A Brief Review of Hyperbaric Oxygen for Stroke Rehabilitation
A. Steenblock, M.S., D.O.
Mission Viejo, California
is a natural gas that is absolutely necessary for life and healing.
Purified oxygen is defined as a drug but is the most natural of all
drugs. Oxygen under pressure is still the same gas but is more able
to penetrate into parts of the body where the arterial flow is hindered
- producing ischemia (loss of blood flow) and hypoxia ( lack of oxygen).
When oxygen under pressure is breathed by a patient in a sealed chamber
it is termed a hyperbaric oxygen treatment (HBOT). The treatment lasts
from 45 to 120 minutes during which time the person’s body is surrounded
by air pressure equivalent to the pressure produced by diving 16 to
33 feet underwater (7.35 to 14.7 pounds per square inch = 1.5 to 2 ATA).
to raising the arterial levels of oxygen 10 to 15 times higher than
that produced by normal atmospheric pressure, the pressure exerted within
the body can and does exert therapeutic benefits on acute and chronically
traumatized and swollen tissues.
suggestion that raised air pressures might be used in the treatment
of human illness was made in 1664 by Henshaw in England. The first hyperbaric
chamber to investigate the therapeutic action of compression of the
air on the human body was described and built by Junod in 1834. Using
1 1/2 atmospheres of pressure, Junod was reported to have treated patients
with paralysis with beneficial results. This pioneering work was not
continued until 1965 when Ingevar and Lassen demonstrated positive results
in 4 patients suffering from focal cerebral ischemia. Since then, numerous
articles have been published demonstrating that hyperbaric oxygen is
useful for the treatment of both acute and chronic stroke.
physiological and anatomical basis for why hyperbaric oxygen improves
acute and chronic stroke and brain damaged individuals has been developed
over the past 100 years.
R. Pfeifer reported autopsy studies of human brains that had undergone
exploratory punctures, months before their deaths. He recognized on
the margins of the resulting brain injuries that the scars had numerous
nerves and nerve fibres that were regenerating.
"marginal" neurons remain intact, alive and in place for more
than the few months reported by Pfeifer was reported in 1934. Cyril
B. Courville demonstrated the persistence of the processes of disintegration,
of phagocytosis and repair in the brain of a 57 year old who had been
shot in the head twenty-two years previously. Seriously damaged nerve
cells had maintained their morphologic identity throughout this long
period. In summarizing this case Courville stated, " Morphologically,
crippled nerve cells may persist in the margins of wounds of the brain
for many years." "Even after a prolonged interval the larger
nerve fibers continue to show regressive change at the margins of wounds
of the brain."
of an ischemic marginal zone surrounding a central core of infarcted
brain tissue as a component of stroke induced damage was further developed
by Astrup, Symon, Branston, and Lassen in 1977. Their baboon studies
showed that electrical activity was lost at the periphery of a cerebral
infarct when the blood flow fell below 15 ml/100g/min while neuronal
death began to occur when blood flow fell to 6-8 ml/100 g/min. These
low blood flow values may be used to define an area surrounding an infarct
where the tissues remain alive but are not functioning called the "ischemic
Penumbra". Dorland’s Illustrated Medical Dictionary (28th ed.,
1994) defines the ischemic penumbra as "an area of moderately ischemic
brain tissue surrounding an area of more severe ischemia; blood flow
to this area may be enhanced in order to prevent the spread of a cerebral
infarction." Results have accumulated supporting the concept of
the ischemic penumbra as a dynamic process of impaired perfusion and
metabolism eventually propagating with time from the center of ischemia
to the neighboring tissue. As mediators and modulators of this process,
waves of depolarization, extracellular increases in excitatory amino
acids, activation of Ca++ channels, intracellular calcium deposition,
induction of immediate early genes and expression of heat-shock proteins
all play a role.(Heiss, WD, Graf, R 1994)
electrical activity is impaired when cerebral blood flow is reduced
to about 60% of control. (Hossmann, KA et al 1980) (Moraweth RB et al
1979) Protein synthesis is suppressed 50% at a cerebral blood flow of
40% even before spontaneous electrical activity is impaired. (Mies,
G. et al. 1991).
(et al 1974) demonstrated a deterioration in the amplitude of somatically
evoked potentials at approximately 34% of control blood flow which is
also the level of blood flow at which glucose begins to be utilized
more rapidly due to oxygen-debt inhibition of mitochondrial metabolism
and oxidative phosphorylation. Thus glycolysis is stimulated in order
to maintain ATP levels. This produces lactic acid which accumulates
because flow is reduced. Since ATP production by glycolysis cannot fully
compensate for oxidative phosphorylation, AMP and purine levels increase
and tissue adenylates are irreversibly lost either enzymatically or
through blood clearance. Reduction in cerebral blood flow below 30 ml/100
g/min supresses the adenylate cyclase and protein kinase C system (Tanaka
K et al. 1993). The loss of adenylates, accumulation of lactic acid
with a lowering of the pH and the formation of free radicals with subsequent
oxidation of blood vessels walls, blood components and brain tissues
results in induction of early response genes, expression of heat-shock
proteins and diminished blood vessel wall and brain tissue protein synthesis
and responsiveness (Paschen, W. et al 1992) (Newman, GC NIHR01Ns28429-02)
Other studies have implicated a multifactorial interaction at the ischemic
blood-endothelial interface of Factor Vlll/von Willebrand factor, prostanoids,
leukocytes, platelets, platelet-activating factor, leukotrienes, adhesion
receptors, monocytes/macrophages, fibrinogen, viscosity and cytokines
that can impair microvascular perfusion (Hallenbeck JM 1994) Disruption
of the blood brain barrier occurs in focal cerebral ischemia (the animal
model of stroke) and the degree of the disruption correlates inversely
with cerebral blood flow. (Yang GY & Betz, AL 1994) Free oxygen
radicals have been shown to disrupt the blood brain barrier in focal
ischemia which allows large molecules to pass through into the brain.
Free radicals inhibit rather than cause postischemic hyperemia.(Tasdemiroglu
E. et al 1994) which is one more mechanism that causes stagnation of
blood flow through the ischemic penumbral zone. When blood flow is further
reduced to approximately 15%, synaptic transmission is abolished (Branston,
NM et al. 1977) (Heiss, WD et al 1976), extracellular potassium increases
and ATP falls proportionately.. A massive release of extracellular potassium
occurs at blood flow levels below 10%, ATP is totally exhausted, neurons
depolarize, cellular ion homeostasis breaks down and cell death occurs.(Astrup,et
al. 1977. (Welsh, F.A. et al. 1978) (Paschen, W et al 1992)
of an infarct are usually strikingly irregular. The explanation for
this probably lies in the preservation of the circulation in some limited
areas through better anastomosis of collateral vessels. (W. Freeman
1933) (Tamura A. et al. 1981), (Tyson GW)
about the size of the penumbra revolves around the methods used to study
it. The morphological evidence is much less than the size shown by autoradiography
(rat-Tyson et al 1984; cat-Ginsberg et al, 1976) and this area is much
less than that shown by functional assessment (Symon et al., 1976).
Substantial areas of flow reduction beyond the infarcted area(s) can
be delineated by CT and MRI, while concurrently, oxygen utilization
is decreased in these areas (Raynaud et al., 1987)(Benveniste H et al
1991). Repeat multitracer PET studies with human stroke victims have
shown viable tissue in the border zone of ischemia up to 48 hours after
the cerebrovascular attack. With few exceptions, these tissues suffer
progressive metabolic derangement and had decreased cerebral metabolic
rates of oxygen (-17.2% vs -26.1% as compared to normal mirror image
regions of interests) within two weeks after the stroke. (WD Heiss et
al. 1992). For many years cerebral ischemia has been thought to release
glutamate from the hypoxic, damaged cells and this glutamate was thought
to potentiate and propagate the initial hypoxic damage. Recently described,
an alternative explanation for glutamate-mediated injury is hypoxia
as well but caused by peri-infarct spreading depresssion-like depolarizations.
These irregular depolarizations are thought to initiate or worsen hypoxic
episodes (due to energy expenditures) and cause a further suppression
in protein synthesis, a gradual deterioration in energy metabolism and
a progression of irreversibly damaged tissue into the penumbra zone.
Thus "interventions to improve ischemic resistance should therefor
aim at improving the oxygen supply or reducing the metabolic workload
in the penumbra region." (Hossmann KA 1994)
cerebral ischemia is the animal model of stroke and in this model there
is evidence for a reduction of the number of perfused capillaries in
the affected penumbral areas. This loss of capillary perfusion is probably
the result of a combination of changes that occur in the terminal capillary
bed in the wake of the acute ischemic process. RBC aggregation, platelet
aggregation, endothelial swelling, increased blood and plasma viscosity,
etc are just some of the factors that contribute to the loss or decrease
in the flow properties of red cells through ischemic tissue capillaries.
Plasma, on the other hand, has been shown to reach all ischemic and
post-ischemic capillaries and is able to pass through capillaries where
red cells are no longer able to pass due to the constrictive and restrictive
changes created by the ischemic process. (K.Kogure, K.A. Hossmann and
B.K.Siesjo 1993) One of the mechanisms of action of hyperbaric oxygen
is to increase the oxygen solubility in blood plasma. It is possible
to dissolve sufficient oxygen (. i.e. 6 vol% in plasma) to meet the
oxygen needs of the brain. (K.K.Jain, 1996) Thus in the acute stroke
patient, the use of hyperbaric oxygen is able to provide oxygen to ischemic
neurons and to keep them alive while either endogenous or exogenous
fibrinolytic mechanisms are brought to bear on the cerebral thrombosis
that is causing the ischemia. This results in the salvage of the ischemic
penumbra to a degree impossible with any other therapy..
injury to the brain, blood vessels are damaged or destroyed. The tissue
that surrounds the area of outright necrosis has had its circulation
compromised and may be only receiving a fraction of the blood flow and
oxygen that it needs for optimum health. Thus a disruption in structure
creates immediately a change (decrease) in function. This decrease in
function remains for months or years and the neurons in these areas
are said to be in "hibernation" or "sleeping". Hyperbaric
oxygen treatments when given daily stimulates a process called "angiogenesis"
or the formation of new blood vessels. New blood vessels form in the
vicinity of the damaged tissues as a result of certain chemical signals
(e.g. angiogenin) that are produced by the newly re-energized neurons,
endothelial cells and macrophages and are then secreted into the surrounding
tissues. These signals stimulate new blood vessels which slowly reconnect
to the damaged tissues and within 60 days of daily treatments, the "sleeping"
neurons wake up and resume their normal functions as the proper structures
return back in place. The hyperbaric oxygen induced blood vessel repair
results in a permanent structural change in the blood vessels that re-supply
the previously damaged and nonfunctioning nerve tissue which was occurring
due to diminished and inadequate blood flow. These new blood vessels
improve the blood flow and oxygen delivery to the damaged brain tissues
and this results in permanent improvements in the stroke and traumatically
brain injured person. Clinically, what you see is the return to life
of a previously paralyzed and useless limb or limbs, improvement in
swallowing, speech, thinking (cognition), memory, etc. Quite obviously
not all of the disabilities disappear since there was a central core
of dead tissue that can not be revived. However, after the two months
of therapy, these people may continue to improve for at least two years
after their treatment with hyperbaric oxygen especially if they continue
with physical therapy. This all occurs in patients who may have not
seen any improvement in their conditions for years after their stroke
even with the use of any and all other therapies indicating that the
brain’s milieu intérieur has been altered for the better since the neurons
are able to slowly re-establish their lost connections in ways not possible
before hyperbaric oxygen.
in stroke may be predicted to some degree by the volume of tissue affected.
Comparative functional volume obtained by single photon emission computerized
tomography (SPECT) often indicates a larger region of recoverable tissue
than CT.(Mountz, JM 1990) This functional volume of the infarct size
can be demonstrated to decrease after one to several hyperbaric oxygen
treatments (Neubauer, 1990, 1992) and this increase in blood flow to
the area of infarction that occurs as a result of hyperbaric oxygen
can serve as a clinical test to determine if there is salvageable neurons
still present in the penumbra. Presumably, if the test (SPECT first,
then HBO then repeat SPECT) is positive, the person should receive benefit
from the use of a series of hyperbaric oxygen treatments because of
the revitalization of the ischemic penumbral tissues.
a good test if the test is positive since we are generally assured that
the person will experience improvement with hyperbaric oxygen. However,
what if the test is negative? Since the literature and clinical experience
predicts that between 80 to 90 percent of stroke victims will be helped
by hyperbaric oxygen, perhaps the SPECT scan may be missing some other
fundamental mechanism by which hyperbaric oxygen is helping these people
improve. For example, when rat’s forebrains are made ischemic for 10
minutes and then after 1, 2, 3 weeks and 3 months their cerebral glucose
utilization is measured, generalized reductions in glucose utilization
is found throughout the majority of gray matter indicating that widespread
alterations of functional activity prevail in postischemic brains beyond
the selectively vulnerable regions. (Beck T, et al 1995) Following acute,
localized lesions of the central nervous system, arising from any cause,
there are immediate depressions of neuronal synaptic functions in other
areas of the central nervous system remote from the lesion. These remote
effects result from deafferentation, a phenomenon known as "diaschisis".
(Von Monakow C. 1914)
an interval of time, which will vary directly with the severity of the
lesion, functional recovery may occur to some degree due to synaptic
reactivation of neurons. This is favorably influenced by rehabilitation.
Diaschisis most commonly manifests itself by such neurological signs
as impaired consciousness or cognitive impairments including dementia,
dyspraxias, dystaxias, dysphasias, inco-ordination and sensory neglect.
The nature of diaschisis has been demonstrated by widespread depressions
of local cerebral blood flow and metabolism extending far beyond the
anatomical lesion. Von Monakow pointed out that development of diaschisis
is enhanced by latent circulatory disorders in both the affected and
unaffected areas of the brain. Recovery of function is associated with
recovery of local perfusion and metabolism. (Meyer, JS,et al 1993)
PET scans have shown that diaschisis does not independently add to the
clinical deficit in human cerebral infarction but represents part of
the damage done by the stroke. (Bowler JV et al. 1995) "Diaschisis
is a functional phenomenon that correlates with both stroke severity
and infarct hypoperfusion volume" (Infeld B; et al.1995)
PET scan study of 31 patients with infarcts involving the frontal sensorimotor
cortex, 23 had persistent diaschisis up to 5 years after onset while
the remaining 8 had the diaschisis recover without recovery of oxygen
metabolism in the infarcted area (implying that tissue in the ischemic
penumbra did recover and this is what allowed for recovery of the diaschisis).
(Miuura H; et al.1994.)
functionless ischemic penumbral tissue can be "re-activated"
and be made to function again, a coresponding amount of the areas of
diaschisis will be returned to normal with normal blood flow and function
In a number
of studies in normal dogs, monkeys and Man, hyperbaric oxygen has been
shown to diminish cerebral blood flow from 1 to 29% (average 14.7%)
which some people have claimed to be detrimental to a stroke or brain
injured patient. All of these studies were done in normal non-brain
injured subjects while the studies that were done in brain injured patients
all showed an increase in cerebral blood flow (Jain, 1996 page 239).
Dr. K.K. Jain states, "Vasoconstriction and reduced cerebral blood
flow do not produce any clinically observable effects in a healthy adult
when pressures of 1.5 to 2 ATA are used. ..The effects of HBO are more
pronounced in hypoxic/ischemic states of the brain. HBO reduces cerebral
edema and improves the function of neurons rendered inactive by ischemia/hypoxia.
The improvement of brain function is reflected by the improved electrical
activity of the brain."
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55 year old female presented with muscle weakness, slurred speech,
memory loss and problems with balance following a stroke.
After completing 43 HBOT sessions, the patient was able to walk
a long distance for the first time, she could climb stairs without
using the handrails, and muscle strength continued to improve.
Overall, she reports 70-75% improvement in symptoms and overall
well-being since starting treatments
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