 |
Description  |
|
|
BACKGROUND OF THE INVENTION
Cerebrovascular accident, a disease commonly known as "stroke" remains a
leading cause of death and probably constitutes the single largest
category of long term disability in this country. In spite of current
medical knowledge and available treatments, a major central nervous system
vascular occlusion is attended by irreversible damage to the affected
brain region(s). A "completed stroke" is manifest by a fixed and permanent
neurological deficit. Millions of dollars have been expended in stroke
research and care by Federal and private agencies without a single
substantial gain in our present chemotherapeutic abilities for a completed
stroke. On a clinical level, once vascular flow in any portion of the
central nervous system has ceased for longer than a few minutes, a
permanent "stroke" invariably follows. Accordingly, a long felt need
exists to prevent permanent damage and/or reverse neurologic deficits
resulting from interrupted vascular flow.
Over the years, many experiments have been conducted with materials
possessing high oxygen-dissolving properties, many of which have been
incorporated as constituents in "artificial blood". The concept of
utilizing materials possessing high oxygen-dissolving properties for the
maintenance of tissue respiration was first reported by Rodnight in 1954.
See Rodnight, R.; Biochemistry Journal, Vol. 57, pg. 661. Rodnight
capitalized upon the considerable oxygen solubility found in silicone
oils, and sustained tissue slices by incubation in these oxygen laden
oils. Approximately 12 years later, Clark reported experiments involving
the total immersion of small animals in silicone oils and fluorocarbon
liquids. Rats totally immersed in oxygenated silicone oil survived for one
hour with no apparent ill effects, but died several hours after removal,
from unknown causes. Similar experiments using synthetic fluorocarbon
liquids, which dissolve about 3 times more oxygen than do the silicone
oils, were performed with some success. Under these conditions, animals
survived immersion in oxygenated synthetic fluorocarbon liquids and
thereafter returned to apparent health. See Clark, L. C. Jr. and Gollon,
F.: Science, Vol. 152, pg. 1755, (1966); and Gollon, F., Clark, L. C.
Jr.,: Alabama Journal of Medical Science, Vol. 4, Pg. 336, (1967). While
arterial oxygenation was reported as excellent for Clark's studies in
rats, coincident impairment of carbon dioxide elimination was also
reported, as was pulmonary damage from breathing fluorocarbon liquids. One
rat, which was observed for five days following liquid breathing, was
described as being in respiratory distress and as succumbing within 15
minutes after the sub-cutaneous administration of hydrocortisone (50 mg),
with copious loss of body fluid from the trachea. In this regard, Clark
concluded:
These organic liquids should prove to be of value in studies of gas
exchange in living tissues in animals. Organic liquids, since they can
support respiration with oxygen at atmospheric pressure and have other
unique qualities, may find use in submarine escape, undersea oxygen
support facilities, and medical application. The pulmonary damage caused
by the breathing of the organic liquids available at the present time
remains a major complication of their use in man. Science, Vol. 152, pg.
1756.
Following these observations, fluorocarbon liquids were used as an
incubation medium for isolated rat hearts. See Gollon and Clark, The
Physiologist, Vol. 9, Pg. 191, (1966). In this work, myocardial oxygen
requirements were apparently well met, however these hearts did not
flourish without intermittent fluorocarbon removal and washing with
oxygenated, diluted blood. This phenomen has been explained in terms of
aqueous phase lack in pure fluorocarbons such that necessary ionic
exchange is impeded.
More recently, considerable attention has been directed to the use of
fluorocarbons as constituents of artificial blood. Sloviter, in order to
overcome the problem of aqueous-metabolite fluorocarbon insolubility, made
an emulsion with fluorocarbon and albumin. Sloviter's emulsion sustained
the isolated rat brain by a vascular perfusion as well as did an
erythrocyte suspension. See Sloviter, H. A. and T.: Nature (London), Vol.
216, Pg. 458, (1967). A better emulsion was later developed comprising a
detergent, "Pluronic F 68" (manufactured by the Wyandotte Chemical Corp.,
Wyandotte, Michigan), and fluorocarbon liquids which were properly
emulsified using sonic energy. This improved emulsion permitted the
replacement of most of the blood of a rat which was then reported as
surviving in an atmosphere of oxygen for five to six hours. See Geyer, R.
P.: Federation Proceedings, Vol. 29 No. 5, September-October, 1970; and
Geyer, R. P. : Med u Ernohn, Vol. 11, Pg. 256, (1970).
Experiments have also been reported wherein fluorocarbons have been used to
perfuse livers. Ten hours after in vitro fluorocarbon perfusion, the
isolated liver ATP; AMP; lactate/pyruvate ratio; and a number of other
metabolites were found to be as good or better than livers perfused in
vitro with whole blood. See Krone, W., Huttner, W. B., Kampf S. C., et
al.: Biochemika et Biophysica Acta, Vol. 372, Pgs. 55-71, (1974). These
detailed metabolic studies indicated that the organs perfused with 100%
fluorocarbon liquid were redeemed "intact"; while only 75% of the whole
blood infused organs maintained a similar degree of metabolic integrity.
The ability of fluorocarbon perfusion to maintain cellular integrity was
confirmed by electron-microscopy studies. The cells had normal
mitochondrial ultra structure after ten hours of fluorocarbon support,
indicating the persistence of normal or adequate aerobic metabolism.
Fluorocarbons have also been used in experiments involving cerebral blood
circulation. In Rosenblum's studies, mouse hematocrits were reduced to
10-15 by exchanging the animal's blood with a fluorocarbon solution. When
the animals were respired with 100% oxygen after intravascular
fluorocarbon infusions, the brains remained metabolically sound. These
organs were able to reverse rising NADH levels and EEG abnormalities
induced by short period nitrogen inhalation. The EEG's of fluorocarbon
treated animals could be activated by the central nervous system stimulant
metrazole. By these criteria, intravascular fluorocarbon does support the
cerebral microcirculation and provides functions of oxygenation,
metabolism and electrical activity which are normally associated with
blood transport. Please refer to Rosenblum, W. I.; "Fluorocarbon Emulsions
and Cerebral Microcirculation", Federation Proceedings, Vol. 34, No. 6,
Pg. 1493, (May 1975).
As reported by Kontos et al., the marked vasodilation of small cerebral
surface arteries which occurs in response to acute profound hypoxemia may
be locally obviated by perfusing oxygen equilibrated fluorocarbon into the
space under the cranial window. See Kontos, H. A., et al., "Role of Tissue
Hypoxemia in Local Regulation of Cerebral Microcirculation", Americal
Journal of Physiology, Vol. 363, Pgs. 582-591, (1978). Kontos et al.
described the effect of perfusions with fluorocarbon with 100% oxygen as
resulting from increased supplies of oxygen to the neural cells and
consequent partial or complete relief of hypoxia, rather than to a local
increase in the oxygen tension in the immediate environment of the
vascular smooth muscle of the pial arterioles. Two other potential
explanations for the observed action are suggested in the Kontos et al.
article.
In 1977, Doss, Kaufman and Bicher reported an experiment wherein a
fluorocarbon emulsion was used to partially replace cerebrospinal fluid
with the intention of evaluating its protective effect against acute
anoxia. According to this experiment, systemic hypoxia was produced
through one minute of 100% nitrogen inhalation. A bolus of oxygenated
fluorocarbon placed in the cisterna magna immediately prior to nitrogen
breathing increased regional cerebrospinal fluid O.sub.2 tension by a
factor of 5. During the one minute experimental period, the fluorocarbon
emulsion provided twice as much brain tissue oxygen as was found in saline
injected controls. Doss et al. found the anticipated regional tissue
oxygenation decline attending nitrogen inhalation to be halved by the
administration of the oxygen bearing fluorocarbon emulsion.
In spite of the above described experiments, there has yet to be any
reported information of a practical therapeutic approach to the treatment
of ischemic tissue, and particularly human ischemic central nervous system
disease.
SUMMARY OF THE INVENTION
The present invention provides a novel nutrient formulation for circulation
through cerebrospinal fluid pathways, and systems and methods for using
same to treat central nervous tissue hypoxic-ischemic conditions. Through
its use, a new diagnostic methodology is also disclosed.
The cerebrospinal fluid (CSF) pathway system, which intimately bathes and
permeates brain and spinal cord tissues, constitutes a unique anatomical
relationship within the body. Although it has some similarities to
systemic lymphatics, its anatomical arrangement differs considerably from
that of lymph. Indeed, this system has been named the "third circulation".
Due to the extensive area of CSF-tissue contact over the cerebral and cord
surfaces, in the miniature Virchow-Robins spaces, and cerebral ventricles,
the cerebrospinal fluid system constitutes a vast, complex and intimate
therapeutic avenue for access to central nervous tissue. Excepting certain
infections and neoplasms where the cerebrospinal fluid is now utilized as
an a treatment conduit, the cerebrospinal fluid system has not been
otherwise widely exploited as an easily accessible therapeutic route and
has never been used as a continuous therapeutic diagnostic circulation
system in man. The present invention is predicated on the recognition
that, when regional cerebral blood flow is interrupted, such as after
major stroke, or is otherwise seriously impeded by profound vaso-spastic
states, the cerebrospinal fluid pathway actually represents the only
practical and viable anatomical route by which these tissues may be
readily treated. This results from the fact that the usual vascular
delivery system is either occluded or nonfunctional, and thus tissues
within affected territories cannot by properly served.
In accordance with the present invention, essential cellular substrates are
delivered to beleaguered ischemic brains regions by utilizing the "back
door" cerebrospinal fluid delivery route. Accordingly, the present
invention provides a novel nutrient emulsion, circulatory method and
system which provide necessary nutrient penetration into regions suffering
vascular deprivation.
It has been found that the cerebrospinal fluid to brain relationship is not
characterized by the rigid and highly selective barrier mechanisms which
are present at the blood-brain interface. Thus, the penetration rate of
materials from cerebrospinal fluid regions to the brain relate largely to
molecular size, that is, small substances penetrate deeply while large
molecules move more slowly into brain substance. Although entry rates are
generally inversely proportional to molecular weight, penetration is also
influenced by lipid solubility and the molecular configuration of the
penetrating substance. Accordingly, the present invention provides a
nutrient emulsion containing essential brain nutrients including selected
electrolytes, having a relatively low molecular size which, in accordance
with the methods of the present invention, are caused to relatively freely
diffuse from either the ventricular or subarachnoid fluid regions into the
brain matter to be treated. Accordingly, the present invention provides a
novel nutrient emulsion which has been purified, balanced, and perfected
to fall within the narrow physiologic limits while nonetheless providing
the desired nutritional characteristics referred to above.
In accordance with the preferred embodiment of the present invention, this
nutrient emulsion constitutes "synthetic cerebrospinal fluid" comprising
pre-selected electrolytes, glucose, amino acids, at least one
oxygen-carrying component, typically a fluorocarbon, and other components
which impart to the composition a pre-selected pH, buffering capability,
and osmolarity. This nutrient emulsion is prepared by controlling
sonication time and by properly dialyzing the material to achieve a toxic
free emulsion. The resulting solution may be rapidly oxydated to O.sub.2
pressures of 650 mm of mercury by simply bubbling 100% oxygen gas through
at atmospheric pressures. In a covered glass container, the resultant
nutrient emulsion will not appreciably decline in its pO.sub.2 for at
least two hours. As a result, a novel oxygenated nutrient emulsion is
provided which is believed to exhibit exceptional therapeutic properties.
The present invention also provides a novel method and apparatus for
circulating the oxygenated nutrient emulsion through cerebral spinal fluid
pathways, particularly those pathways which contact brain and spinal cord
tissue. According to these methods, treated tissues exhibit a
substantially improved ability to resist and/or repair damage which would
otherwise result from vascular occlusion. In accordance with the preferred
method of the present invention, the novel oxygenated nutrient emulsion is
circulated through this cerebrospinal fluid route by injecting it into
brain ventricles and withdrawing it from the cisterna magna (as shown in
FIG. 1, via withdrawal means 30) or the spinal subarachnoid space (as
shown in FIG. 1, via withdrawal means 30b) to nourish and to treat central
nervous tissues. In other instances the fluid may be injected into the
subarachnoid space and withdrawn from another subarachnoid position (as
shown in FIG. 2). The preferred embodiment oxygenated nutrient emulsion
should be circulated to tissues to be treated in amounts sufficient to
provide adequate gas exchange. Pure fluorocarbon may contain 50 ml O.sub.2
per 100 ml at one atmosphere oxygen while normal blood contains only 20 ml
O.sub.2 /100 ml under the same conditions. The oxygen carrying capability
per ml of the final emulsion is considerably less than that of pure
fluorocarbon by reason of its content of other constituents for
normalizing osmotic pressure, buffering, eletrolytes, and other
physiologic balancing materials. Thus, the preferred embodiment nutrient
emulsion may be charged with oxygen (100% O.sub.2 at one atmosphere) to
attain pO.sub.2 tensions of 650-700 ml of mercury and an O.sub.2 content
of 20 ml per 100 ml. Under rapid circulation conditions, the integral
O.sub.2 exchange (fluorocarbon to tissue) had been found to be about 50%.
Thus, an oxygen exchange value of ten (10) O.sub.2 /100 ml nutrient
emulsion is provided by the present method.
In accordance with the preferred embodiment of the present invention,
sufficient nutrient emulsion should be supplied to counteract oxygen
deprivation to the affected tissue. For example, the entire supertentorial
adult cat brain weighs 12 grams (plus or minus 2) and the normal metabolic
consumption of oxygen of the cat brain equals 3-4 ml per 100 grams per
minute. This total metabolic need may be met with the circulation rate of
6-8 mls per minute. Metabolic needs necessary to simply sustain and/or
salvage tissue can be achieved by perfusion rates of one half or less of
this optimum. Within these constraints an easily achieved sustenance flow
rate of 20 ml/minute would be anticipated to salvage 100 gms of human
brain tissue. It has been found experimentally that it is possible to
supply sufficient oxygen to counteract the deprivation of the affected
tissue through circulation of the nutrient emulsion through the
cerebrospinal fluid route. In fact, under carefully controlled conditions,
it is believed within the scope of the present invention to nourish the
entire human brain using the preferred embodiment apparatus, method and
substance of the present invention. In this manner, central nervous
neurons deprived of major blood supply may be sustained without
significant damage.
In accordance with the preferred embodiment of the present invention, a
novel system is disclosed for administering and maintaining the oxygenated
nutrient emulsion for delivery and circulation through the cerebrospinal
route.
The preferred embodiment system of the present invention effectively
carries out the circulation and equilibration of the nutrient emulsion
during treatment. This system, which is diagrammatically illustrated in
FIG. 1, generally comprises a reservoir containing nutrient emulsion;
means for delivering the nutrient emulsion at pre-selected flow rates; an
oxygenation means for equilibrating the nutrient emulsion to desired
gaseous tension levels; heat exchanger and/or cooling unit means for
selectively controlling the temperature of the nutrient emulsion;
filtering means for cleansing the nutrient emulsion; and circulation
monitoring means for insuring that desired circulation flows and pressures
are maintained within the system.
The present invention also provides a method of diagnosing conditions of
neurologic tissue in mammals. This novel method generally comprises
providing an artificial spinal fluid of known composition, injecting that
artificial spinal fluid into at least a first portion of the cerebrospinal
pathway of a mammal, withdrawing a diagnostic fluid from a second portion
of that pathway to create a circulation of fluid at least through a
portion of said pathway, monitoring the composition of said diagnostic
fluid, and comparing for at least a selected difference in the
compositions of said artificial spinal and diagnostic fluids, whereby the
detected differences in those compositions are at least diagnostic of
neurologic tissue disposed along said portion of the cerebrospinal
pathway. In accordance with the diagnostic methods of the present
invention, the diagnostic fluids may be monitored for differences in
oxygen content, lactic acid concentration, carbon dioxide concentration,
potassium and/or sodium ion concentration, enzyme concentration, pH
difference, ammonium concentrations, GABA (gamma-aminobutyric acid) and
other amino acid(s) concentrations, microorganism content, bacterial
count, myelin fragments, cellular fragments or organelles, malignant
cells, and/or poisons.
It is also within the scope of the present invention to provide a novel
nutrient liquid and/or diagnostic liquid for treating cerebrospinal tissue
containing various novel specified components which is formulated using
novel methodology.
It is additionally within the scope of the present invention to provide a
novel apparatus for treating patients having ischemic-hypoxic tissues,
including novel injection means (20a or 30a) and withdrawal means (30, 30b
or 30c) comprising a novel catheter means which is particularly adapted
for injecting oxygenated nutrient liquid into a cerebral ventricle without
danger of substantially damaging neurologic tissue in the vicinity of that
ventricle.
In addition to the methods described above, it is within the scope of the
present invention to provide additional therapeutic agents to the nutrient
emulsion, such as antineoplastic agents; antibiotics, and/or other
therapeutic agents for use in treating the target tissue(s).
Accordingly, the primary object of the present invention is the provision
of a method, substance, and system for providing early stroke treatment.
Other objects of the present invention are to provide treatments for brain
and spinal cord injuries, cerebral hemorrhage, cerebral vasospasm,
senility, after general hypoxia and other hypoxic-ischemic related
neurological disorders.
It is a further object of the present invention to provide therapeutic
treatment which may sustain the life of the brain and central nervous
system tissues in case of profound shock and/or temporary
cardio-respiratory failure.
It is a further object of the present invention to provide life-sustaining
support to the brain and/or spinal cord tissues during the conduct of
neurological or cardiovascular surgery.
Other objects of the present invention are the provision of methods which
may compliment treatments of central nervous system neoplasms by either
external radiation and chemotherapy by providing local tissue
hyperoxygenation or drug which may enhance drug or radiation tumorocidal
effects.
Further objects of the present invention include the provision of methods
which are useful in treating anoxic states attending birth injury. The
present method will also assist in removal of central nervous system
poisons.
These and other objects of the present invention will become apparent from
the following more detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a diagrammatic view of the preferred embodiment treatment system
of the present invention illustrating the circulation of nutrient emulsion
from a reservoir, into a cerebral ventricle, such as a lateral ventricle,
through a portion of the cerebrospinal fluid pathway for output from the
spinal subarachnoid space or from the cisterna magna.
FIG. 2 is a diagrammatic view of a portion of the preferred embodiment
treatment system of FIG. 1 illustrating an alternate circulation route
wherein oxygenated nutrient emulsion is injected into the spinal
subarachnoid space and is collected from the cisterna magna;
FIG. 3 is a diagrammatic view of a portion of the preferred embodiment
treatment system illustrated in FIG. 1 showing an alternate circulation
route wherein oxygenated nutrient emulsion is injected into the cisterna
magna for passage through the spinal subarachnoid space for withdrawal
from a lumbar region.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the following more detailed description, numerous examples have been
selected for the purpose of explanation and illustration of the preferred
embodiments of the present invention. One of ordinary skill in the art
will readily recognize that numerous substitutions or alterations from the
examples set forth may be made without departing from the spirit of the
present invention, which is defined more particularly in the appended
claims.
Referring now to FIG. 1, the preferred system for circulating nutrient
emulsion through a cerebrospinal pathway is diagrammatically illustrated.
As shown in FIG. 1, a nutrient emulsion reservoir 10 is provided for
receiving and retaining nutrient emulsion, the preparation of which will
be described more fully hereinafter. In accordance with the preferred
system and method of the present invention, the nutrient emulsion is
injected into a cerebrospinal pathway following pH adjustment and
filtering, temperature adjustment, oxygenation, and adjustment of the
pressure and flow rate of the nutrient input stream 19. In FIG. 1, these
steps are illustrated diagrammatically at 12, 14, 16 and 18 respectively.
Preferably, the nutrient input stream 19 is delivered to a ventricle of
the brain, and more particular to a lateral ventricle 20 of the human
brain designated generally 22. Injection of the nutrient input stream
permits the oxygenated nutrient emulsion to come into contact with the
subarachnoid spaces, miniature Virchow-Robins spaces, cerebral and cord
surfaces, and cerebral ventricles. For the system illustrated in FIG. 1,
the nutrient input stream 19 is diagrammatically illustrated as being
injected into a lateral ventricle 20. Since the lateral ventricle is in
fluid communication with other portions of the cerebrospinal pathway, the
withdrawal of fluid from a portion of the pathway which is remote from
that ventricle will create a circulation of fluid within the cerebrospinal
pathway. More particularly, circulation of the nutrient input stream
through at least a portion of the cerebrospinal pathway may be
accomplished by withdrawing fluid (via withdrawal means 30c) from the
spinal subarachnoid space, diagrammatically illustrated as 26 in FIG. 1,
or alternatively, from the cisterna magna 24 (via withdrawal means 30 or
30b).
As illustrated in FIG. 1, circulation of fluid through the cerebrospinal
pathway is intended to permit the treatment of at least cerebral tissues.
It is within the scope of the present invention, however, to focus
treatment on selected neural tissue areas, in which case alternative
points of injection and withdrawal of fluid may be selected by the
attending physician. For example, in the case of spinal cord injury, it is
anticipated that the point of injection of oxygenated nutrient emulsion
may preferably be in the lumbar, spinal subarachnoid space, with the point
of withdrawal being at the cisterna magna. See FIG. 2. While the above
mentioned cerebrospinal pathway injection and withdrawal points are
preferred, it is within the scope of the present invention to utilize
other injection and withdrawal locations, provided a substantial
circulation of fluid through the area of affected neurologic tissue is
established by utilizing the selected loci. As shown in FIG. 3, injection
via injection means 30a into the cisterna magna and withdrawal via
withdrawal means 30c from the spinal subarachnoid space is also possible.
The preferred injection means of the present invention comprises a cerebral
catheter means 20a for insertion into a brain ventricle. This injection
means comprises means for preventing a portion of the catheter located
within a brain ventricle from damaging tissues surrounding the ventricle.
In the preferred embodiment, an inflatable balloon tip may be provided for
this purpose. The actual injection of nutrient emulsion into the brain
ventricle is accomplished by providing an arrangment of the outlet holes
disposed as series of slits radially spaced around the catheter tip. Both
the injection means and withdrawal means also further comprise attachment
means for attaching the catheter to the body in the vincinity of the
injection or withdrawal sites. Thus the injection catheter may comprise a
means for fixing at least a portion thereof with respect to the skull to
insure catheter stability. The withdrawal catheter, which may have a tip
with multiple perforations disposed therein, further comprises means for
attaching at least a portion thereof to tissue in the region of the
subarachnoid space. This attachment means may include a staple for
attaching a non-collapsible portion of the catheter to a lumbar region of
the skin.
It is not anticipated that the fluid which is withdrawn from the
cerebrospinal pathway at the point of withdrawal will be identical in
composition to the oxygenated nutrient emulsion which is injected at the
injection point. By taking advantage of differences in composition which
are detected in the withdrawn fluid, which may be considered to be a
diagnostic fluid, the attending physician may easily monitor the
physiologic condition of the neurologic tissue which is being treated.
This diagnostic fluid may also be monitored to assure that treatment is
proceeding according to plan. Accordingly, fluid which is withdrawn from
the cerebrospinal pathway is directed to an output collection means 28 for
collecting diagnostic fluid. Preferably, an output monitor 34 will
continuously monitor various chemical and physical characteristics of the
diagnostic fluid for such properties as flow rate, hydraulic pressure,
potassium and sodium ion temperature, lactic acid concentration, gamma
amino butyric acid and other amino acid concentrations, oxygen
concentration, carbon dioxide concentration, enzymes, and ammonia
concentration. The output of this output monitor will not only provide the
attending physician with information concerning the state of the
cerebrospinal tissue being treated, but also will be fed back to the
monitor, control and alarm systems for at least pressure and flow rate,
temperature, oxygen-carbon dioxide and chemical constituency, as described
more fully hereinafter. This diagnostic system takes advantage of the fact
that ischemic neurologic tissue produces higher concentrations of such
materials as Gamma-aminobutyric acid (GABA), lactate ion (lactic acid),
enzymes and/or LDH (lactic dehydrogenase), ammonia, and other constituents
which have been determined by analyzing cerebrospinal fluids of patents
subjected by disease to similar anoxic conditions.* In accordance with the
system of the present invention, however, a continuous monitoring of the
state of neurologic tissue is possible, since the circulation of
oxygenated nutrient emulsion will produce a continuous flushing of the
affected tissues regions, and thus will result in diagnostic fluid
component variations which are rapidly reflective of the physiologic state
of the tissues being treated. Due to the multi-point injection-withdrawal
method of the present invention, dangers which are inherent in sampling
natural cerebrospinal fluid at a single location are avoided by utilizing
a double venting method wherein the cerebrospinal fluid pressure is at all
times carefully controlled.
*See for example, "Rapid and Sensitive Ion-Exchange Fluorometric
Measurement of G-Aminobutyric Acid in Physiological Fluids", Hare et al.,
Anal. Biochem., Vol. 101, 349-355 (1980) for a preferred GABA measurement
method.
It is within the scope of the present invention to sterilize and
reconstitute that diagnostic fluid as shown at step 32, whereupon that
reconstituted diagnostic fluid may be provided as nutrient emulsion to the
nutrient emulsion reservoir 10. As shown in FIG. 1, the output monitor 34
may monitor the diagnostic fluid during the sterilization and
reconstitution processes and, if desired, ensure that the reconstituted
fluid satisfies the requirements of the nutrient emulsion reservoir. As
shown in FIG. 1, in order to ensure that appropriate degrees of
oxygenation, filtration and chemical balancing, temperature adjustment,
and pressure and flow rate are maintained, the nutrient input stream is
monitored by various monitors, controls, and alarms, which are intended to
provide a fail safe nutrient input stream. In particular, a pressure and
flow rate monitor, control and alarm 38 is provided for monitoring the
pressure and flow rate of the nutrient input stream, for controlling the
pressure and flow rate adjustment 18 to establish desired pressures and
flow rates, and for sounding an alarm in the event that the nutrient input
stream exceeds or falls below preselected pressures or flow rates. If
desired, this alarm may additionally disable the pumping mechanism
producing flow of the nutrient input stream such that the unit "shuts
down" upon detection of unacceptable input stream conditions.
Referring now to the temperature monitor, control and alarm, the
temperature characteristics of the nutrient input stream are similarly
detected, at least to ensure that hyperthermic states except when used as
therapeutic modality are avoided. While in most instances, the nutrient
input stream will be adjusted to a 37.degree. C. temperature, it may be
desired to select hypothermic temperatures in order to establish certain
treatment conditions. In either event, the temperature monitor will
continuously detect the temperature of the input stream, will control the
temperature adjustment 14 to establish a preselected temperature, and will
sound an alarm and/or disable the system in the event that a preselected
temperature range is not maintained in the nutrient input stream.
Referring now to the chemical monitor, control and alarm 42, the nutrient
input stream will be continuously monitored for one or more chemical or
physical characteristics of the nutrient input stream, and will control
the chemical balancing, filtration, etc. which is performed by the
filtration and chemical balancing unit 12. The chemical monitor, control
and alarm may, for example, monitor the pH, osmolarity, electrolyte
component, carbohydrate component, amino acid component, or other
components of the nutrient emulsion to ensure that the nutrient input
stream falls within preselected stream characteristics. In the event that
these characteristics do not fall within the preselected range, the alarm
for unit 42 may sound and/or may disable the system to thereby prevent
further injection of nutrient input stream into the cerebrospinal pathway.
Finally, an oxygen/carbon dioxide monitor, control and alarm unit 36 is
provided which continuously monitors the oxygen and carbon dioxide
contents of the nutrient input stream, which controls the oxygenation unit
16, and which sounds an alarm in the event that the oxygen or carbon
dioxide concentrations do not fall within preselected ranges. It is
anticipated that each of units 36-42 may provide continuous displays of
the information monitored from the nutrient input stream, and may, if
desired, enable back-up units which either manually or automatically may
supplement or replace the functions of units 12-18 in the event that those
units are not functioning to produce a nutrient input stream within the
desired ranges. For example, it is anticipated that a manual or battery
operated pump, oxygenator, filter, and pressure and flow rate adjustments
will be provided to enable emergency operation of the system, since
continual nutrient flow is lifesaving for the devitalized portion of the
treated organ.
The preferred nutrient emulsion of the present invention is comprised of
carefully formulated components which, to the extent possible while
maintaining desired therapeutic activity, mimic the physical and chemical
characteristics of natural cerebrospinal fluid. Generally, tissues and
cells will not fair well if exposed to large volumes of non-physiologic
ionic solutions. Accordingly, it has been recognized that appropriate
electrolyte compositions at the tissue level are indispensable when it is
considered that the circulatory method of the present invention would
otherwise result in the washing and the dilution of electrolytes from the
region even after short terms of circulation, to the detriment of cell
membrane functions. Accordingly, in accordance with the preferred
embodiment of the present invention, sodium, potassium, calcium,
magnesium, and chloride ions are carefully balanced in the nutrient
emulsion of the present invention to thereby create, to the degree
possible, normal extra-cellular compositions. The present invention also
provides a non-aqueous oxygen transfer component for selectively combining
with oxygen and for transferring oxygen to the tissues to be treated.
Numerous compounds are known to the art which are characterized by having
a high solvent property for oxygen, carbon dioxide, and other gases. The
preferred non-aqueous oxygen transfer component of the preferred nutrient
liquid should exhibit when so charged, oxygen vapor pressure ranges of
above 400, and preferably 600, Torr. Such oxygen transfer components
should similarly not have in themselves high vapor pressures which would
boil at body temperatures, nor have viscosities which are difficult if not
impossible to emulsify. Generally, the preferred compounds for use as
non-aqueous oxygen transfer components are fluorocarbon polymers, such as
perfluorocarbons, perfluorinated alkyl polyethers, fluoroethers,
fluoroamines, etc. While compounds within these groups range in molecular
weight from 250 to 7000, their selection for use as non-aqueous transport
components are based upon the combination of features of the proper vapor
pressure, molecular weight, viscosity, emulsifiability, emulsion-stability
and tissue distribution. One such fluorocarbon which has been found to be
particularly suited for the non-aqueous oxygen transport component of the
preferred nutrient liquid is a compound sold by the 3-M Corporation under
the trademark "FC-80". FC-80 has an oxygen solubility coefficient
ScO.sub.2 of 0.45 of ml O.sub.2 /ml at pO.sub.2 of 760 Torr. See Navari et
al., Res. Exp. Med., 170:169-180 (1977), which paper is specifically
incorporated by reference as if fully set forth herein. It should be noted
that whole blood under the same circumstances contain | | |
