Brain Injury and Recovery with Hyperbaric Oxygen Therapy

Dr Philip James

Hyperbaric Oxygen simply means oxygen given at increased barometric pressure.....

The Problem:

  • The complex and almost continuous electrical activity of the brain is so discreet that we are unaware that it is the mechanism behind communication and thus intellectual and motor function.
  • Brain injury can lead to a blockage of the electrical pathways.
  • Depending on the location of the injury, the brain's attempts to re-route through blocked pathways may cause frustrated discharges of activity known as seizures.

What Causes the Blockage?

SPECT scans (computerized brain mapping) show that not only does brain injury produce cell death, but also reduces essential blood flow to a wider area of brain tissue surrounding the dead cells where signal re-routing might be expected to take place.

How Does This Happen?

  • After brain injury, many blood capillaries around the area of cell death become torn open
  • The liquid part of the blood (the plasma) then leaks out causing a swelling that may be very extensive.
  • This reduces cerebral blood flow in the affected areas.
  • Reduction in blood flow means a reduction of essential nutrition (most vitally oxygen), and a build up of waste products from local biochemical reactions (e.g. lactate and calcium), which shut down normal cell function and further block pathways.

    Why Doesn't Capillary Healing Happen?

    • If the capillaries are to heal, they desperately need oxygen.
    • Unfortunately, the tiny tubules leading to the torn capillaries become constricted because of the damage.
    • This means that the Red Blood Cells needed to bring the healing oxygen are too big to get through and simply get stuck in the "pipes."
    • Thus the plasma that is normally very low in oxygen continues to pour out, maintaining the swelling with all its attendant problems which, if left unattended, would last for years, even an entire life time


    Oxygen, The New Growth Factor?

    In recent years, our understanding of the intercellular communication of healing has increased considerably. Cells within a wound receive a myriad of signals from their environment, the sum of which governs the activity of a cell. The term "cytokine" is applied to those substances which function as cellular signals. Growth factors are a subclass of cytokines that specifically stimulate the proliferation of cells. This stimulation may occur through several different mechanisms. For example, some growth factors have activities that attract fibroblasts and inflammatory cells, some act as mitogens, stimulating cell division, and some effect the production and degradation of the extra-cellular matrix. All of these phenomenon’s are the result of a cytokine (growth factor) signaling the cell nucleus to produce proteins, which account for the observed activities. A clear understanding of growth factor physiology carries the promise of clinical advances in wound management. Currently one cytokine, Platelet Derived Growth Factor, is in clinical use for the management of problem wounds. As our knowledge of these substances expands, other growth factors will be added to our clinical armamentarium for the management of non-healing wounds.

    Non-healing wounds can also be managed by optimizing the metabolic requirements of healing e.g. protein, trace elements, and oxygen. The most frequent common denominator in non-healing wounds is inadequate tissue oxygenation, which impairs healing and host defenses. Correction of such hypoxia by means of revascularization or hyperbaric oxygen therapy results in healing for most patients. Conventional wisdom suggests that oxygen is just a metabolite and therefore healing, in these circumstances, is simply a reflection of having sufficient oxygen to meet the energy demands of wound repair. However, some exciting evidence is now emerging to suggest that oxygen serves a dual role as both a metabolite and a growth factor. The conceptualization of oxygen as a growth factor has considerable relevance to the field of hyperbaric oxygen therapy.

    The idea of oxygen acting as a cell signal has already been established in the setting of hypoxia. As an example, gene expression for erythro-protein production is largely proportional to the pO2 level in the kidney. It has been proposed that cells in a non-healing wound may respond to hyperbaric therapy because the supra-physiologic elevation of tissue oxygen serves as a trigger signaling that enough oxygen is in the environment to proceed with normal healing. Subsequent daily exposure to the threshold oxygen level reinforces this signal and results in gene expression of the protein building blocks required for healing. Teleologically, it makes sense for cells to conserve resources until the environmental signals are strong enough and consistent enough to activate the cell nucleus and begin the healing process.

    Two separate groups of investigators have published findings that support this concept of oxygen as a growth factor. Following a single one-hour exposure to hyperbaric oxygen, Hehenberger, et al. (1997) demonstrated a dose dependent stimulation of normal in vitro fibroblasts with a peak increase in cell proliferation at 2.5 ATA O2. The dose-dependent effect of a single 1-hour exposure to oxygen suggests a pharmacologic effect of oxygen on cells, as opposed to an increased metabolic availability of oxygen. These findings suggest, therefore, that a single brief exposure to hyperbaric oxygen on a daily basis provides a strong initiating signal for the intracellular events that culminate in cell proliferation, while sustained hyperoxia has the opposite effect.

    In a study of in vitro fibroblast proliferation using tritium labeled thymidine, Tompach, et al., found that a single dose of HBO (2.4 ATA for 120 minutes) produced a sustained stimulation of fibroblasts for 72 hours. If a second exposure to HBO was given on the same day there was no additional increase in cell proliferation. Similarly, cultured endothelial cells remained stimulated for 72 hours following a single 15-minute exposure to HBO. Again, these findings suggest that we must reconsider oxygen as being more than just a metabolite.

    This new paradigm of oxygen as a growth factor is consistent with the clinical observation that a BID dosing of HBO appears to offer no clear benefit over a QD dosing schedule for the treatment of chronic wounds. As our understanding of oxygen physiology increases, we will be in a better position to determine the optimal dosing of oxygen in both its metabolic and stimulatory roles.

    References:

    1. Siddiqui A, Davidson JD, Mustoe TA. Ischemic tissue oxygen capacitance after hyperbaric oxygen therapy: A new physiologic concept. Plast Reconstr. Surg 1997; 99:148-69.
    2. Hehenberger K, Brismar K, Folke L, Gunnar K. Dose-dependent hyperbaric oxygen stimulation of human fibroblast proliferation. Wound Rep Reg 1997;5:147-50.
    3. Hehenberger K, Brismar K, Folke L, Gunnar K. Dose-dependent hyperbaric oxygen stimulation of human fibroblast proliferation. Wound Rep Reg 1997;5:147-50.

    Hyperbaric Oxygen Therapy In the Treatment of Brain Injury: Report of a Meeting

    On July 25-28, 2001, a meeting was held in which clinicians, clinical investigators and family members reviewed the present status of information about the use of hyperbaric oxygen therapy (HBOT) in the treatment of brain injury1. Nearly all participants in the meeting were advocates of the use of HBOT; there were no presentations by conferees who were either opposed to the use of the therapy for this purpose or whose position was as yet undecided. One of the major topics of discussion was the recent report of the "Montreal trial" that demonstrated significant functional improvement in many of the cerebral palsy children participating in the randomized double-blind HBOT trial, but with no differences in functional outcomes in children treated either with 1.35 ATA of air or 1.75 ATA of 100% oxygen.

    The conferees participated in two broad areas of discussion: (1) reports of clinical experiences that appeared to preserve life and restore impaired function when HBOT was administered soon after brain injury (e.g. traumatic brain injury; drowning; birth hypoxia; meningitis); and (2) the clinical experience that HBOT appeared to restore function in persons (usually children) with disabilities following brain injury at sometime in the past (e.g. cerebral palsy).

    At this meeting, the principle presentations were reports of clinical experience utilizing HBOT, either individual cases or case series. The reports described functional improvement in both the acute and chronic situations following brain injury. In the chronic situation (cerebral palsy), the results of the use of 100% oxygen administered at a variety of atmospheric pressures were discussed (1.75 ATA; 1.5 ATA; 1.35 ATA); all were reported to be associated with positive short term and long term results; no reports were presented that described poor results. The recognized danger of hyperbaric oxygen was discussed (i.e. seizures), as were the less well recognized behavioral manifestations of oxygen toxicty (e.g. agitation; aggressiveness). In the experience of the conferees, it appears that these complications are unusual, but when they do occur they are manageable by the termination of therapy and the use later of lower levels of hyperbaric oxygen.

    One focused item of conference discussion was the Montreal trial and the "implication" that the control subjects receiving air at 1.35 ATA were receiving a "placebo" (a non-therapeutic intervention). It was stated by clinical participants at the conference that air at 1.35 ATA increased both the oxygen level of red blood cells and caused oxygen in the air to dissolve in the blood's fluid (plasma); both increased the availability of oxygen to body tissues--including the brain.

    It was proposed by several conferees that the control group of the subjects in the Montreal study were also receiving an increased oxygen supply to the brain; thus explaining the similar clinical improvement in both segments of the study population. If this is true, should air administered at 1.35 ATA be used instead of HBOT? The question was asked, but not answered.

    In support of the effects of HBOT on the brain, a number of brain imaging studies using SPECT before and after treatment were presented. SPECT provides images of regional cerebral blood flow; by inference, a change in blood flow implies but does not demonstrate a change in cerebral metabolism. In all of the cases presented, SPECT showed increase in cerebral blood flow in a variety of poorly perfused areas of the brain following HBOT. It was hypothesized that these areas of increased blood flow were metabolically more active than prior to HBOT.


    COMMENT:

    The reports presented at this meeting of improved function and cerebral circulation cannot be disregarded by labeling them as "observations by biased advocates". These observations by skilled clinicians and parents need to be explored by appropriate scientific studies that meet the standards of modern research. One study, the Montreal study, clearly indicates that room air delivered at a low level of increased atmospheric pressure (1.35 ATA) gives identical results to 100% oxygen delivered at increased pressure (1.75 ATA). At this time, there is still no scientifically acceptable evidence that HBOT is useful in the treatment of disabilities associated with cerebral palsy. The following questions remain to be answered:

    • Is HBOT (oxygen level? pressure level?) useful in the treatment of disabilities associated with cerebral palsy?
    • Is hyperbaria alone (pressure level?) useful in the treatment of disabilities associated with cerebral palsy?
    • Is oxygen supplementation alone (oxygen level?) useful in the treatment of disabilities associated with cerebral palsy?

    Sufficient clinical experience does exist to support the need for additional controlled studies exploring these questions in a scientifically acceptable manner (i.e. randomized, double-blind trials). Air delivered in a hyperbaric chamber at 1.0 ATA can serve as a control.

    Another issue also requires study: the suggestion that there are "idling" neurones in the brain years after injury that become active after the use of HBOT. At this time, there is no evidence that this is true. However, there are methods available to test this hypothesis: PET brain imaging or metabolic magnetic imaging. These quantitative methods of measuring focal brain metabolism can be applied before & after HBOT and will answer the question.

    Are the above studies do-able? They are. To be successful they must have the active participation of the children to be studied, their caregivers, clinicians, and scientists. They also require the organizational arrangements and financial resources that these studies demand in order to be successful. The UCP Research and Educational Foundation is attempting to see if the necessary personnel, the organizational and the financial requirements can be mobilized to initiate these needed studies to evaluate the usefulness of HBOT in treating children with disabilities due to cerebral palsy.

    1 International Symposium on Hyperbaric Oxygen in Cerebral Palsy and the Brain/Injured Child. Boca Raton, Florida; July 25-28, 2001. Richard A. Neubauer, MD, Chairman, August 2001.

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