Hyperbaric Oxygen Treatment for Stroke Patients
Stroke is an ill-defined lay term that has found its way into general use in medicine and derives from the old English word “stricken.” It relates to the abrupt onset of neurological symptoms, usually a “hemiplegia” with half of the body, most commonly the left side, developing weakness or paralysis. Speech and the muscles of the face may be affected, causing drooping of the mouth. Such symptoms are easily recognized, but, unfortunately, strokes may also affect cognitive function and cause loss of memory and even personality changes often only apparent to near relatives.
Strokes are the equivalent in the brain of a heart attack; indeed they have often been referred to as “brain attacks,” and both are due to the lack of oxygen caused by a reduction of blood flow. As heart attacks may be abruptly fatal, the need for emergency treatment is obvious; nevertheless, patients admitted to the hospital with a stroke are now more likely to die than those who suffer a heart attack. Clearly, if outcome is to be improved, the same urgency is needed in stroke treatment. Strokes are the now the scourge of the Western world: In England and Wales, with a combined population of about 58 million, about 53,000 patients die from a stroke each year, with more than 450,000 surviving with severe disability. The estimated cost of their long-term care is more than £9 billion a year.
Strokes mainly affect older people and are associated with the disease of the lining of arteries known as atherosclerosis, which results from a high-sugar and high-fat diet. The damage reduces the diameter of the vessel and attracts platelets — essential components of clotting — causing thrombosis. Debris from affected areas may dislodge and flow down the artery to lodge and reduce or block blood flow. The mechanism is known as thromboembolism. Unfortunately this disease process is now affecting people in middle age. The Stroke Association in the UK has recently reported that the number of strokes occurring in men between the ages of 40 and 54 has increased by almost 50% in less than 15 years.
Strokes may also occur when material breaks off damaged heart valves and when clots form in the heart. This is most commonly associated with stagnation of blood in the left atrium in patients suffering from the irregularity of contraction known as atrial fibrillation. Fibrocartilagenous emboli from spinal disc degeneration may enter the circulation and cause stroke at any age and is well-recognized in veterinary medicine. Younger stroke patients must also be investigated for the antiphospholipid syndrome known as Hughes syndrome because it can be treated with aspirin. Stroke can also be associated with a persisting hole in the heart, which allows the trapping normally undertaken by the lungs to be bypassed; these holes can now be closed without open-heart surgery. Even a baby still in the womb may suffer a stroke leading to a cerebral palsy evident after birth, although most strokes in newborns are the result of a birth injury.
The symptoms typical of a stroke are not always associated with partial or complete blockage of a major blood vessel in the brain; symptoms indistinguishable from stroke may affect younger patients eventually labeled as having multiple sclerosis — only the age of the patient and a history of other symptoms allow it to be distinguished from a stroke. In this case the reduction of oxygen delivery is due to tissue swelling; the increased water content limits the transfer of oxygen from blood into the tissues.
The only drugs approved for the treatment of stroke are the thrombolytics, popularly known as “clot busters,” which aim to restore blood flow in thromboembolic stroke. The need to restore flow is to improve oxygen delivery, and it would seem obvious that giving patients more oxygen to breathe should be helpful. However, the only measurement made in clinical practice is of the so-called “saturation” of the pigment hemoglobin with oxygen, and most doctors will allege that when the value is 100% there is no value gained from supplementing air with more oxygen. However, this reflects a primary failure in medical education because it is only the oxygen dissolved in plasma that is responsible for the transport of oxygen from blood into cells. The amount dissolved can be safely increased from a typical value of 100 mmHg breathing air at sea level to more than 2000 mmHg breathing pure oxygen in a simple pressure chamber. Also, not in medical consciousness is the fact that oxygen controls both cardiac output and blood flow.
The collection of 3 trillion cells said to comprise the body requires a vast hydraulic system of blood vessels to stay alive, and the brain itself contributes about 100 billion. Despite being only 2% of body mass, blood flow through the brain requires 20% of the cardiac output, and the brain is responsible for 20% of the blood oxygen consumed. The most important function of the cardiovascular system is to deliver oxygen and, because of the unique vulnerability of the brain to a lack of oxygen, the provision of blood vessels is very generous; astonishingly, a cubic millimeter of the cortex of the brain of a mouse contains a thousand capillaries (Figure 1). In practice this means that brain cells can survive if a capillary is blocked by circulating debris, an event that is probably more common than we recognize judged from the “unidentified bright objects” commonly seen on MRIs.
The capillary network in the gray matter of a mouse brain (Courtesy of Drs. Tsai and Blinder)
Air embolism in divers is one cause of stroke where the use of hyperbaric oxygen treatment is well-established and, as treatment is normally prompt, it is usually very effective. The recommended pressure is 2.8 atmospheres absolute (ATA). Air embolism is often overlooked clinically but may complicate many invasive medical procedures, especially open-heart surgery. Air embolism of the middle cerebral artery (arrowed) occurred in the case of the patient whose CT image is shown in Figure 2. It followed an attempt to insert a central venous line. Because of a delay in the use of hyperbaric treatment, the right brain hemisphere (right image) was extensively damaged.
CT images: air embolism of the right middle cerebral artery
Clearly the compression of gas bubbles reduces their size, redistributes them in the circulation, and assists in their reabsorption. The lack of oxygen and the associated inflammation is also reduced by hyperbaric oxygen treatment.
There can be no question that procedures like the US Navy Treatment Table 6 (TT6), which use oxygen at 2.8 ATA, have been largely successful in treating acute air embolism and also neurological decompression sickness, although there is an important problem associated with such a high oxygen pressure that is rarely discussed — it may cause deterioration of neurological symptoms. This is almost certainly due to the vessel constriction produced limiting blood flow “upstream” of the damaged tissue, which is responsible for convulsions at 2.8 ATA. The pressures used, especially for chronic neurological disease, are controversial, reflecting the lack of understanding of the physiology involved. Although the oxygen delivered is usually 100% and the treatment pressure is set accurately, it does not indicate the oxygen level present in the arterial blood, which determines the response to treatment. This is mainly because of the mismatch between the areas of the lung engaged in ventilation and those through which blood is flowing. This is known as the “ventilation/perfusion ratio,” but, unfortunately, it cannot be measured during treatment.
The actual level of oxygen a patient breathes also depends upon the delivery system; for example, masks are notoriously prone to leakage. An indication of the variation in blood oxygen level comes from measurements made in a New York University study in 1983. Using a well-designed full-face mask at an accurate chamber pressure of 2 ATA, the lowest blood oxygen level measured was 1.11 ATA and the highest was 1.59 ATA — almost 45% higher. Clearly, the chamber pressure determines the maximum level possible breathing 100% oxygen, but not the minimum level.
There are also variations in the transfer of oxygen into damaged tissue because of the inevitable involvement of the internal microcirculation. The patient’s response can be seen by looking in the eye; in some patients there is a very marked reduction of the diameter of the arteries of the retina; in other patients the reduction is minimal. Once an oxygen deficiency has been corrected, the oxygen level should be lowered so that the constriction of the blood vessels does not limit the transport of other agents in blood vital for recovery. This approach is used in TT6; the sessions of oxygen breathing at 2.8 ATA are interrupted by breathing chamber air because of the risk of a convulsion, and after three or four cycles of oxygen breathing at 2.8 ATA, the oxygen pressure is reduced to 2 ATA. Divers are usually young and fit and their condition is acute. In trials of hyperbaric oxygen treatment in stroke, the delay to treatment has often been many hours, and by this time use of high oxygen pressure is inappropriate. The treatment of patients with multiple sclerosis and mild traumatic brain injury over the past 40 years has confirmed beyond doubt the effectiveness of oxygen pressures lower than those used for divers. In general, the longer treatment is delayed, the lower the oxygen pressure that should be used. Military doctors recommend treatment at a pressure of 2 ATA for the subtle residua post treatment that may be detectable only on psychometric testing. Importantly, much animal evidence indicates that a pressure of just 2 ATA is as effective in resolving acute air embolism, and, as in other forms of stroke, the window of opportunity is just a few hours.
The symptoms described as a stroke may result from rupture or, more commonly, a partial or complete obstruction of an artery. The arteries in the brain have thinner walls than those in other parts of the body, and rupture may occur if blood pressure rises, leading to hemorrhage, and pressures as high as 250 mmHg can be generated by straining. Arteries may be obstructed by an embolus or by a thrombosis that forms on an area of damage to the artery lining associated with the common disease atherosclerosis. In both conditions, hyperbaric oxygen treatment may be valuable. Animal studies support the use of oxygen in brain hemorrhage, and the author has personal experience of a very positive outcome in a diver who suffered an intracranial hemorrhage from a ruptured berry aneurysm after completing a shallow dive. Because it was not possible to eliminate gas embolism due to pulmonary barotrauma as the cause of his symptoms, he was treated on TT6 and regained consciousness breathing oxygen at a pressure of 2.8 ATA. However, he lost consciousness as pressure was reduced and, after assessment at a local hospital, was transported by helicopter to a regional neurosurgical unit. The surgeon was astonished at the diver’s rapid recovery post surgery given the severity of the hemorrhage seen on CT imaging. The down regulation of neutrophil activity and inflammatory genes by oxygen provides a sound scientific basis for hyperbaric oxygen treatment in subarachnoid hemorrhage.
The blockage of blood flow in an artery of the brain only causes a major problem when other blood vessels cannot compensate for the reduction in blood flow: Flow must be rapidly restored to allow the transport of critical oxygen to resume. Most of the arteries of the brain connect to other arteries — they anastomose — which can minimize damage from a blockage. Unfortunately, vessels in the middle of the brain, known as the lenticulostriatal arteries, do not have such connections, which leave the areas of the brain they supply, including those known as the internal capsules in the middle of each hemisphere, vulnerable. They are known as “end arteries,” and the optic nerves and areas of the spinal cord also have end arteries. The lenticulostriatal arteries in one hemisphere are highlighted in Figure 3. Damage to the fibers passing through these areas is the most common cause of stroke.
Clot-busting drugs, the only helpful treatment, must be used within an hour of the onset of symptoms to be properly effective; after four hours, they are not beneficial and increase the risk of bleeding. Their use is effectively restricted to just 5% of stroke patients because of this complication. Because of this time constraint, the treatment of stroke will never be entirely satisfactory; about a third of patients with stroke die, and, sad though it is for the loved ones, this limits the human effort expended and the costs to society. A third of patients will eventually make a reasonable recovery and regain their independence, but this leaves the remaining third as survivors in need of constant care, often in an institution.
The human and financial costs are truly enormous and, with the population aging, are getting ever greater. If the treatment of stroke could be improved with fewer patients suffering prolonged disability, much suffering could be avoided and enormous savings made. Attempts to develop drugs for stroke by three major drug companies — Pfizer, Glaxo Smith Kline, and Astra Zeneca — have been abandoned after billions of dollars in investment have not yielded results. As it is universally recognized that a stroke is caused by lack of oxygen, the question arises: Can giving oxygen under hyperbaric conditions with clot-busting drugs improve the immediate treatment of stroke patients?
Oxygen delivery obviously depends on blood flow, and when the heart stops, the arrest of blood flow to the brain could be termed a “global” stroke. It is commonly stated that unless the heart is restarted, the brain dies in four minutes. This is not the case; detailed postmortem studies published in a research letter in The Lancet in 1998 titled “Recovery of Axonal Transport in Dead Neurons” have shown that brain cells remain viable for many hours in culture provided that oxygen and glucose are supplied. The damage occurs when blood flow returns after the heart is restarted; this is called reperfusion injury. A heart removed from a donor must be used within four hours; otherwise it deteriorates, leading to the death of the recipient. Heart transplant research in the 1970s has shown that the damage to the heart occurred when blood flow was reestablished due to the release of oxygen free radicals. For many years biochemists pondered the obscure ways in which free radicals may be involved, but the answer was provided by research that followed a world event — a little girl named Jessica fell down a well in Midland, Texas. Her blackened leg was saved by hyperbaric oxygen treatment. Controversy followed — it was suggested in a letter published in JAMA, despite the leg being saved, that a high level of oxygen in a pressure would have worsened her condition because of free radicals. In fact, giving more oxygen prevents the formation of oxygen free radicals, and it is an intriguing story that involves white blood cells called neutrophils.
Following the controversy, Dr. William Zamboni received funding to study hyperbaric oxygen treatment in limb salvage. Using a ligature to stop blood flow in an experimental model, he watched events under a microscope when flow was released after four hours. White blood cells returning with the blood flow began to stick to the walls of the veins, eventually blocking flow and leading to the death of the muscle.
However, a large dose of oxygen delivered under hyperbaric conditions stopped the white blood cells from sticking, and the muscle survived. Dr. Zamboni reported that he could reimplant severed human limbs successfully up to 12 hours post injury. The fall of the oxygen level attracts neutrophils to the affected area, and, if the lack of oxygen is not relieved, they release free radicals, which damage the walls of blood vessels as they are programmed to do in infection. This undoubtedly happens as a stroke develops and may lead to the most serious complication, the bleeding into the tissues of the brain, known as a hemorrhagic stroke. The red blood cells are broken down, and the iron released from their hemoglobin generates the most toxic of free radicals, the hydroxyl radical, causing the death of cells in their vicinity.
It is critical to progress for it to be recognized that these events occur entirely within the confines of blood vessels, and they apply to the restoration of blood flow in any organ — including the brain. Hyperbaric oxygenation is the key to preventing this problem because it stops neutrophil aggregation and, hence, their release of free radicals in the tissues. The case for using high levels of oxygen in acute stroke together with thrombolysis is supported by sound science, including a large number of animal models of stroke, most using rats, which, with a brain weight of only 2 grams, represent a “worst case” situation.
The question then remains: Is there benefit to stroke patients beyond the acute stage with long-term disability? Here it is necessary to discuss a concept first proposed by neurologists in the 1980s that has since been demonstrated by SPECT imaging. Judged by the certain yardstick of the pathology that results from stroke, some brain tissue dies and slowly is replaced by scar tissue. However, a much bigger volume of tissue is affected and remains for years “not dead but sleeping.” It is termed the ischemic penumbra. The brain cells survive because the brain has two circulations: one of blood, and the other of the tissue liquid known as cerebrospinal fluid (CSF). The CSF can assist in maintaining low levels of oxygen, ensuring that neurons, while not having sufficient energy available to function, can survive. However, for new capillaries to grow and establish an adequate blood flow for function requires additional energy and a greater availability of oxygen. It is now well-established that the adult human brain contains stem cells capable of rebuilding the brain by forming new cells. Also, bone marrow stem cells can migrate into the brain, as they can into the heart, but, as with drug delivery, their migration is hampered when blood flow is reduced and the water content of the tissues increases due to swelling. Long-standing tissue swelling can be reduced by hyperbaric oxygen treatment, allowing in stem cells to rebuild damaged areas, which makes a substantial difference to both the extent of permanent damage and the speed of recovery.
Several studies of hyperbaric oxygen treatment in acute stroke patients in the 1960s and ’70s showed that patients often improved while in the chamber breathing oxygen. In most cases, the patients had only a single treatment, and, not surprisingly, the improvements usually disappeared shortly after the session was completed. There was very limited understanding of the biology of oxygen at the time, and no studies were undertaken using a course of oxygen treatment to see if the improvement would persist. There were, however, notable exceptions to this approach. Dr. Edgar End in Milwaukee County Hospital, who rarely published his work, started treating stroke patients in the 1940s, and he had seen sustained improvement from courses of treatment. In 1980, he collaborated with Dr. Richard Neubauer to publish the results from the treatment of 122 patients in the journal Stroke using what were regarded at the time as low oxygen pressures — that is, from 1.5 to 2 ATA. This was a critical move away from the much higher pressures used in diving and many benefits were found.
Drs. Neubauer, Gottlieb, and Kagan described the benefit of a course of hyperbaric oxygen treatment for a 60-year-old female patient in a letter titled “Enhancing ‘idling’ neurons,” published in The Lancet in 1990. The patient had suffered a stroke 14 years previously but regained the ability to live independently, and her improvements correlated with remarkable changes evident on SPECT imaging undertaken before and after treatment. The images identified still-viable brain tissue in the area surrounding the zone of tissue death. It is telling that the letter in The Lancet did not generate any correspondence, but the concept has been confirmed by further imaging studies. In 2007, an issue of the journal Neurological Research was dedicated to detailed papers on the use of oxygen treatment in neurological conditions, including stroke.
With drugs failing to show benefit, the need to focus efforts on oxygen, the only proven neuroprotective agent, is all too apparent, and a comprehensive study has recently been completed in the Assaf Harofeh Hyperbaric Centre near Tel Aviv, Israel. SPECT imaging was used before and after treatment. Figure 4 shows the 3D brain images of a 72-year- old man who still had right-sided weakness 34 months after a stroke. He was unable to hold either his right arm or leg against gravity and had little movement of the fingers of his right hand. He could only communicate with single words, being unable to complete sentences. A course of 40 sessions of hyperbaric oxygen treatment was undertaken using 100% oxygen by mask at 2 ATA five days a week. The session time in the chamber was a total of 90 minutes.
After the course of treatment, he was able to hold both his arm and leg against gravity and to move his fingers. His speech was significantly improved with the ability to complete sentences. The baseline 3D SPECT image of the brain prior to oxygen treatment shows a wide area of penumbral brain tissue (green regions) around the stroke area (blue region) involving part of the left motor cortex, which correlates with the impairment of his right leg and hand function. The left cortex of the frontal lobes, Broca’s area, which is responsible for speech, also shows improved blood flow, as do the areas in the midbrain known as the basal ganglia. To put his treatment into perspective, it must be remembered that the sessions took a total of 60 hours — that is, less than a week of his life. The use of SPECT imaging provides spectacular evidence (pun intended) of the importance of oxygen in restoring viable brain tissue. Given the cost of institutional care, these results desperately need to be translated into practice, as many patients will be able to retain their independence. The care in the community model developed for multiple sclerosis patients provided in 65 centers in the U.K. can provide an inexpensive way of adding life to the years that medical science has made possible.
The known science relating to the fundamental role of oxygen in healing stands in stark contrast to the lack of knowledge of its actions in the medical community. The unique role of oxygen in controlling the circulation — the output of the heart and blood flow — and the regulation of our key genes must be taught in our medical schools.
All references in this article can be found in the following publication:
James PB. Oxygen and the Brain: The Journey of Our Lifetime. North Palm Beach, FL: Best Publishing Company, 2014.