attenuation of stroke-inducible proinflammatory chemokine response and reduces stroke lesion volume (40).

A randomized experimental study has shown that hyperbaric oxygen in combination with thrombolysis using tPA achieved neuroprotection in acute ischemic stroke in rats by reducing infarct volume and improving functional outcome in the early poststroke period as compared to control animals, whereas thrombolysis alone did not show a significant benefit (24). In an experimental study comparing normobaric and hyperbaric oxygen, only hyperbaric oxygen reduced hemoglobin extravasation in the ischemic hemisphere, whereas both decreased infarct size after thromboembolic ischemia only if recanalization was successful (50). Therefore, combining normobaric or hyperbaric oxygen with thrombolysis seems promising.

In a similar experimental study, thrombolysis as well as its combination with hyperbaric oxygen led to increased permeability of the blood-brain-barrier, whereas hyperbaric oxygen alone did not (33). This study concluded with the recommendation that long-term consequences of simultaneous thrombolysis and hyperbaric oxygen need to be addressed by further studies to identify therapeutic potencies in acute stroke, and to avoid unfavorable courses following combined treatment. A criticism of this study is that the hyperbaric oxygen was given at 2.4 ATA and the authors considered even a higher pressure to stabilize blood-brain-barrier integrity when given in combination with thrombolysis, whereas even 2.4 ATA is much higher than 1.5 ATA recommended in stroke patients. This is a common error made in studies comparing hyperbaric oxygen to normobaric oxygen and is an explanation why sometimes the results of normobaric oxygen are better than hyperbaric oxygen, but the ideal effective yet safer pressure for treatment of stroke is somewhere in between normobaric oxygen and hyperbaric oxygen at 2.4 ATA. In ischemic stroke models, hyperbaric oxygen has a neuroprotective effect by enhancing the effects of tPA thrombolysis, with improved neurologic functions likely due to increased percentage of oxygen dissolved in the plasma, upregulated level of endogenous r-tPA, and stabilization of the blood-brain barrier (59).

Hyperglycemia is known to aggravate cerebral infarction and hemorrhagic transformation after ischemic stroke in which oxidative stress and matrix metalloproteinases play an important role. Preconditioning rats with hyperbaric oxygen prior to inducing a stroke by occlusion of the middle cerebral artery attenuated hemorrhagic transformation of infarct (47). Hyperglycemia also impairs cerebral energy metabolism, reduces the level of ATP and nicotinamide adenine dinucleotide, and aggravates blood-brain barrier disruption and neurologic deficits after middle cerebral artery occlusion. In a rat model of hyperglycemia with middle cerebral artery occlusion, hyperbaric oxygen (one hour at 2 ATA) induced activation of ATP and nicotinamide adenine dinucleotide, protected the blood-brain barrier, and reduced hemorrhagic transformation of the infarct, providing a rationale for the use of hyperbaric oxygen for the treatment of acute ischemic stroke in diabetic patients and those treated with tPA (18). Preconditioning with hyperbaric oxygen offers more neuroprotective effect than its use later for treatment of experimental intracerebral hemorrhage (36).

In a rat model of ischemic stroke, hyperbaric oxygen treatments mobilize bone marrow stem cells to an ischemic area, stimulate expression of trophic factors, and improve neurogenesis and gliosis (26). These effects may help in neuronal repair after ischemic stroke.

Hyperbaric oxygen for the chronic phase of stroke has been studied in rat models that survive for 1 week after 2-hour occlusion of the middle cerebral artery, and treatment is continued for 6 weeks (17). In this model, hyperbaric oxygen enhances endogenous neurogenesis and improves neurofunctional recovery, which is possibly mediated by reactive oxygen species/hypoxia-inducible factor-1 alpha/beta-catenin pathway.

A single treatment of hyperbaric oxygen immediately after middle cerebral artery occlusion in mice followed by 24 hours of reperfusion was shown to significantly reduce cerebral edema and improve perfusion (38). Toll-like receptor 4 knockout also protects mice from ischemic damage, but to a lesser extent than hyperbaric oxygen treatment, as shown in this study. Preconditioning strategies have been used for protection against ischemia/reperfusion injury in reperfusion phase following acute ischemic stroke. Most of the currently used measures in practice are pharmacological. Evidence from experimental studies suggests the benefits of hyperbaric oxygen when used as a preconditioning stimulus in the setting of ischemia/reperfusion injury (15). A preclinical study has shown that preconditioning with hyperbaric oxygen is a robust prophylactic measure against sequestration of inflammation inherent in stroke, possibly by facilitating the transfer of resilient mitochondria from astrocytes to inflammation-susceptible neuronal cells for mitigating cell death (28). However, translation of the beneficial effects of hyperbaric oxygen into clinical practice requires a thorough consideration of risk factors, comorbidities, and comedications that could interfere with protective effect of hyperbaric oxygen.

In a systematic review of experimental studies on the effect of hyperbaric oxygen on stroke, 51 that met the inclusion criteria were identified among the 1198 studies examined (57). When compared with control group data, hyperbaric oxygen therapy resulted in reduction of infarct size or improved neurologic function. Mortality was 18.4% in the hyperbaric oxygen group and 26.7% in the control group. Subgroup analysis showed that a maximal neuroprotective effect was reached when hyperbaric oxygen was administered immediately after middle cerebral artery occlusion with an ATA of 2 and more than 6 hours of hyperbaric oxygen treatment.

A review of in vivo experimental studies on middle cerebral artery occlusion and clinical data indicates the potential benefits of hyperbaric oxygen on cerebral ischemic/reperfusion injury (52).

Evidence in patients with acute ischemic stroke. It is difficult to evaluate the efficacy of hyperbaric oxygen based on clinical examination alone in a patient with acute cerebral ischemia that may be evolving or resolving. Brain imaging studies have limited value. Proton magnetic resonance spectroscopic imaging (1 H-MRS) has been used to measure the effect on cerebral lactate accumulation resulting from ischemia and to determine the effect of hyperbaric oxygen in a progressive ischemic stroke patient (25). Lactate levels returned to normal within 11 days under hyperbaric oxygen therapy, whereas constantly high levels usually persist for more than 1 month after ischemia. In this case, hyperbaric oxygen was used successfully as an adjunct measure for neuroprotection during the period from the onset of stroke to an extra-intracranial bypass operation as a definitive measure.

A prospective study with a control group (no hyperbaric oxygen) assessed the efficacy and safety of hyperbaric oxygen as an adjuvant treatment on acute ischemic stroke in patients who did not receive thrombolytic therapy (06). Both early and late outcomes of the hyperbaric oxygen group showed significant difference, whereas in the control group there was only significant difference in early outcome.

In a randomized, prospective, controlled pilot study, early use of hyperbaric oxygen therapy (2.5 ATA) was found to be safe and effective in ameliorating the long-term neurologic sequelae in diabetic patients suffering from acute hemorrhagic stroke (56).

Acute cerebrovascular occlusions and ischemia due to other causes. Prompt use of hyperbaric oxygen in acute vascular occlusions has been shown to considerably save disability. In a case reported from Saudi Arabia, hyperbaric oxygen was used in a young woman who developed hemiplegia and seizures after accidental catheterization of the right common carotid artery and infusion of parenteral nutrition (04). Carotid angiography and magnetic resonance imaging showed evidence of arterial occlusion and ischemic infarction. Hyperbaric oxygen treatment at 2.5 atmospheres absolute was instituted 6 hours after this episode, and the patient showed considerable improvement within a few hours of the treatment. This was followed by daily hyperbaric oxygen treatments for 1 week, and the patient recovered with minimal residual neurologic deficit. Magnetic resonance imaging showed considerable regression of the infarct.

In 1 series, 12 patients with postcardiac surgery strokes who presented within the first 48 hours were treated with hyperbaric oxygen; full neurologic recovery was seen in 10 patients, residual hemiplegia in 1, neurologic death in 1 (11). Although prospective data are lacking in this area, based on sound pathophysiological principles, the authors recommend that patients suffering a stroke following open cardiac surgery should be considered for hyperbaric oxygen therapy.

Chronic poststroke stage. Use of hyperbaric oxygen in chronic poststroke stage is based on the concept of penumbra. Hypometabolic, but potentially viable, areas in the brain can be identified using hexamethylpropyleneamine oxime SPECT in conjunction with hyperbaric oxygen. Data presented by Neubauer and colleagues support the hypothesis that idling neurons are capable of reactivation when given sufficient oxygen (34). Changes in tracer distribution after hyperbaric oxygen may be a good prognostic indicator of viable neurons.

The metabolic activation of neurons by restoration of oxygen supply or by action of molecular oxygen is still possible months, and in some cases years, after the onset of stroke. Some patients may not show a positive response to the first treatment, and regression also occurs following recovery during initial treatments. However, repeated daily treatments have a cumulative effect, and improvement is long-lasting. This is the basis of the use of hyperbaric oxygen as an aid to the rehabilitation of patients in the chronic poststroke stage. Hyperbaric oxygenation treatments at 2.5 atmospheres absolute have been shown to result in partial improvement in patients with subcortical frontal syndrome due to small vessel disease and associated with leukoaraiosis (55).

In a prospective, randomized, controlled trial on 74 patients who suffered a stroke 6 to 36 months prior to inclusion, hyperbaric oxygen therapy led to significant neurologic improvements, implying that neuroplasticity can still be activated in the chronic post-stroke stage (09).

In an open study on a small number of chronic poststroke patients, all reported a clinical improvement following hyperbaric oxygen therapy, mostly in language fluency and motor paresis (05). fMRI analysis of these patients demonstrated changes that were consistent with the clinical improvement, suggesting a possible role of fMRI in revealing neuronal functional correlates of neuronal plasticity and hyperbaric oxygen-related neoangiogenesis.

As of May 2021, 3 clinical trials of hyperbaric oxygen for stroke are ongoing. One of these is a double-blind trial in Canada, the HOPES study at the University of British Columbia, which is a randomized trial (hyperbaric oxygen with 100% oxygen vs. sham hyperbaric oxygen) in post-established stroke (referred to as poststroke stage in this article) to test the effectiveness of hyperbaric oxygen (daily 2-hour treatments, 5 days a week) in improving neurologic function in patients who are 6 to 36 months postischemic stroke (NCT02582502). This trial is active but not recruiting. In the phase 4 trial at Hyperbaric Center, Basel, 10 patients having suffered a stroke and being rehabilitated will be treated with 40 consecutive hyperbaric oxygen treatments after a minimal delay of 3 months after stroke and will be neurologically assessed before and 3 months after therapy (NCT04297358). A phase 1 trial at Abington Memorial Hospital, Philadelphia, is combining hyperbaric oxygen with osteopathic manipulative therapy tor restoration of motor function following stroke (NCT03352232). A retrospective analysis of 162 patients who were treated with hyperbaric oxygen therapy for chronic stroke defined by the authors as over 3 months after onset showed significant improvements in all cognitive domains (13).

Spasticity. This is the most troublesome complication of stroke and one that interferes with the physical rehabilitation of patients. Spasticity is defined as a velocity-dependent response of a muscle to passive stretching, increased resistance to passive manipulation of the paretic limb, and is most marked in the antigravity muscles. Spasticity does not bear any definite relation to the degree of paralysis or the time of onset of the stroke; usually it becomes noticeable a few weeks after the onset of stroke. The underlying mechanism is controversial. The final common pathway for the expression of muscle tone is the anterior horn cells and myoneural junction. Spasticity may be viewed as alpha-overactivity. A slight amount of spasticity of the paretic leg may be helpful in ambulation, but spasticity in the hand interferes with fine movements. Persistent spasticity can lead to contracture of muscles, tendons, and joint capsules.

Conventional methods of management of spasticity included the following:

(1) Physical medicine (2) Drugs: baclofen, botulinum toxin, and tizanidine (3) Surgery: orthopedic and neurosurgical procedures

None of the procedures are satisfactory. Botulinum toxin has been shown to be safe and effective in treatment of spasticity following stroke. The limitations of this method are that the studies are short term (a few months) and that the benefit is limited to patients who still have some retained function in a limb. Hyperbaric oxygen, on the other hand, leads both to relief of spasticity and to improvement of motor function. In an open study of hyperbaric oxygen in combination with simultaneous physical therapy, hyperbaric oxygen was shown to improve motor function and relieve spasticity in 50 patients who presented in a chronic poststroke state with fixed neurologic deficits (19). Improvement persisted in most of the patients with repeated daily treatments. The mechanism of relief of spasticity by hyperbaric oxygen is not known.

Hyperbaric oxygen as adjunct to poststroke physical therapy. A randomized controlled trial on patients with upper extremity hemiparesis at 3 to 48 months after stroke showed that hyperbaric oxygen combined with upper limb exercise and mental imagery rehabilitation program is feasible and safe in chronic stroke patients and showed trends for improved functional recovery (46).

Poststroke depression. Poststroke depression occurs in one third of patients after the acute stage and persists in the chronic poststroke stage. Hyperbaric oxygen has been reported to improve depression during recovery after acute stroke. A clinical trial has evaluated the effectiveness of hyperbaric oxygen (58). Patients were randomized into 3 groups: fluoxetine group, hyperbaric oxygen therapy group, and hyperbaric oxygen combined with fluoxetine group. Combined hyperbaric oxygen with fluoxetine was more effective than the other treatment methods. A systematic review and metaanalysis of studies on patients with hyperbaric oxygen monotherapy achieved a slightly higher response rate with fewer adverse effects than patients with antidepressants monotherapy (27).

Surgical treatment of cerebrovascular diseases. Hyperbaric oxygen has also been used as an adjunct to surgical treatment of cerebrovascular diseases. Some examples are as follows (21).

	• Carotid endarterectomy
		- Hyperbaric oxygen as part of a decision tree to select patients - Hyperbaric oxygen for cerebral protection during surgery
	• Extracranial and intracranial bypass operation; hyperbaric oxygen response can be used as an indication for operation.
	• For prevention of postoperative neurologic deficits due to complications of intracranial aneurysm surgery: vasospasm, vascular occlusion, and cerebral edema.
	• As an adjunct to surgery of intracerebral hematoma. The role of surgery in evacuation of hypertensive intracerebral hemorrhages is controversial. One way to decide is that patients who are initially treated with hyperbaric oxygen and who show improvement of their symptoms are selected for surgery. Eighty-one patients with hypertensive putaminal hemorrhage and treated with hyperbaric oxygen after an initial CT scan have been reviewed (23). The surgical technique used was mostly stereotactic aspiration of the clot. Open craniotomy was used in only 3 cases. The patients were divided into 4 groups: (1) patients who showed improvement with hyperbaric oxygen and underwent surgery (n=21); (2) patients who showed improvement with hyperbaric oxygen but did not undergo surgery; (3) patients who showed no improvement with hyperbaric oxygen but underwent surgery; and (4) patients who showed no improvement with hyperbaric oxygen and did not undergo surgery. Of all the groups, patients who showed clinical improvement with hyperbaric oxygen had significantly better outcomes than those who did not respond to hyperbaric oxygen. The number of surgical procedures performed for intracerebral hemorrhage has declined considerably at the authors’ institution following the adoption of the policy that only responders to hyperbaric oxygen are operated on. The authors have not tried to maintain the patients only on hyperbaric oxygen, stating that the effects of hyperbaric oxygen are not durable. It is conceivable that hyperbaric oxygen alone may be able to sustain clinical improvement in these patients in the acute phase, and it may be unnecessary to operate on these patients at all. However, this approach has not been tested in any clinical study.

Discussion

	• Some of the reasons for lack of widespread use of hyperbaric oxygen for stroke are not due to lack of efficacy but due to lack of information and financial reasons.
	• Another problem is lack of controlled clinical trials. A few poorly designed randomized studies showed lack of efficacy of hyperbaric oxygen for stroke.
	• Overwhelming data from experimental studies and nonrandomized studies as well as scientific rationale support the use of hyperbaric oxygen for stroke.

Some reasons for the lack of widespread acceptance of hyperbaric oxygen for stroke are as follows:

	• Few controlled clinical trials due to lack of sponsorship.
	• No industrial sponsorship because of low commercial prospects and the inexpensive product used (oxygen). This contrasts with the pharmaceutical support of clinical trials for expensive drugs.
	• Not approved for reimbursement by insurance.
	• Poor information of the public and the medical profession, particularly neurologists, about the potential of this therapy.

Prevalent view. Hyperbaric oxygen has not been proven to be effective by double-blind controlled studies. In a condition like stroke, where spontaneous improvement takes place, the value of an intervention is difficult to assess unless the study is conducted under controlled conditions. In acute stroke, administration of hyperbaric oxygen may not be technically feasible and may delay the institution of more effective methods such as thrombolysis. Finally, concern is harbored regarding adverse effects of hyperbaric oxygen, which include oxygen toxicity (manifested by convulsions) and aggravation of free radical load due to oxygen administration. Even if the treatment is reasonably safe, extra costs incurred in hyperbaric oxygen treatment cannot be justified without firm proof of efficacy.

One published clinical trial was a prospective, double-blind, sham-controlled pilot study of 33 patients who presented with acute ischemic stroke and did not receive thrombolytics over a 24-month period (43). Patients were randomized to treatment for 60 minutes in a monoplace hyperbaric chamber pressurized with 100% oxygen to 2.5 atmospheres absolute in the hyperbaric oxygen group or 1.14 atmospheres absolute in the sham group. Primary outcomes measured included a percentage of patients with improvement at 24 hours using standard scales. Secondary measurements included complications of treatment and mortality at 90 days. Results revealed no differences between the groups at 24 hours. At 3 months, however, a larger percentage of the sham patients had a good outcome defined by their stroke scores compared with the hyperbaric oxygen group with loss of statistical significance in an intent-to-treat analysis. It was concluded that hyperbaric oxygen does not appear to be beneficial and may be harmful to patients with acute ischemic stroke.

The conclusion of a publication from The Cochrane Database of Systematic reviews of hyperbaric oxygen for stroke is that “evidence from the 11 randomized clinical trials is insufficient to provide clear guidelines for practice, the possibility of clinical benefit has not been excluded. Further research is required to better define the role of hyperbaric oxygen in this condition” (02).

A within-subject study of effect of hyperbaric oxygen on ischemic stroke patients used 40 sessions of 2, 4-week 90-minute sessions over a 12-week period (41). Results of this study showed improvements in cognition and executive function as well as physical disabilities following hyperbaric oxygen treatment that were maintained up to 3 months following the last treatment.

Author's view. Oxygen is the logical way to correct ischemic hypoxia. As 100% oxygen given by inhalation cannot reach the hypoxic areas of the brain in a case of arterial obstruction, hyperbaric oxygen is necessary. Oxygen breathing by mask is the routine first aid measure in most ambulances that transport stroke patients. Yet, the most efficient way of administering oxygen, hyperbaric oxygen, is questioned. Hyperbaric oxygen has been used on an adequate number of patients to demonstrate its safety and efficacy. More basic studies exist to back up hyperbaric oxygen than many other treatments used in medical practice, many of which have not been subjected to double-blind trials.

It is technically feasible to have portable hyperbaric chambers (inflatable bags that can be pressurized) included in ambulance equipment. Ambulance attendants can be trained in the use of this equipment. Hyperbaric oxygen administration should be started for patients with a reasonable suspicion of stroke at the time they are picked up by the ambulance and continued until they arrive at the emergency department of a hospital. The only exceptions to this would be a concomitant condition requiring more specific initial treatment that could prevent the patient's placement in a hyperbaric device. Hyperbaric oxygen treatments can be continued even if the patient is selected for another specific treatment such as thrombolysis or surgery.

Safety of hyperbaric oxygen has been demonstrated, and complications are infrequent. If administered at pressures of 1.5 atmospheres absolute with duration of treatment not exceeding 1 hour, hyperbaric oxygen is not known to aggravate the free radical load in the injured brain or to produce any other biochemical or metabolic disturbances. Rather, it tends to improve the situation in injured or hypoxic brain tissues by reducing free radical formation and improving metabolism.

A poorly designed clinical trial concluded that hyperbaric oxygen was ineffective in stroke (43). A criticism of the clinical trial is as follows (20):

The authors were aware of previous human studies in stroke patients indicating that 100% oxygen at pressure of 1.5 ATA is better tolerated than higher pressures by the brain injured by acute ischemia, yet they chose a pressure of 2.5 ATA. It is not surprising that the sham patients who received oxygen at 1.14 ATA did better than those who received it at 2.5 ATA because the former is closer to the ideal pressure of 1.5 ATA. There was no stratification of the patients according to the time from stroke or any restriction to the time window of 3 or 6 hours when the neuroprotective effect of hyperbaric oxygen should be tested.

For the reasons mentioned above, the study served no useful purpose in resolving the controversy about the role for hyperbaric oxygen in stroke but, rather, made it more difficult to obtain any support for further clinical trials.

As hyperbaric oxygen is used for neuroprotective effect in acute stroke, it should be used within the 3-hour window. It is feasible to combine hyperbaric oxygen with tPA thrombolysis. Safety and efficacy of this combination has been demonstrated in controlled clinical trials on patients with acute myocardial infarction.

Use of hyperbaric oxygen as an aid to rehabilitation in the subacute and chronic phase is safe because some of the early biochemical disturbances following initial insult are stabilized by that time. Animal experimental evidence shows that the use of hyperbaric oxygen in the acute stage after the 6-hour time window may be harmful. Applying hyperbaric oxygen within 6 hours of ischemia-reperfusion injury could benefit the patient, but applying hyperbaric oxygen 12 hours or more after injury could harm the patient.

Although it is difficult to assess a treatment for acute stroke, a patient in a chronic poststroke state with fixed neurologic deficits is easier to evaluate. If neurologic deficits improve transiently following a treatment and recur after the effects of hyperbaric oxygen wear off and this phenomenon can be shown repeatedly, then it can be considered proof of the efficacy of the treatment, particularly when it correlates with the improvement in SPECT scan. Longitudinal studies of hyperbaric oxygen-treated patients in the chronic poststroke stage with objective measurements by clinical and objective brain imaging studies are more valuable than any statistical analyses of double-blind studies. Finally, having demonstrated some degree of improvement in each poststroke patient undergoing hyperbaric oxygen plus physical therapy treatment in chronic state, it would be an ethical dilemma to give sham treatments to such patients. These patients were selected because their condition had remained status quo despite adequate physical therapy. It would make no sense to return them to a double-blind study where they would be getting the same physical therapy without the hyperbaric oxygen environments.

Resolution

	• To resolve the controversy, it is well recognized that controlled clinical trials of hyperbaric oxygen for stroke are required and some are already in progress.
	• Like any drug therapy, variations in response to hyperbaric oxygen may be due to individual differences and a personalized approach could be useful.
	• Future prospects for approval of hyperbaric oxygen for stroke are promising.

A special symposium with joint participation of neurologists, stroke specialists, and hyperbaric physicians was convened to debate this issue in 1998, and the proceedings were published (22). There was a critical and frank discussion to resolve some of the issues and to define future objectives.

It was agreed that well-designed, controlled clinical trials should be conducted in acute stroke patients. The central point of discussion was how to organize such trials. For optimal effect, hyperbaric oxygen would need to be administered as soon as possible after onset of acute stroke and preferably within the first few hours. A logistic problem exists because the currently accepted tPA thrombolytic therapy is also administered within the 3-hour time window. Dr. Thomas Brott, who successfully conducted the National Institute of Neurological Diseases and Stroke tPA trials, led the topic discussion. The possibility of taking those patients who did not qualify for tPA thrombolysis was discussed as an enrollment criterion. An alternative was to administer hyperbaric oxygen when the patient is being transported to the hospital or waiting for a CT scan so that no extra time is lost. The possibility that an initial hyperbaric treatment, by its neuroprotective effect, could extend the window of opportunity for treatment beyond 3 hours was also considered. The additional advantages of hyperbaric oxygen are that it can be used in hemorrhagic stroke (a contraindication for tPA therapy) and for the relief of cerebral edema. The possibility of hyperbaric oxygen as an add-on therapy to tPA was also considered. There was also discussion concerning mobile hyperbaric chambers and whether the treatment should be given en route or in a fixed hyperbaric facility in a hospital. Treatments given at 1.5 atmospheres absolute were felt to be safe. Further discussions centered on the use of brain imaging methods for documentation of changes in the brain following stroke as well as its modification with hyperbaric oxygen. The possibility of conducting further animal experiments and human safety studies were discussed; however, it was generally felt that considerable data exist on these topics. No similar meeting has taken place nearly 2 decades following this symposium, and no significant changes have occurred in the views on this topic.

Clinical trials of hyperbaric oxygen in stroke are presently underway. No consensus has emerged yet on the role of hyperbaric oxygen in the treatment of stroke. A systematic review of clinical trials reveals that the overall evidence is insufficient to determine the effectiveness of hyperbaric oxygen therapy in any subgroup of stroke patients.

Another factor to be taken into consideration is that the variation in response to hyperbaric oxygen in individual patients is like variations in response to pharmaceutical preparations. As technologies are available to study gene expression patterns in response to hypoxia as well as hyperoxia, this information would be useful for monitoring the response and personalizing hyperbaric oxygen treatment for individual patients for optimal effect.

Several studies promote the use of 100% normobaric oxygen for the treatment of stroke. There is nothing new in this approach as 100% oxygen inhalation has been used in the emergency care of patients including those with acute stroke. The problem with 100% oxygen is that it cannot be delivered as effectively to ischemic tissues as hyperbaric oxygen. Moreover, 100% oxygen can also induce vasoconstriction without compensating for reduced oxygen supply due to the reduction in cerebral blood flow whereas hyperbaric oxygen compensates for vasoconstriction by increasing oxygen tension.

As of May 2021, the controversy about use of hyperbaric oxygen in acute ischemic stroke has not been resolved. This therapy, however, is being used clinically more frequently than 5 years ago. Well-designed experimental studies support the usefulness of a combination of hyperbaric oxygen with thrombolytic therapy in acute stroke, and clinical trials of this combination are justified. A retrospective statistical analysis of an older study (pre-thrombolytic era) of stroke patients treated with hyperbaric oxygen focused on those who received treatment within 7 hours following stroke onset (32). The authors concluded that during the first 3 hours poststroke, hyperbaric oxygen administration has the most promise for efficacy and improvement of rtPA therapy.

Despite the controversy generated by clinical trials, individual patients with acute stroke are still being treated with hyperbaric oxygen safely and with good results. A series of hyperbaric oxygen treatments was given to a patient who suffered an acute ischemic stroke with cerebral infarction and did not qualify for thrombolytic treatment because the time to admission following stroke onset was longer than 5 hours (07). The treatment resulted in improvement of neurologic deficits as well as improvement of cerebral perfusion shown on brain imaging studies.

Use of hyperbaric oxygen for other conditions associated with cerebral ischemia is less controversial that its use for acute stroke. A postoperative course of hyperbaric oxygen in patients undergoing intracranial aneurysm surgery is complicated by cerebral vasospasm and cerebral ischemia. A randomized study has shown beneficial effect of early hyperbaric oxygen as an adjunctive treatment following surgery for intracranial aneurysms (51). Effectiveness of hyperbaric oxygen is due to attenuation of vasospasm, brain edema, and cerebral ischemia.

Future outlook. Basic and clinical data suggest that hyperbaric oxygen could be a safe and effective treatment option in the management of acute stroke, but further studies are needed to clarify its clinical utility when applied within the treatment window of 3 to 5 hours (44). Hyperbaric oxygen preconditioning for stroke is based on the concept of mild oxidative stress priming the brain for tolerating the full-blown oxidative stress inherent in stroke. Preclinical studies have shown that hyperbaric oxygen increases survival of grafted stem cells and optimizes their function in the postischemic environment (29; 08). According to a retrospective analysis, SPECT/CT-based measurement of the volume of the penumbra may be an effective method for predicting the efficacy of hyperbaric oxygen therapy for poststroke patients; those with large penumbra significantly benefitted along with diminution of its size during therapy, whereas those with a relatively small volume of the penumbra zone did not benefit from therapy (12). The U.S. Food and Drug Administration has approved the use of hyperbaric oxygen for central retinal artery occlusion, and treatments for this indication are reimbursed by healthcare insurance and Medicare. It is hoped that hyperbaric oxygen use for stroke, which is currently off-label in the United States, will be approved in the future.