U.S. patent number 3,776,241 [Application Number 05/171,575] was granted by the patent office on 1973-12-04 for system and method for controlling vascular responses.
This patent grant is currently assigned to Iowa State University Research Foundation, Inc.. Invention is credited to James H. Magilton, Curran S. Swift.
United States Patent |
3,776,241 |
Magilton , et al. |
December 4, 1973 |
SYSTEM AND METHOD FOR CONTROLLING VASCULAR RESPONSES
Abstract
A method and a system are disclosed for producing changes in
systemic arterial blood pressure, cerebrospinal fluid pressure and
heart rate; as well as producing selective brain hypothermia in
animals by irrigating the nasal mucosa.
Inventors: |
Magilton; James H. (Ames,
IA), Swift; Curran S. (Ames, IA) |
Assignee: |
Iowa State University Research
Foundation, Inc. (Ames, IA)
|
Family
ID: |
22624277 |
Appl.
No.: |
05/171,575 |
Filed: |
August 13, 1971 |
Current U.S.
Class: |
607/105 |
Current CPC
Class: |
A61F
7/00 (20130101); A61F 7/12 (20130101); A61M
19/00 (20130101); A61B 2017/00084 (20130101) |
Current International
Class: |
A61F
7/12 (20060101); A61F 7/00 (20060101); A61M
19/00 (20060101); A61B 17/00 (20060101); A61f
007/00 () |
Field of
Search: |
;128/400,303.1,401,2H |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
J N. Hayward et al.-Brain Research, 16 (1969), pp. 417-440 .
J. H. Magilton et al.-Journal of Applied Physiology-Vol. 27, No. 1,
p. 18 .
J. H. Magilton et al.-The Physiologist, Vol. 10, No. 3 -Aug. 1967,
p. 241.
|
Primary Examiner: Trapp; Lawrence W.
Claims
We claim:
1. A system for controlling the temperature of the brain of an
animal comprising temperature sensitive means sensing the
temperature of blood the angularis oculi vein of said animal for
generating a signal representative of said temperature; circuit
means receiving said signal for generating a signal representative
of a difference between the temperature in said angularis oculi
vein and a reference temperature; a source of fluid; means for
controlling the flow rate of said fluid responsive to said error
signal; timing circuit means for inhibiting said control for a
predetermined time sufficient for a change in said flow rate to be
sensed by said temperature sensitive means; and means for directing
said cooled gas against the nasal mucosa of said animal.
2. The apparatus of claim 1 wherein said fluid is a gas and further
comprising means for humidifying said fluid gas.
3. The system of claim 1 further comprising means for introducing a
local anesthetic into said fluid stream to apply said anesthetic to
said nasal mucosa.
4. Apparatus for controlling the brain temperature of an animal
comprising: temperature sensitive means adapted for placement in
close proximity to the angularis occuli vein of the animal for
generating a signal representative of the temperature of the venous
blood in said vein flowing from the nasal mucosa; means including a
source of fluid cooled below the normal temperature of said venous
blood and adapted to direct said fluid against the nasal mucosa of
the animal, said means further including control means for
controlling the flow rate of said fluid; circuit means receiving
said temperature signal for driving said control means to vary the
flow rate of said fluid to effect a desired temperature in said
venous blood, said circuit further including means for delaying the
driving of said control means in response to a sensed temperature
for a period of time between the application of said fluid and
sensing of the corresponding change in temperature sensed by said
temperature sensitive means.
5. The apparatus of claim 4 wherein said fluid is a gas and further
comprising means for adding an anesthetic to said gas prior to
contacting said nasal mucosa; and means for adding humidity to said
gas after cooling the same and prior to contacting said nasal
mucosa.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method and system for producing:
1) cardio-vascular changes; and 2) selective brain hypothermia in a
mammal in response to irrigating the nasal mucosa with water at
variable temperature levels.
It has been suggested that the hazards of cardio-vascular surgery
and cerebral edema following brain trauma would be greatly reduced
if the temperature of the brain were reduced within controlled
limits. Three reasons for this suggestion are that: (1) oxygen
consumption in the brain decreases almost linearly with lowering of
the temperature under controlled conditions; (2) cerebral blood
flow and mean systemic arterial blood pressure decrease while
cerebrovascular resistance increases with hypothermia; and (3)
cerebral blood flow and brain volume change in the same direction.
This hypothermia would reduce the blood flow to the brain, thereby
reducing brain volume, and increase the tolerance of the brain to
hypoxia.
An early method of reducing the temperature of the brain included
circulating a refrigerated solution through a metal capsule (with
connecting tubing) which had been placed in the brain. Total body
hypothermia, as an indirect means of cooling the brain, replaced
this early method. Total body hypothermia has cetain disadvantages
including the need for a large amount of equipment to maintain the
low temperature, and the tendency of the heart to go into
fibrillation at low body temperatures. Attempts have been made,
therefore, to produce selective brain hypothermia--that is,
lowering of the brain temperature without lowering the temperature
of the rest of the body significantly. One suggested method of
selected brain hypothermia is to cool the esophagus, as reported in
the technical documentary port No. SAM-TDE-63-19 of the USAF SCHOOL
OF AEROSPACE MEDICINE, Aerospace Medical Division, Brooks Air Force
Base, Texas. Attempts have also been made to achieve selective
brain hypothermia by cooling blood destined for the head in an
"extra-corporeal" cooling system. The objections to this approach
have caused it to be abandoned. At present there is no surgical
technique to our knowledge that is commonly accepted for the
selective inducement of brain hypothermia.
2. Published Work
An abstract of a paper given by us was published in The
Physiologist, Vol. 10, No. 3, August, 1967, in which we reported
achieving cooling of the brain of the canine by irrigating the alar
folds of the maxilloturbinates with water having a temperature of
12.0.degree. C. We reported that the venous blood passing from the
alar folds into the cavernous sinus cooled the arterial blood
passing to the brain by way of the latter sinus. This arterial
blood absorbed heat from the brain after passing through components
of the circle of Willis and their distributing vessels. We
postulated at the time of this work that two separate heat exchange
mechanisms were involved -- one, which we called the external heat
exchange system, is located in the alar fold of the
maxilloturbinate and cools blood which flows into the cavernous
sinus by way of the angularis oculi vein, and the second, which we
called the internal heat exchanger, is in the cavernous sinus where
heat is transferred from the warm arterial blood destined for the
brain to the cooler venous blood in the cavernous sinus.
In a subsequent article of Hayward and Baker entitled "A
Comparative Study of the Role of Cerebral Arterial Blood in the
Regulation of Brain Temperature in Five Mammals," published in
Brain Research, Vol. 16, p. 417, work was reported in this area on
different species of mammals, and as a result, the authors
classified their subjects into two broad categories: (1) those of
the "internal carotid" artery type which includes the monkey and
the rabbit and is characterized by having a single large vessel
passing through the cavernous sinus thereby providing a flow
pathway from the common carotid artery to the circle of Willis; and
(2) the "carotid rete" type which is characterized by having more
than one communicating vessel from the common carotid artery to the
circle of Willis: 1) via the cavernous sinus as in the dog and
sheep; and 2) in close proximity to a venous plexiform network in
cats.
Based on their experiments, these researchers concluded that heat
exchange occurs between the cooler venous blood in either the
cavernous sinus (for the dog and sheep) or the venous plexiform
network (in the case of the cat) and the warmer arterial blood only
in those animals of the "carotid rete" type. Further, these
researchers believed themselves to have demonstrated that for
animals having a single internal carotid artery conducting blood
through cavernous sinus, there was no heat exchange at the base of
the brain. These studies concluded that this was a major difference
between the two classifications.
The results of our further experimental work on the physiological
heat exchange systems for controlling the brain temperature of a
dog are reported in an article appearing in the IEEE Conference
Record, Fifth Annual Rocky Mountain Bioengineering Symposium
entitled "Description of Two Physiological Heat Exchange Systems
for the Control of Brain Temperature" and in an article published
in the Journal of Applied Physiology, Vol. 27, No. 1, p. 18,
entitled "Response of Veins Draining the Nose to Alar-Fold
Temperature Changes in the Dog."
SUMMARY
As a result of our experimentation, including work performed on
horses which have a single large carotid artery leading from the
common carotid artery and passing through the cavernous sinus to
the circle of Willis, we believe we have demonstrated that
selective brain hypothermia can be induced by irrigating the nasal
mucosa of animals with a single internal carotid artery as well as
those with a carotid rete with cold water. As a result of further
experimentation with dogs, we have been able to induce changes in
cerebrospinal fluid pressure, systemic blood pressure, and heart
rate by irrigating the nasal mucosa. That is, we have been able to
selectively increase the cerebrospinal fluid pressure, systemic
blood pressure and heart rate by irrigating the tip of the nose
with hot water; and we have produced reductions in cerebrospinal
fluid pressure, systemic blood pressure and heart rate by
irrigating the tip of the nose with cold water. Thus, we believe we
have demonstrated a method of controlling blood flow to the brain
of a mammal. While not limiting the effect of our invention, we
postulate that there are two principal physiological mechanisms or
systems which have a bearing on the brains's temperature. One such
system we call the venous temperature control system; and it
regulates the cooling of the venous blood destined for the
cavernous sinus. The second system we call the cardio-arterial
control system; and it acts in a manner to assist the venous
temperature control system in regulating brain temperature. That
is, when the venous control system has reached the limits of its
capability to cool the venous blood, the cardio-arterial system
will further influence the rate of heat exchange occurring between
arterial and venous blood in the cavernous sinus by apparently
altering arterial blood flow through the sinus. We believe the
arterial flow through the cavernous sinus will be altered as a
result of the changes in heart rate, systemic arterial pressure and
cerebrospinal fluid pressure which we have demonstrated in our
work.
When the regulatory effects of both of these physiological systems
are overridden by irrigating the nasal mucosa with a medium of
adequate cold temperature one can induce selective brain
hypothermia and hence alter the flow of cerebral arterial
blood.
Although the invention is not so limited, some of the clinical
applications, as alluded to above, include selectively reducing the
temperature of the brain without causing corresponding low
temperatures in the remainder of the body. This has an advantage in
heart surgery due to the fact that the oxygen requirement of the
brain is reduced linearly with reduction in brain temperature.
Therefore longer interruptions in cerebral blood flow can be
tolerated. In addition, the heart can be maintained at near normal
body temperature which reduces the propensity of this organ to go
into fibrillation when manipulated in surgery.
Other features and advantages of the present invention will be
apparent to persons skilled in the art from the following detailed
description of a preferred embodiment accompanied by the attached
drawing wherein identical reference numerals will refer to like
parts in the various views.
THE DRAWING
FIG. 1 is a pictorial diagram of the head of a subject dog showing
the irrigation of the nose and the placement of temperature sensors
on the angularis oculi veins.
FIG. 2 is a graph illustrating changes in cerebrospinal fluid
pressure and arterial blood pressure resulting from the
irrigation;
FIGS. 3A-3G are graphs illustrating the various vascular responses
during irrigation; and
FIG. 4 is a block schematic diagram of a system for use in the
practice of the present invention.
DETAILED DESCRIPTION
We have shown in our laboratory that temperature alone can produce
changes in the cardio-arterial system of animals which appear to
vary cerebral blood flow and cerebral temperature in a manner that
has not been reported elsewhere. The cardio-arterial changes are
seen as a change in systemic arterial blood pressure (ABP),
cerebrospinal fluid pressure (CSFP) and heart rate (HR). These
cardio-arterial changes were induced by changing the temperature of
the venous blood destined for the cavernous sinus by irrigating the
alar fold of the maxilloturbinate. These cardio-arterial changes
were such as to indicate that an increase in cerebral blood flow
occurred when the temperature of the nasal mucosa was increased by
irrigation with warm water; and a decrease in cerebral blood flow
was indicated when the nasal mucosa was irrigated with cold water.
Further, these cardio-arterial changes appear to be brought about
by an autonomic reflex uniquely responsive to temperature. That is,
the usual response to autonomic manipulation is such as to maintain
a constant cerebral blood flow; whereas the autonomic response to
the temperature changes we employed appears to have altered
cerebral blood flow (heat making the flow increase and cold making
it decrease). Furthermore, these cardio-arterial changes have
occurred independently of carbon dioxide, oxygen and pH levels of
the arterial blood, as has already been reported.
We believe that brain temperature regulation is accomplished
through the agency of two systems. The first system provides for
irrigating or circulating the surface of the nasal mucosa (more
specifically, the alar fold of the maxilloturbinate) with an
external media such as water, air or other gas. A portion of this
temperature conditioned blood flows to the cavernous sinus where it
baths arteries which conduct blood to the brain. In our early work
this system was referred to as the "external heat exchange
mechanism"; in our present work it is referred to as the venous
temperature control system (VTCS). The second system involves
control of the blood flow in the arteries just mentioned which are
being bathed in the venous blood in the cavernous sinus which, in
turn, has been temperature conditioned at the site of the external
heat exchange mechanism. In our early work this system was referred
to as the "internal heat exchange mechanism"; in our present work
it is referred to as the cardio-arterial control system.
VENOUS TEMPERATURE CONTROL SYSTEM
Intracerebral temperature gradients are basically dependent upon
the rate of removal of heat from the brain by arterial blood. This
arterial blood is cooled by the flow of heat from the arterial
blood to venous blood in the cavernous sinus. The temperature of
the venous blood, in turn, is regulated by what is referred to
herein as the venous temperature control system (VTCS). This system
functions in two ways. The first includes a transfer of heat from
the vessels in the nasal mucosa (that is, the alar fold of the
maxilloturbinate) to the irrigating water or circulating air or
other gas. The second manner in which the venous temperature
control system works is to regulate the differential blood flow
from the vessels in the nasal mucosa via the dorsal nasal veins to
the angularis oculi veins on the one hand, and the facial veins on
the other hand. The blood entering the angularis oculi veins flows
through the ophthalmic veins to the cavernous sinus where it baths
arterial blood destined for the brain. The blood entering the
facial veins bypasses the cavernous sinus.
We have established through experiments the existence of a feedback
control pathway from the brain to the venous temperature control
system. We selected man as the experimental subject in an attempt
to demonstrate this feedback control. The reasons we selected man
were: (1) the anatomical arrangement of the necessary structures is
similar to that in the dog; (2) the subjects would be fully
cooperative and would be able to perform precise mental tasks; and
(3) previous experimental work (5) has shown that mental activity
increases metabolic rate which, in turn, increases heat production.
As a result of our work, physiological evidence that the venous
temperature control system is involved in brain temperature
regulation was shown. It was found that mental activity
(subtracting from 5000 by sevens as fast and accurately as
possible) was accompanied by adjustments in the venous temperature
control system which resulted in changes in the temperature of the
angularis oculi veins (the assumption is made that an increase in
metabolism in an organ is accompanied by an increase in the
temperature of the organ).
Further evidence pointing to the involvement of the venous
temperature control system in brain temperature regulation was seen
in the unanesthetized sheep where an increase in the temperature of
the reticular formation was accompanied by a cooling of the nasal
mucosa. In this case an increase in the temperature of the
reticular formation was shown to occur by direct measurment. The
cooling of the nasal mucosa in synchrony with the temperature
changes occurring in the brain demonstrates the adjusting of the
venous temperature control system to obtain optimum brain
temperature.
There is also evidence that adjustments which occur in the venous
temperature control systems do not depend upon conscious activity.
For example, in dogs under sodium pentobarbital anesthesia,
uniformity was found to be lacking in the shape of the temperature
curves between the angularis oculi and facial veins on the
homolateral side. These variations in temperatures indicate
variations in blood flow in the respective veins, and it is
therefore evident that the homolateral reflex pathways involving
the venous temperature control system are functional under
anesthesia. Additionally, not only are the reflex pathways between
the veins on the homolateral side intact (angularis oculi and
facial) but also, the reflex pathways between veins of the venous
temperature control system on opposite sides are intact and
functional (evidenced by lack of uniformity between the
temperatures of the right and left angularis oculi veins).
These variations in blood flow between the angularis oculi and
facial veins on the same side and between the angularis oculi veins
on opposite sides is considered important because blood entering
the angularis oculi vein enters the cavernous sinus by way of the
ophthalmic vein, whereas blood entering the facial vein passes into
the external maxillary and then into the external jugular vein,
thus bypassing the cavernous sinus. It is evident then that the
blood entering the angularis oculi vein is involved with heat
transfer (consequently brain temperature regulation) between
arterial blood destined for the brain and venous blood in the
cavernous sinus, whereas the blood entering the facial vein is
not.
We have found evidence that autonomic control exists at the level
of the angularis oculi and facial veins not only in the
time-response variation of these veins between cold- and hot-water
irrigation as will be discussed, but also in the response of the
angularis oculi veins to the clamping of the facial veins.
The mode of action of the autonomic innervation to the vessels in
the venous temperature control system is considered important
because of the system's involvement with brain temperature
regulation, as previously mentioned. In this regard, the nasal
vessels possess unique neural characteristics which indicate that
their response to the autonomic stimulation is different from the
responses of vessels in other parts of the body of autonomic
stimulation. For example, there is reason to believe that the
frequency of sympathetic impulses necessary to maintain vascular
tonus and to mediate reflex vasoconstriction is different in the
nasal vessels than in vessels in other parts of the body. If this
is the case, then the sympathetic nervous system could exert
differential control over the nasal veins on the one hand and the
dorsal nasal, angularis oculi, and facial veins on the other hand,
by means of variation in the impulse frequency.
Another example of the uniqueness of neural characteristics of
arteries and veins in the nasal passage is that adrenergic
receptors cannot be physiologically demonstrated in them. This
means that in situations of high emotional stress, accompanied by
adrenergic dominance, the only response attainable is constriction
of the arteries and veins in the nasal passage. This agrees with
work done by others wherein adrenalin was injected intravenously
and produced a marked constriction of the vessels lining the nasal
passage. This constriction results in less cooling of the venous
blood in the venous temperature control system due to a reduction
in the rate of heat transfer occurring from the vessels to the
ambient air.
If the assumption can be made that emotional stress situations are
often accompanied by an increase in heat production in the brain
due to an increase in mental activity, then a situation could
develop during emotional stress where an increase in brain
temperature would be accompanied by a decrease in the efficiency of
the cooling system for the brain.
As already mentioned, we believe that brain temperature regulation
is accomplished by the interaction of two systems: (1) cooling of
venous blood destined for the cavernous sinus (the venous
temperature control system described previously) and (2) control of
the cerebral blood flow through the cavernous sinus by a
cardio-arterial control system. The more efficient the venous
temperature control system is, the less the cardio-arterial control
system will have to alter cerebral blood flow in order to obtain
optimum brain temperature. Some of the conditions which will
determine the efficiency of the venous temperature control system
are: (1) environmental temperature, (2) environmental humidity, and
(3) nasal respiratory rate and amplitude, and (4) emotional
stress.
If the ambient temperature is excessively high, heat transfer from
the nasal vessels to the inhaled ambient air is reduced and
cardio-arterial adjustments occur (i.e., an increase in heart rate
(HR), an increase in systemic arterial pressure (ABP), and an
increase in cerebrospinal fluid pressure (CSFP)), which are
evidence of an increase in cerebral blood flow. The opposite
cardio-arterial adjustments occur when the temperature is
excessively low. In further explanation, the venous temperature
control system, by itself, is able to regulate brain temperature as
long as ambient temperature remains within as yet undetermined
limits of heat and cold. Consequently, it is only when these limits
of heat and cold are exceeded that the cardio-arterial control
system comes into play by adjusting cerebral blood flow in an
effort to complement the venous temperature control system. The
role of the cardio-arterial control system, when the heat and cold
temperature limits are exceeded, is that of obtaining optimum brain
temperature regulation. These relationships have been verified by
experimental work conducted in our laboratory. Using running water
to obtain maximum heat transfer both toward the blood in the nasal
vessels (with 42.degree.-50.degree. C water irrigation) and away
from the blood in the nasal vessels (with 15.degree. C water
irrigation), we were able to obtain the cardio-arterial adjustments
to be described below in connection with FIG. 3.
Humidity is another factor influencing the amount of heat transfer
occurring in the venous temperature control system. In this regard,
humidity affects the amount of cooling which occurs on the mucosal
surface. For instance, the higher the humidity, the less the heat
loss occurring from the mucosal surface as a result of evaporation.
For this reason, the limits of ambient heat and cold, beyond which
the cardio-arterial control system comes into play to complement
the venous temperature control system, are partially determined by
humidity. We believe that, under normal conditions, the resultant
loss os efficiency in heat transfer in the venous temperature
control system due to humidity would be compensated for by the
cardio-arterial adjustments pointing toward increasing blood flow
as previously described.
The temperature of the blood in the venous temperature control
system can be lowered by increasing the nasal respiratory rate and
amplitude in man. Also, the CSFP (a part of the cardio-arterial
control system) can be lowered to zero in man by increasing
respiratory rate and amplitude under conditions which make it
unlikely that blood gas levels would completely account for the
reduction. Although different procedures were used, similar results
to those in man, i.e., lowered blood temperature in the venous
temperature control system during respiration and vice versa and
lowered CSFP during deep respirations, were obtained in our
laboratory using the dog. In man the temperature was lowered by
increasing the respiratory rate and amplitude, whereas in the dog
it was lowered by irrigation of the nasal mucosa with 15.degree. C
tap water. In both species it appears that the cold temperature
limit for regulation of brain temperature by the venous temperature
control system had been exceeded thereby activating the
cardio-arterial control system. Also, in both species some degree
of feedback control of the two systems was removed -- in man by
voluntary respirations and in the dog by irrigation under
anesthesia. this assumption was supported by the fact that the
changes in CSFP seen in both species were due to over-cooling of
the venous blood in the venous temperature control system.
The interaction between the venous temperature control system and
the cardio-arterial control system to obtain optimum brain
temperature can be manipulated and changed in useful ways. First,
as a method for inducing differential brain hypothermia, the
temperature of the blood in the venous temperature control system
can be lowered to a level at which not even the cardio-arterial
control system can adequately compensate, and brain temperature is
thereby lowered. Among the clinical benefits accruing from this
differential brain hypothermia are: (a) a decrease in cerebral
metabolic rate allowing for extended vascular interruptions to the
brain; (b) infarction can be prevented or rendered clinically
undetectable when the middle cerebral artery is ligated during
whole body immersion in ice water; and (c) no cellular inflammatory
reaction to injury is noted, and development of cerebral edema can
be suppressed as long as the brain remains cold.
Additionally, these two control systems can be manipulated so as to
reduce cerebral blood flow (along with a decrease in ABP, CSFP, and
HR) as noted during the cooling of the venous blood destined for
the cavernous sinus. This would: (a) facilitate hemostasis during
brain surgery and (b) facilitate surgical procedures by reducing
brain volume and intercranial pressure.
It appears that stimulating the cardio-arterial control system with
temperature invokes a unique autonomic response in the circulatory
system, i.e., increase in ABP (vasoconstriction) and an increase in
CSFP (vasodilatation) with heat, and the opposite ABP and CSFP
responses with cold. This autonomic response to temperature is
unique in that it is not the all-or-nothing response usually seen
with autonomic stimulation, i.e., increase in ABP
(vasoconstriction) and a decrease in CSFP (vasoconstriction) with
epinephrine; and the opposite ABP and CSFP responses with
artificial stimulation of the vagus.
In this regard, it is recognized that alpha and beta adrenergic
receptors make it possible for the adrenergic nerves to dilate
blood vessels as well as to constrict them. However, this dual
response has not be demonstrated for the cholinergic nerves to our
knowledge, consequently vasoconstriction would have to be the
result of adrenergic nerve stimulation. In view of this, the
constriction of cerebral vessels during cold water irrigation of
the nasal mucosa (if due to autonomic stimulation) would have to be
due to adrenergic action. There is definite evidence, on the other
hand, that the adrenergic nerves are not responsible for the
extra-cranial vasodilatation during cold water irrigation (decrease
in ABP). That is, in our laboratory cold water irrigation was
accompanied by excessive lacrimation which is considered to be a
response to cholinergic stimulation.
The all-or-nothing response of the blood vessels to stimulation of
the autonomic nervous system for epinephrine (constriction) and
electrical stimulation of the vagus (dilatation) appears to be for
the purpose of maintaining a constant cerebral blood flow. The
response of the autonomics to the stimulus of temperature applied
to the cardio-arterial control system, on the other hand, appears
to be for the purpose of varying blood flow (increase in ABP, HR
and CSFP from heat indicating an increase in flow; decrease in ABP,
HR and CSFP from cold indicating a decrease in flow).
Turning now to FIG. 1, the nature of our experiments will be
described. The subject is a dog, only the head of which is
illustrated. Resting before the nose of the dog is a base plate
generally designated by reference numeral 10 in which there are
embedded an input lead 11 and a bifurcated output conduit 12
leading into the nose of the dog as illustrated. The input conduit
11 is connected to a source of cool water (not shown) or other
cooled fluid such as air, and the distal ends of the bifurcated
output conduit 12,12 are located adjacent the tip of the dog's nose
and oriented so as to direct a stream of the cool water principally
onto the alar folds of the dog's nose. The pressure of the water
passing through the output conduits 12,12 is only sufficient to
cause an upward flow of water of only a few inches.
Leading from the alar folds of the dog are two angularis oculi
veins, a left and a right vein, which communicates venous blood
from the alar folds into the cavernous sinus of the dog. Placed
adjacent the left and right angularis oculi veins are first and
second thermistors designated respectively 13 and 14, and these are
arranged by means of wires 16 and 17 respectively to monitor the
temperature of the blood flowing in the left and right angularis
oculi veins of the dog.
EXPERIMENTS
Eight dogs weighing from 30-40 pounds were anesthetized and placed
in ventral recumbancy (as illustrated) with the head elevated by
securing the zygomatic arches to a metal rack with bone screws. The
long axis of the head was held at a 45.degree. angle in relation to
the long axis of the neck by ventral traction on the anterior
extremity of the upper jaw.
Five dogs (Exps. 8, 9, 10, 11, 12) were anesthetized with 20
percent Urethan (ethyl carbamate manufactured by Matheson, Coleman
and Bell of East Rutherford, New Jersey) in distilled water given
intravenously to effect. Three dogs (Exps. 13, 14, 15) were first
given Surital (sodium thiamylal manufactured by Parke, Davis &
Co. of Detroit, Mich.) 4 percent intravenously. Anesthesia was then
continued with Metofane (methoxyflurane manufactured by
Pitman-Moore of Indianapolis, Indiana) in a Heidbrink Model 2000
closed circle anesthetic gas machine Endotracheal catheters were
employed in all experiments.
Respiration was monitored only in experiments 8 through 12 by a
thermistor needle probe placed in the endotracheal catheter. Body
temperature was monitored via a rectal probe and a
Telo-Thermometer. The temperature of the right and left angularis
oculi veins were monitored by needle thermistors placed on the deep
face of the veins near the medial canthus of the eye as shown at 13
and 14 of FIG. 1. The temperature of the water irrigating the end
of the nose was monitored by a thermistor placed in the water hose
10 at about four in. from the open ends of the irrigating tube
12,12 which, in turn, were placed in the nostrils as illustrated.
The systemic arterial pressure was measured by connecting a
fluid-filled cannula from the femoral artery to a Statham P23BC
pressure transducer. The cerebrospinal fluid pressure was measured
through a 19-gauge needle inserted into the cisterna magna and
attached by a fluid-filled cannula to a Statham P23BC pressure
transducer. The EKG was also sensed and processed by a Grass Model
7P4AB Tachograph for heart rate indication. All of the transduced
parameters along with a marking signal were recorded on a
10-channel Grass Model 7 ink-writing recorder. The two pressure
signals and the heart rate signal were electrically damped to
provide a write-out of mean values.
The experimental procedure carried out with each animal was as
follows. After anesthesia and attachment to the rack, a 10-15
minute rest period was allowed in order to establish resting or
normal values of all recorded parameters. Then the tip of the nose
(with special emphasis upon the alar fold of the maxilloturbinate)
was irrigated with cold water (15.degree. C.) for 10-15 minutes.
The experimental trials then followed. A trial is defined as one
change in irrigating water temperature (from cold to hot or from
hot to cold). The hot water temperature was in the range of
45.degree.-48.degree. C.
After completion of the trials the brains were probed. The probe on
the right side was inserted after a maximum increase in both
cerebrospinal fluid pressure and systemic pressure had been
obtained during hot water irrigation. The probe on the left side
was inserted after the right side probe had been withdrawn and
after a maximum decrease in both pressures had been obtained during
cold water irrigation.
A 4-inch long 25-gauge needle was employed as the brain probe. It
was passed through holes 2 mm in diameter drilled through the skull
with a dental burr just posterior to the frontopariental suture and
1 cm lateral to the dorsal midline on both the right and left
sides. The probe was passed ventrally through the dura mater and
brain until it impinged on the bone at the base of the skull and
then withdrawn a measured distance.
When the physiological aspects of the experiments were completed,
the brains were removed from six dogs Three dogs (Exps. 10, 11 12)
were removed from the rack, placed in lateral recumbancy,
exsanguinated, and embalmed with 10 percent formalin solution
through the common carotid artery. The probe tracts in the brains
were then exposed and photographed. Three dogs (Exps. 13, 14, 15)
were exsanguinated while still in the rack and comparisons of the
two sides of the unembalmed brain were made by visual inspection
and then photographed.
In all of the 56 reported trials during which the temperature of
the irrigating water was increased or decreased, the cerebrospinal
fluid pressure (CSFP) and femoral arterial blood pressure (ABP)
always increased or decreased respectively. In the fifty trials in
which heart (HR) was monitored, this parameter, with a few
exceptions, also showed an increase or decrease with a respective
increase or decrease in irrigating water temperature. The above
responses when applied to two succeeding trials (cold to hot and
back to cold) are defined by the authors to be examples of "overall
normal responses." Furthermore, the temperature of the angularis
oculi vein always followed in the same direction as the water
temperature.
The significant results are summarized in Table I. The table
indicates that there were 32 trials carried out under
Urethan-chlorolose anesthesia and 24 with Metofan anesthesia. Also,
there were 28 Metofane and 28 hot-to-cold trials. The pressure and
time entries in the table are the means values obtained in each
type of trial.
FIG. 2 graphically illustrates the pressure and time relationships
recorded in Table I. In FIG. 2, the abscissa is time; and the
ordinate is pressure. The results of hot and cold water irrigation
are shown above and below the abscissa respectively. The solid
lines represent changes in cerebrospinal fluid pressure, and the
dashed lines represent changes in femoral arterial blood pressure.
Time was measured as starting when the water temperature change was
detected by the thermistor in the water-conducting tube. The
beginning point of each line, which lies on the time axis, is the
mean time for the first detectable pressure change to occur. The
vertical coordinate of the end point of each line is the mean
maximum change in pressure that occurred. Finally, the horizontal
coordinate of the end point of each line is the mean time it took
for the maximum pressure change to appear.
FIG. 2 illustrates the following points:
Whether the irrigating water temperature was hot or cold:
1. All pressure levels reached their maximum excursions sooner
under Urethan-chlorolose anesthesia.
2. The rate of change of pressure (slope of each line) was greater
in absolute value with Urethan anesthesia.
3. In 3 of the 4 pairs of lines (paired by type of pressure), the
initial change in pressure came sooner when Urethan-chlorolose
anesthesia was used.
4. Greater pressure changes were noted with Metofane
anesthesia.
Regardless of the type of anesthesia used:
1. All pressure levels reached their maximum excursion sooner under
hot water irrigation (change from cold to hot).
2. Hot water irrigation caused greater pressure changes to occur in
all cases except in the ABP measurement under Metofane
anesthesia.
3. The rate of change of each pressure was greater in absolute
value with hot water irrigation.
In our experiments the responses of the cardio-arterial system to
temperature changes in the brain were such that the pressure and
resistance relationships seen in the classical response to
autonomic stimulation did not apply. That is, a decrease in both
cerebrospinal fluid pressure (CSFP) and heart rate (HR) and an
increase in femoral arterial blood pressure (ABP) usually seen
during sympathetic stimulation; and an increase in CSFP and HR
along with a decrease of ABP usually seen in vagal stimulation did
not usually occur. Vasoconstriction (sympathetic), vasodilatation
(vagus) and changes in heart rate are manifestations, both
intracranially and extracranially, of autonomic stimulation. These
responses are (among other possibilities) aimed at maintaining a
more or less constant cerebral blood flow. The nature of the
responses of the arterial system to temperature changes in our
experiments, however, are interpreted to have changed cerebral
blood flow. As cerebral resistance increased (vasoconstriction -
decrease in CSFP), ABP did not increase, but instead it decreased.
Inasmuch as heart rate (HR) also decreased, indications are that
the flow of blood to the brain diminished when the alar fold of the
maxilloturbinate was cooled. Further, when the temperature of the
alar fold was increased by irrigation with warm water CSFP, ABP and
HR increased, indicating an increased flow of blood to the brain.
We therefore conclude that by cooling the nasal mucosa to a degree
such that neither the venous temperature control system nor the
cardio-arterial control system was able to compensate, the
temperature of the brain was lowered. The lowering of the brain
temperature was accompanied by cardio-arterial changes which
indicated that blood flow to the brain was being reduced.
It appears that there are two routes over which the brain receives
information relating to temperature changes originating at the
nose. In one of the above cited reports, we noted that when the
irrigating water was changed from hot to cold, the temperature
response in the region of the posterior communicating artery lagged
the response of the angularis oculi vein by 6 seconds. In the
present series of experiments, changes in CSFP (FIG. 3C), ABP (FIG.
3B), and HR (FIG. 3A) always lagged the temperature changes in the
irrigating water (FIG. 3E) and usually lagged temperature changes
in the angularis oculi veins (FIG. 3F). FIG. 3D is a common time
marker for all the graphs of FIGS. 3A-3C, and 3E-3G. In one
experiment, however, pressure and rate changes occurred before
temperature changes were observed in the angularis oculi veins.
There is a possibility in view of this that in some cases the brain
is receiving stimuli by a route other than the venous return route
from the nose to the cavernous sinus. The time lag between the
change in water temperature and the changes in pressures and heart
rate (3-5 seconds), considering that water temperature was being
measured in the conducting hose 4 inches before reaching the nose,
suggests that the second route is a nerve pathway.
Body temperature varied slightly with the temperature of the
irrigating water (see FIG. 3G). Increases in body temperature were
presumed to be the result of warming the circulating blood by the
hot water which was irrigating the end of the nose and
vice-versa.
The swelling, produced by passing a probe into the brain during hot
water irrigation, was found to be irreversible even after a cold
water irrigation span of 10 minutes. This response appeared to be
unilaterally confined to the side where the injury occurred. A
rapid increase in CSFP, in addition to the increase obtained during
hot water irrigation, was often seen shortly after the probe was
inserted. In one such experiment the CSFP began to increase 24
seconds after insertion of the needle and during the ensuing 45
seconds the pressure increased by 4mm/Hg. Since the CSFP was
monitored in the cysterma magna, it is assumed that the same CSFP
was exerted equally on both cerebral hemispheres. It thus appears
that the swelling seen on the right side could not have been caused
by interference with venous drainage from the cerebral cortex to
the dural sinuses. That is, if drainage interference had been the
cause both hemispheres would have been swollen. As it was, the left
hemisphere actually appeared to be shrunken. The response of the
brain to injury, i.e., an increase in blood flow to the injured
area, appears to be similar to the inflammatory response to injury
seen in other parts of the body.
Some conception of the effect of temperature on the dynamics of the
cerebral vasculature may be had when considering that CSFP was
reduced from +7 to -2 mm/Hg in approximately 1 minute in the face
of a presumed persistent swollen condition in the right cerebral
cortex. However, in other trials where the probe was withdrawn,
with continued hot water irrigation, the CSFP remained on the
positive side.
The side of the brain probed during cold water irrigation was more
firm than the side probed during hot water irrigation. This was
more evident in the fresh specimens than in those that were
embalmed for probe tract studies. In fact, obtaining a cross
section for photography was difficult in the fresh specimens
because the right side (probed during hot water irrigation) was
very flacid. The left side (probed during cold water irrigation)
was firm, held its shape well and sliced much the same as liver.
The results obtained, relative to inflammation and swelling, by
irrigating the alar fod with cold tap water are in agreement, thus
far, with those of other researchers obtained by immersion of the
animals in ice water.
An investigation of the relative amounts of hemmorrhage in the
probe tracts made during hot and cold water irrigation revealed
hemorrhage to be more extensive when hot water was being used. The
tract made during cold water irrigation was evidenced by a very
faint gray line dorsal to the lateral ventricles.
We have concluded that there are two physiological mechanisms which
are responsive to hot and cold water irrigation of the alar fold of
the maxilloturbinate; namely, the venous temperature control system
and cardio-arterial control system both of which have already been
discussed. Three physiological variables which appear to be a
manifestation of these mechanisms are systemic blood pressure (as
measured in the femoral artery), cerebrospinal fluid pressure
(which reflects cerebral vasodilatation or vasoconstriction) and
heart rate. We have observed that these variables normally respond
in such a way that they appear to vary cerebral blood flow.
a. The response of the cerebral vasculature to hot water irrigation
is vasodilatation (increase in cerebrospinal fluid pressure) which
is usually accompanied by a concurrent increase in femoral arterial
blood pressure and heart rate.
b. The response of the cerebral vasculature to cold water
irrigation is vasoconstriction (decrease in cerebrospinal fluid
pressure) which is always accompanied by a concurrent decrease in
femoral arterial blood pressure and usually in a decrease in heart
rate.
In general, the animals had a greater sensitivity to changes in
water temperature when anesthetized with urethan than with
metofame. However, greater pressure changes were observed when
metofame was used.
Swelling occurred when the brain was probed during continued hot
water irrigation while swelling did not occur when the brain was
probed during continued cold water irrigation.
Turning now to FIG. 4, there is a block-schematic diagram shown of
a system intended for use in inducing brain hypothermia and
changing the flow of blood to the brain in humans. Reference
numeral 20 generally designates a Wheatstone bridge circuit
arrangement having three precision resistors 21, 22 and 24 in
adjacent branches and one sensing thermistor 23 in the other branch
of the bridge. The thermistor 23 is intended for surface placement
on the skin of the patient over the left or right angularis oculi
vein. There may be included a separate system for measuring
temperature in the other of these veins, of course. The thermistor
should be suitably embedded in heat insulating material so that
only the surface which engages the skin of the patient is exposed
and sensitive to temperature changes. The bridge 20 is energized by
means of a battery 25 and the output signal from the bridge,
representative of changes in the temperature of the angularis oculi
vein of the patient is taken from diagonally opposite corners of
the bridge and fed to a differential amplifier 26.
The other input to the amplifier 26 is received from a circuit
including a variable resistor 27 and a reference voltage source,
schematically denoted by +V.sub.R. The signal thus generated and
fed into the reference input of amplifier 26 is a reference signal
against which the signal from the bridge circuit 20 is compared.
The output signal of the amplifier 26 is an error signal
representative of the difference between the temperature of the
venous blood in the angularis oculi vein and a signal
representative of reference temperature.
Any suitable means may be employed for holding the thermistors 23
and 24 in contact with the surface of the skin over the angularis
oculi veins, but care should be taken so that the thermistors are
sensitive only to the temperature of those veins and do not impede
blood flow in the veins.
The amplifier 26 is energized by means of a power supply 28, and
the output signal of the amplifier 26 is fed to a meter 29 which
may simply be a voltage meter calibrated to display the error in
temperature. The output signal of the amplifier 26 is also fed
through a power amplifier 30, the output of which is connected to a
set of normally open contacts of a relay 31. Power amplifier 30 is
a conventional linear amplifier designed to boost power level
sufficient to drive a servo-motor 32 when the coil of relay 31 is
energized to close its contacts. A square wave oscillator 33 is
powered by the power supply 28 and has its output connected to the
coil of relay 31 for energizing that relay periodically. The
oscillator 33 may be of conventional design, and it preferably has
a variable frequency rate and a variable duty cycle. The function
of the oscillator 33 is to provide timing means to delay operation
of the error signal from amplifier 26 for a period of time at least
sufficient to permit the system to sense temperature changes in the
angularis oculi veins produced by irrigating the nasal mucosa. That
is, it takes a few seconds from the time at which irrigation of the
nasal mucosa begins until a corresponding temperature change is
sensed in the angularis oculi vein. The oscillator 33, then,
periodically interrupts the transmission of the error signal
representative of temperature of the blood in the angularis oculi
vein for a predetermined time, sufficient to enable a quiescent
state to be reached after the application of a coolent. By having
the oscillator 33 of variable frequency, the periodicity of this
time delay may be controlled; and by having the duty cycle of the
output square wave of the oscillator 33 also being variable, it is
possible to control the time delay effected by it. In a typical
situation, the duty cycle may be such that the oscillator 33 would
energize the relay 31 for a time of 20 to 40 per cent of its cycle
which may nominally be around 10 seconds, but variable, as
mentioned.
When relay 31 is energized and its contacts closed, the output of
power amplifier 30 drives the servomotor 32 which also receives
power from the power supply 28 as indicated.
The shaft of the servomotor 32 (as diagrammatically indicated by
the dashed line 32A) controls a flow valve 34 which passes a fluid
such as compressed gas from a source 35. The gas from the source 35
passes through a pressure regulator 36 into the flow valve 34 and
thence into a heat extractor or cooler 37. The cooler 37 extracts
heat from the gas passing through it and it may take the form of
stainless steel tubing immersed in ice water. The function of the
cooler 37 is to maintain a constant but adjustable temperature. The
cooling ability of the gas, of course, increases with the flow rate
of the gas which is predetermined by the adjustment of the flow
valve 34 via servomotor 32. The gas emanating from the cooler 37 is
treated by means of a humidifier and source of anesthetic 39. The
gas is humidified so that the nasal membranes upon which the gas
impinges will remain moist. If desired, graded amounts of local
anesthesia may be applied to the nasal membranes to insure adequate
venous drainage.
Having thus described in detail a method and apparatus for
practicing our invention, persons skilled in the art will be able
to modify certain of the steps disclosed and to substitute
equivalent elements for those which have been described while
continuing to practice the inventive principles; and it is,
therefore, intended that all such modifications and substitutions
be covered as they are embraced within the spirit and scope of the
appended claims.
* * * * *