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Dr Philip
James
Hyperbaric Oxygen simply means oxygen given at
increased barometric pressure.....
The Problem:
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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:
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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.
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Hehenberger K, Brismar K,
Folke L, Gunnar K. Dose-dependent hyperbaric oxygen stimulation of
human fibroblast proliferation. Wound Rep Reg 1997;5:147-50.
-
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. |