U.S. patent application number 13/674601 was filed with the patent office on 2013-05-09 for rapid cooling of body and/or brain by irrigating with a cooling liquid.
This patent application is currently assigned to NEUROSAVE, INC.. The applicant listed for this patent is NEUROSAVE, INC.. Invention is credited to Thomas Kreck.
Application Number | 20130116761 13/674601 |
Document ID | / |
Family ID | 40901650 |
Filed Date | 2013-05-09 |
United States Patent
Application |
20130116761 |
Kind Code |
A1 |
Kreck; Thomas |
May 9, 2013 |
Rapid Cooling of Body and/or Brain by Irrigating with a Cooling
Liquid
Abstract
Methods and devices are disclosed for providing therapeutic
hypothermia using irrigation of the aerodigestive tract with cooled
liquids. The disclosed method provides much more rapid therapeutic
cooling to lower temperatures than could previously be achieved,
thereby improving clinical outcomes. Novel cooling liquids and
cooling devices are disclosed for carrying out the method. An
external turbulent flow of cooling liquid may also be applied to
the exterior of the head to further promote heat exchange. Multiple
embodiments of devices are disclosed for performing rapid induction
and maintenance of therapeutic hypothermia either in a hospital
setting or in the field so that hypothermic treatment can be
quickly instituted before significant tissue damage occurs. Methods
are also disclosed for targeting brain cooling by irrigating the
upper airway/aerodigestive tract, and more generalized cooling by
irrigating the esophagus and/or stomach.
Inventors: |
Kreck; Thomas; (San
Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NEUROSAVE, INC.; |
San Francisco |
CA |
US |
|
|
Assignee: |
NEUROSAVE, INC.
San Francisco
CA
|
Family ID: |
40901650 |
Appl. No.: |
13/674601 |
Filed: |
November 12, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12842860 |
Jul 23, 2010 |
8308787 |
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13674601 |
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PCT/US2009/031924 |
Jan 24, 2009 |
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12842860 |
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61023706 |
Jan 25, 2008 |
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Current U.S.
Class: |
607/105 |
Current CPC
Class: |
A61H 35/008 20130101;
A61M 16/0486 20140204; A61M 2210/0618 20130101; A61H 2201/025
20130101; A61M 2205/3606 20130101; A61M 16/0479 20140204; A61F
7/0053 20130101; A61M 19/00 20130101; A61M 16/0409 20140204; A61M
16/0438 20140204; A61F 7/12 20130101; A61M 16/04 20130101; A61F
2007/0006 20130101; A61M 16/0459 20140204; A61F 2007/0002 20130101;
A61F 2007/0063 20130101; A61F 2007/0056 20130101 |
Class at
Publication: |
607/105 |
International
Class: |
A61F 7/12 20060101
A61F007/12 |
Claims
1. An organ hypothermia method, comprising: introducing a free
flowing cold biologically compatible irrigation liquid from a
reservoir, the reservoir comprising a container sized to receive a
head of a subject such that the subject's head is at least
partially immersed in the liquid in the reservoir, into the upper
airway and at least a portion of the esophagus of the subject, with
the irrigation liquid substantially filling and directly contacting
the walls of the upper airway and the at least a portion of the
esophagus, wherein the irrigation liquid comprises a temperature of
-30.degree. C. to 20.degree. C.
2. The method of claim 1, wherein the irrigation liquid is
introduced at a first flow rate during an induction stage, the
method further comprising reducing the flow rate to a second flow
rate during a maintenance or rewarming stage.
3. The method of claim 1, wherein a flow of liquid is externally
applied to the head of the subject by directing a flow of the
irrigation liquid toward the head of the subject from a liquid flow
tube.
4. The method of claim 1, wherein introducing the irrigation liquid
into the at least a portion of the esophagus comprises placing at
least one catheter in the esophagus to deliver the irrigation
liquid to the at least a portion of the esophagus.
5. The method of claim 4, wherein introducing the irrigation liquid
into the at least a portion of the esophagus comprises introducing
the irrigation liquid to a point substantially in the middle
section of the esophagus of the subject.
6. The method of claim 4, wherein introducing the irrigation liquid
into the at least a portion of the esophagus comprises introducing
the irrigation liquid into the lower esophagus of the subject.
7. The method of claim 4, wherein introducing the irrigation liquid
into the at least a portion of the esophagus comprises introducing
the irrigation liquid into substantially the entire esophagus of
the subject.
8. The method of claim 4, further comprising introducing the
irrigation liquid into the stomach of the subject.
9. The method of claim 8, wherein introducing the irrigation liquid
into the stomach comprises placing at least one catheter in the
stomach to deliver the irrigation liquid to the stomach.
10. A method for selective and non-invasive cooling of the brain,
comprising: placing a head of a subject in a container having a
reservoir of cool liquid such that the cool liquid covers the mouth
and nose of the subject to provide a continuous path of liquid
between the reservoir and the upper airway of the subject, and
introducing a free flowing cool liquid into the upper airway and at
least a portion of the esophagus of the subject, wherein the cool
liquid substantially fills the upper airway, circulates within the
upper airway and the at least a portion of the esophagus, and flows
out of the upper airway into the reservoir of liquid in the
container, thereby internally cooling the brain; while inhibiting
entry of the cool liquid into the lungs.
11. The method of claim 10, further comprising cooling the liquid
by circulating the liquid through a heat exchanger.
12. The method of claim 11, wherein circulating the liquid through
a heat exchanger comprises pumping the liquid from the container to
a heat exchanger external to the container, then pumping the liquid
back to the container and into the upper airway of the subject.
13. The method of claim 10, wherein inhibiting entry of the cool
liquid into the lungs comprises inserting an endotracheal tube into
the subject.
14. The method of claim 13, wherein the endotracheal tube comprises
an inflatable cuff, and the cuff is inflated to inhibit entry of
cool liquid into the lungs.
15. The method of claim 10, wherein introducing the flow of cool
liquid into the upper airway of the subject further comprises
introducing an esophageal liquid introduction catheter into the
esophagus of the subject, inflating an esophageal cuff on the
esophageal liquid introduction catheter to inhibit flow of cool
liquid into the stomach, and pumping the cool liquid into the
esophagus through a port in the esophageal liquid introduction
catheter that is proximal to the esophageal cuff.
16. The method of claim 13, wherein the cool liquid comprises a
temperature of less than +10.degree. C.
17. A device for cooling the brain and washing the aerodigestive
tract of a subject, comprising: a reservoir of cooling liquid, the
reservoir being adapted for receiving and maintaining at least a
portion of a head of a subject such that the subject's head is at
least partially submerged in the cooling liquid; a first liquid
delivery catheter operatively connected to the reservoir and
configured for insertion into a nasal cavity of the subject for
delivery of the cooling liquid into the nasal cavity, and a second
liquid delivery catheter operatively connected to the reservoir and
configured for insertion into an oral cavity of the subject for
delivery of the cooling liquid to the oral cavity of the subject;
at least one liquid circulation tube operatively connected to the
reservoir; at least one pump for circulating the cooling liquid
into the at least one liquid circulation tube and into the first
and second liquid delivery catheters; and a filter to remove
microbes from the cooling liquid that is discharged from the
aerodigestive tract.
18. The device of claim 17, wherein the cooling liquid comprises a
water-based solution with 0.45-5% by weight of sodium chloride.
19. The device of claim 17, wherein the cooling liquid comprises a
water-based solution with 0.45-5% by weight of sodium
bicarbonate.
20. The device of claim 17, wherein the cooling liquid comprises a
water-based solution with 5-25% by weight of at least one of
propylene glycol, dextrose, glucose, and sucrose.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 12/842,860, filed Jul. 23, 2010, which is a
continuation-in-part of PCT Patent Application No.
PCT/US2009/031924, filed Jan. 24, 2009, which claims the benefit of
U.S. Provisional Application No. 61/023,706, filed Jan. 25, 2008.
Each of these applications is incorporated herein by reference in
its entirety.
FIELD OF THE INVENTION
[0002] A device and method are disclosed for inducing rapid cooling
of the brain and/or body in a subject.
BACKGROUND OF THE INVENTION
[0003] Permanent damage to the brain is a common sequelae of
stroke, trauma and cardiac arrest. Each year in the United States,
over 350,000 people experience an out-of-hospital cardiac arrest,
and only 6.4% survive until hospital discharge without significant
neurological damage. Cardiac arrest is the leading cause of death
in the United States, with a direct medical cost of $2 billion per
year. Stroke is the third leading cause of death and the leading
cause of disability, with the cost of treatment, supportive care
and lost productivity estimated at $43 billion per year. There are
more than 1.5 million new head injuries in United States each year
with an estimated annual cost of $53 billion. About 5.3 million
people in the United States (2% of the population) are living with
a permanent disability from traumatic brain injury. In spite of the
tremendous financial cost and personal suffering caused by these
conditions, currently available techniques to reverse cerebral
damage have been generally ineffective.
[0004] There are well documented cases of incidentally preserved
neurological function in drowning victims who have had prolonged
cardiac arrest in cold water. Hypothermia can substantially reduce
deterioration in hypoxic or anoxic neurological, myocardial or
other tissue by slowing some of the thermodynamic tendency toward
tissue death and by protecting against reperfusion injury. Tissue
cooling can also reduce brain edema that raises intracranial
pressure and reduces perfusion of already damaged brain tissue, or
reduce swelling of the spinal cord that accompanies traumatic
injury. Many other types of inflammation can also be reduced by
cooling of affected tissue.
[0005] Animal studies have found significantly greater neurological
function after cerebral anoxia if the brain is cooled; however
human studies have not consistently found this benefit. The reasons
for this difference are not well understood, but it is believed
that the prolonged time needed to cool the brain using existing
clinical methods is partially responsible for a lack of definitive
benefits in humans. The depth of cooling may also be a
therapeutically limiting factor.
[0006] Cerebral hypothermia treatment has previously employed
cooling of the entire body to cool the brain. Total body cooling
requires cooling of a mass much larger than the head that
inherently slows the rate of brain cooling. For example, passive
total body cooling by applying cold liquid or a cooling blanket to
the skin induces hypothermia, but this approach is slow because of
the low surface-to-volume ratio of the skin to the body. In
addition, a therapeutically optimal body and brain temperature is
often not achieved using these methods. Total body cooling also
subjects other organ systems to the same or greater degree of
cooling as the brain, risking unwanted systemic effects or
damage.
[0007] Active total body cooling involves an intervention to more
quickly cool the blood or internal body cavities. Such
interventions often require highly skilled medical teams to
implement them, and initiation of therapy may be significantly
delayed due to the invasiveness and complexity of the treatment.
Various methods of actively infusing cold liquids into the body
have been described but these methods usually require cooling of
the entire body in order to effect cooling of the brain. U.S. Pat.
No. 5,927,273 discloses a cardiopulmonary resuscitation method in
which gas in the lungs is replaced with a cooled oxygen-carrying
liquid. U.S. Pat. No. 6,962,601 discloses phase-change
perfluorocarbon particulate slurries that can be used to induce
hypothermia by administering them internally or circulating them
through a cooling cap or blanket.
[0008] Localized cooling of various structures in the head has been
described but rates of cooling are slow and the desired level of
cooling is often not achieved. Devices for enclosing the head in a
helmet or shroud that externally circulates cooling fluid around
the scalp are shown in U.S. Pat. Nos. 4,920,963; 5,755,756; and
7,052,509. U.S. Patent Publication No. 2007/0123813 discloses a
method of cerebral and systemic cooling in which a nebulized liquid
is delivered as a mist or spray to the nasal and/or oral cavities
of a subject. A similar method is also disclosed in Brown et al.,
Surgical Forum 15:413-415, 1964, in which a dog's head was immersed
in circulating ice water, and large bore catheters were inserted
into the nostrils of an animal to perfuse the nasopharynx with ice
water at a rate of 1.1 to 1.6 L/min. An even more invasive
localized hypothermia technique is illustrated in U.S. Pat. No.
7,156,867, which discloses a head-cooling cap and a brain-cooling
probe for insertion into the lateral ventricle of the brain.
Cooling liquid is infused through the probe into the ventricles of
the brain to circulate cooling fluid and cool the brain.
[0009] U.S. Pat. No. 7,189,253 introduces cooled liquid through a
catheter that is advanced through the nostril of a subject with the
tip placed at the level of the back of the tongue. A balloon
carried by the catheter is expanded with cold liquid to fill the
nasal cavity without allowing the cool liquid to contact the walls
of the nasal cavity or the vascular nasal mucosa.
[0010] None of these techniques is known to provide the rapid
cerebral hypothermia that achieves desired tissue protection, for
example against permanent neurological damage following brain
insults such as cardiogenic shock, stroke or direct traumatic
damage to the brain. The need for an improved device of this nature
has been highlighted by recent efforts in the medical community to
routinely provide head or body cooling to patients who have had a
myocardial infarction, or are undergoing heart surgery, to avoid
permanent brain injury. Such cooling methods range from total body
immersion in cold liquid to lowering the thermostat in the hospital
rooms of patients. However, such interventions have been largely
unsuccessful, and many of them have required sophisticated devices
and surgical interventions that have limited use of induced
hypothermia outside of a hospital setting. There is a need for
therapeutic hypothermia techniques that can selectively and rapidly
cool the brain or the entire body, and for techniques that are
suitable for rapid application outside a hospital under emergency
conditions. There is also a need for techniques that can provide
for deeper levels of hypothermia in the brain while keeping the
body relatively warmer.
SUMMARY OF THE INVENTION
[0011] The slow rate of cooling and delays in initial of treatment
in prior therapeutic hypothermia devices and methods have been
important reasons that hypothermic induction has not been more
effective in preserving tissue function (such as neurological
function) following hypoxia, myocardial function following
myocardial infarction, or other types of function following
inflammation or injury in clinical trials. These problems have been
addressed herein by providing a system that permits much more rapid
and/or deeper therapeutic hypothermia. In certain embodiments of
the method, the cooling can be targeted to the brain (for example
to preserve neurological function following a stroke, brain injury,
myocardial infarction or episode of cardiac arrest) or more
generally to the entire body (to control generalized inflammation
or injury to non-brain structures such as the spinal cord or
myocardium).
[0012] The improved system for inducing rapid hypothermia takes
advantage of the inventor's recognition that the aerodigestive
tract is capable of accommodating a much larger flow of cooling
liquid than had previously been appreciated, and that a continuous
flow of a high volume of liquid along the irregular surface of the
tract provides unexpectedly rapid cooling to lower temperatures
than were previously achievable in such short periods of time. In
addition, the inventor recognizes the unexpected benefit of
lengthening the region of the aerodigestive tract with regard to
heat transfer and cooling the brain. By lengthening the regions of
the aerodigestive tract that is cooled, and thereby increasing the
residence time of the blood in the cooling zone, the inventor has
increased the depth of cooling possible and the rate at which brain
cooling can be achieved. This rapid cooling permits the method to
be used more effectively in urgent situations so that effective
cooling can be induced prior to completion of irreversible tissue
damage. Following induction, the method is also capable of
effectively maintaining cooling for sustained periods of time to
provide maximal therapeutic benefit. Variations of the method can
achieve targeted or selective cooling of the brain, or less
selective cooling of both the brain and the body, as required by
clinical conditions.
[0013] In certain disclosed embodiments, organ hypothermia is
induced by introducing a high volume flow of non-nebulized cold,
biologically compatible irrigation liquid into the aerodigestive
tract but not the lungs of the subject so that the cold irrigation
liquid substantially fills and directly contacts the walls of the
aerodigestive tract to achieve rapid and effective heat exchange
over the large and irregular surface of the tract that the liquid
contacts. The cold irrigation liquid is maintained at a temperature
of -30.degree. C. to 20.degree. C., and is introduced into the
length of aerodigestive tract. The liquid is allowed to flow in a
coherent large volume mass through the aerodigestive tract and
along the exposed irregular surface of the aerodigestive tract. In
some embodiments, a turbulent flow of liquid is also directed
externally against the head of the subject (such as the face and/or
scalp) to further accelerate cooling. The head of the subject may
be at least partially immersed in cold liquid that is agitated to
apply the turbulent flow, and/or a flow of the cold liquid is
directed toward the head of the subject from a liquid flow tube
even when the head is not immersed in the cool liquid.
[0014] In one embodiment of the method, the irrigation liquid is
introduced into the aerodigestive tract by placing catheters in the
aerodigestive tract and flowing liquid through the catheters into
the aerodigestive tract. The catheters in some examples are placed
in the aerodigestive tract to introduce the liquid only above the
level of the trachea and esophagus to achieve selective targeted
cooling of the brain by primarily cooling the structures near the
brain and in contact with blood vessels that supply blood to the
brain.
[0015] In other examples, the catheters are placed to introduce the
liquid into the esophagus and/or stomach to achieve non-selective
organ cooling by bringing the liquid into contact with the
insulated structures of the mediastinum through which venous blood
returns to the heart. The insulated, small, anatomic chamber
provided by the mediastinum permits excellent heat exchange with
the circulating blood to achieve the desired rapid non-brain
specific cooling effect. In addition to the placement of catheters
in the esophagus and stomach, one or more catheters can also be
placed to introduce the flow of liquid into the upper aerodigestive
tract structures above the level of the esophagus to provide
additional or maximal cooling. For example, the catheters are
placed with their introduction ports or tips in the nasal cavity,
oral cavity, and/or hypopharynx (and preferably all three). In
other embodiments, the catheters have multiple lumens and/or
multiple ports to introduce the cooling liquid at multiple points
along the length of the catheters to increase the flows outside of
the catheter that have been found to be effective in the rapid
protective induction of therapeutic hypothermia.
[0016] The subject can also be intubated with an endotracheal tube
having a cuff on the tube so that the cuff can be inflated to
inhibit entry of the irrigation liquid into the lungs. An
additional cuffed tube can be placed above the larynx to provide
further inhibition of fluid entry into the lung. In addition, a
tube with an inflatable balloon can be placed in the esophagus and
the cuff inflated to substantially inhibit flow of liquid out of
the upper airway into the lower esophagus and stomach. Isolating
the gastrointestinal tract (including the esophagus) from the flow
of cold liquid in the upper airway helps direct the cooling effect
to the upper airway and the structures (including blood vessels)
that are in heat transferring proximity with the cold liquid.
[0017] To help achieve and maintain rapid and effective cooling of
the desired anatomic structures, it is useful to provide a
sufficient reservoir of pre-cooled liquid for introduction
internally into the aerodigestive tract and/or externally against
the head. In view of the large volumes of cooling liquid that are
circulated to induce rapid hypothermia and maintain it, an external
reservoir of irrigation liquid is provided that supplies a
sufficient volume of cool liquid at the selected flow rate. In some
embodiments, the reservoir is also a container in which the head is
completely or partially immersed. Alternatively the reservoir
partially or completely surrounds a receptacle in which the head is
placed, and the receptacle collects cooling liquid that flows out
of the mouth and/or nose after it has circulated within the
aerodigestive tract outside of the irrigation catheters. In other
embodiments, the reservoir is placed in a back support that also
contacts the back and optionally cools the body and structures of
the back, such as the spinal cord. These and other embodiments can
be incorporated into devices that can be attached to or will roll
in tandem with a stretcher so that the hypothermia therapy can be
administered to a patient in transit.
[0018] The liquid that is introduced into the aerodigestive tract
leaves the aerodigestive tract by flowing out of the mouth and/or
nose of the subject to return to the external reservoir. The return
of the liquid can be passive, and not contained in a suction tube,
so that the cool return liquid flows along the length of at least
the upper airway or along the entire aerodigestive tract to
intimately contact the entire irregular surface of that tract. In
particular embodiments, the aerodigestive tract other than the
lungs is substantially filled with the cooling liquid. Passive
return of the liquid also helps avoid traumatic damage to the
aerodigestive tract that could occur if a return lumen is occluded
in a system that requires flow through such a circuit for removal.
Liquid that flows out of the mouth and nose of the subject can
return passively to the reservoir to be cooled, or circulated
externally of the reservoir for cooling. In particular embodiments,
the external reservoir is a container in which at least part of the
head is contained, or over which the head is positioned, to collect
the liquid that flows out of the mouth and/or nose of the subject
by gravity-assisted flow of the liquid.
[0019] In particular embodiments of the method, the liquid
reservoir is a neck support on which the neck of the subject is
positioned with the neck tilted backwards (extended) to help
protect the airway of the subject and promote the flow of liquids
through the aerodigestive tract (and not the lungs). In embodiments
in which the neck is extended, the head may be tilted back into a
container of cool liquid to partially or substantially completely
immerse the head in the cold liquid. Alternatively, the liquid
reservoir is a back and neck support that helps stabilize the spine
(for example in cases of possible spinal injury). The support
itself may be hollow and contain the reservoir of cold liquid, or
the support may be a body supporting platform suspended over a tub
of cold water, for example a tub that is large enough to receive
the body that is suspended above it and in which ice or other cold
items are placed to provide the large supply of cooling liquid. In
particular examples, the reservoir has 1-50 liters of cool liquid
in it, or liquid to be cooled. The volume of cool liquid in the
reservoir can vary depending on the clinical circumstances. For
example, smaller volumes (1-20 L) are preferred outside of an
inpatient setting (for example in an ambulance), but larger volumes
(greater than 20, 30 or even 40 L) can be used for inpatient
settings.
[0020] This specification also discloses multiple devices for
carrying out the methods of inducing organ cooling in a subject. In
one example, a head receptacle is adapted for receiving and
maintaining a head of the subject at least partially immersed in
cool liquid, and a neck support for supporting the neck of the
subject with the head of the subject tilted backwards into the
liquid container. The container can include a liquid reservoir of
cold cooling liquid outside of the receptacle, or the receptacle
itself can serve as the reservoir. The device further includes an
outflow port for delivering cold liquid from the reservoir, and one
or more outflow lines (such as catheters) are connected to the
outflow port for placement in the aerodigestive tract of the
subject. One or more pumps withdraw liquid from the reservoir to
move it through the catheter and into the aerodigestive tract. In
particular examples, the one or more pumps are capable of
delivering a total of 0.5-50 L/min of cooling liquid to the
aerodigestive tract of the subject. Flow rates in the higher range
can increase the diameter of the compliant regions of the upper
aerodigestive tract, such as the hypopharynx and esophagus, which
can further improve heat transfer by increasing the surface area
being cooled.
[0021] In one embodiment of the device, the liquid reservoir is a
compartment that at least partially abuts the head receptacle, and
a drain communicates between the head receptacle and the liquid
reservoir to return liquid from the head receptacle to the liquid
reservoir. The liquid reservoir may be an at least partially hollow
backboard for supporting a back of a subject, and the backboard
that contains the cooling liquid can be thermally conductive so
that cool liquid within the backboard cools the back of a subject
placed on the board. The backboard may include a top,
body-supporting surface and an inclined neck tilt inducing surface
that inclines into the head receptacle to support the body above
the head receptacle. The top surface of the backboard may incline
upwardly to elevate the thorax relative to the feet, and then
downwardly to provide a downwardly sloping surface on which the
head rests with the neck extended. The top surface of the backboard
may further include a neck support that is placed at the level of
the cervical spine of the subject. The neck support may be
adjustable in height and/or padded.
[0022] One advantage of the disclosed method and device is that it
is suitable for use outside of or in transit to the hospital, for
example in an ambulance or on a stretcher that is being moved. For
example, a wheeled stretcher has a body support surface on which a
back board is placed, a neck support board that inclines from the
back support board into a reservoir for liquid, and a head support
member carried by the neck support board. The position of the head
support member is adjustable along the neck support member to
adjust the head at a desired height (or depth) in the reservoir. In
some embodiments, a wheeled support is provided beneath the
reservoir so that the reservoir can be wheeled in tandem with the
stretcher.
[0023] In some embodiments of the device, the head receptacle
comprises a bottom support surface, a back wall, side walls and a
front wall, wherein the front wall is shorter than the back and
side walls to support the neck of the subject. The front wall is
adjustable in height to support the neck of the subject at
different heights, and may be padded for the protection of the
patient. The head receptacle is surrounded by a container that
serves as the reservoir.
[0024] The system further includes catheters for placement in the
aerodigestive tract of the subject and a pump for circulating
liquid from the receptacle into the aerodigestive tract.
[0025] In other disclosed embodiments, the brain is cooled by
direct external cooling of the head and cooling of blood that is
delivered to the brain. The head is placed in a container that
holds a reservoir of circulating cold liquid that externally cools
the brain. Cold liquid is infused into the upper airway through
catheters placed in the nasal cavity, oral cavity and/or upper
chest to directly cool the inferior surface of the brain and the
brainstem, and indirectly cool other areas of the brain by cooling
blood that passes through the carotid and vertebral arteries.
Delivering high volumes of cool liquid to the upper airway
substantially fills the upper airway with the cool liquid and
induces a turbulent flow of the liquid which then flows out of the
nose and mouth and into the reservoir of cool liquid that is
circulating around the head in the container.
[0026] In some disclosed embodiments, the head in the container is
completely submerged in the cool liquid, with the liquid covering
the nose and mouth to help completely fill the upper airway with
the liquid.
[0027] A particular disclosed device or system for carrying out the
method and cooling the brain includes a liquid container for
receiving and maintaining the head of the subject at least
partially immersed in cool liquid, and a source of cool liquid for
absorbing heat to induce brain hypothermia. A plurality of liquid
delivery catheters are connected to the source of cool liquid for
insertion into the nasopharynx and oropharynx of the subject for
direct delivery of cool liquid to those sites. A liquid circulation
tube is also connected to the source of cool liquid and is placed
in the container to circulate cooled liquid around the head of the
subject in the container. Pumps are operatively associated with the
device to move liquid from the container through the liquid
delivery catheters and into the patient. The system cools the outer
surface of the brain through the cranium, cools the inferior
surface of the brain and brainstem through cool liquid delivered
into the nasopharynx, and cools the blood perfusing the brain from
the arteries of the mediastinum and neck (such as the internal
carotid and vertebral arteries) through liquid delivered into the
pharynx and/or esophagus.
[0028] The cool liquid can be maintained, for example, at a
temperature of -30.degree. C. to +20.degree. C. to transfer heat
from the brain at a sufficient quantity and at a sufficient rate to
quickly induce hypothermia. Suitable liquids for this purpose
include a perfluorocarbons, oils, and water mixtures containing
salts and/or simple sugars and/or organic compounds (such as
propylene glycol).
[0029] The source of cool liquid preferably provides sufficient
liquid to substantially fill the upper airway (including the
nasopharynx, oropharynx, hypopharynx, and proximal trachea) with
the cool liquid. In other embodiments, the source of liquid is also
sufficient to substantially fill the upper esophagus, entire
esophagus, and/or stomach.
[0030] The foregoing and other objects, features, and advantages of
the invention will become more apparent from the following detailed
description, which proceeds with reference to the accompanying
figures.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] FIG. 1A is a schematic sectional side view of a human head
and upper thorax with nasal and oral catheters inserted to perform
high-flow irrigation of cooling liquid through the upper
aerodigestive tract to achieve selective brain cooling. An
endotracheal tube with an inflated cuff is shown inserted into the
proximal trachea. External catheters apply turbulent liquid flow
externally against the head.
[0032] FIG. 1B is a schematic sectional side view of a human head
and upper thorax, similar to FIG. 1A, but also showing a catheter
obstructing flow into the esophagus.
[0033] FIG. 2A is a view of the upper thorax and head, illustrating
the placement of external irrigation tubes that direct a turbulent
flow of cooling liquid against the face and head, and irrigation
tubes that deliver a high flow of cooling liquid to the esophagus
and stomach for inducing hypothermia in the body (without more
selectively cooling the head and brain).
[0034] FIG. 2B shows the structures of the mediastinum that form a
thermally insulated compartment that helps maintain mediastinal
cooling induced by the methods and devices disclosed herein.
[0035] FIG. 3 is a partially schematic side view of the head of a
supine subject placed in a container of cool liquid with liquid
instillation and recirculation tubes inserted in the nose, mouth
and upper esophagus, and an endotracheal tube in the trachea.
[0036] FIG. 4 is a schematic side view of the head, neck and chest
of a subject illustrating the upper airway and some of the blood
vessels that are cooled by circulating cool liquid through the
aerodigestive tract during selective cooling of the brain.
[0037] FIG. 5A is a top view of a head receptacle with a
surrounding cooling liquid reservoir, with a head of a subject
placed in the receptacle. FIG. 5B is a side-view of FIG. 5A
illustrating extension of the neck of the subject. FIG. 5C shows
the device in use, with cooling liquid filling the receptacle. FIG.
5D shows an alternative version of the device with a front wall
having an adjustable height for supporting the neck of a subject in
different degrees of neck extension. FIG. 5E shows the device of
FIG. 5D with the head receptacle filled with cooling liquid. FIG.
5F is yet another embodiment of the head receptacle, in which a
mesh net forms the receptacle that supports the head over the
reservoir of cooling liquid, and forms a permeable barrier through
which the liquid returns from the receptacle to the reservoir.
[0038] FIG. 6A is a side view showing in cross section a back
support and head receptacle, wherein the back support serves as the
reservoir of cooling liquid. FIG. 6B is a view similar to FIG. 6A,
but showing a back support that has an upwardly included surface to
elevate the upper thorax above the waist.
[0039] FIG. 7 is a view of another embodiment of the device in
which a flat body support platform is fixed in, on or slightly
above a large tub of cooling water with ice floating in it to cool
the water in the tub.
[0040] FIG. 8 is a side view of a patient being transported on a
stretcher, with a head receptacle that also serves as the cooling
liquid reservoir, and the head receptacle moves with the
stretcher.
DEFINITIONS
[0041] "Aerodigestive tract" refers to a complex of organs that, in
total, make up the tissues and organs of the upper respiratory
tract and the upper part of the digestive tract. The aerodigestive
tract, as used herein, is the lips and mouth, tongue, nose, throat,
vocal cords, esophagus, stomach and trachea. The aerodigestive
tract does not include the lungs or the intestines. "Introducing
liquid into the aerodigestive tract" includes introducing liquids
into any part of the aerodigestive tract, such as the nasal cavity,
upper airway (nasal and oral cavity and pharynx), the nasal cavity
and upper airway and esophagus, or the nasal cavity and upper
airway and esophagus and stomach, or any combination or
sub-combination thereof.
[0042] "Extension" of the neck refers to bending the neck to move
the head posteriorly.
[0043] "Pharynx" refers to the part of the neck and throat situated
immediately posterior to the mouth and nasal cavity, but superior
to the esophagus, larynx and trachea. It is anatomically divided
into the nasopharynx (posterior to the nasal cavity), oropharynx
(posterior to the oral cavity) and hypopharynx or layngopharynx
(between the oropharynx and the esophagus).
[0044] "Hypothermia" refers to a condition in which body or organ
temperature is below normal physiological temperatures.
"Therapeutic hypothermia" refers to hypothermia induced to attempt
medical benefit in a subject. Inducing "selective hypothermia" does
not require absolute selectivity; relative selectivity of cooling a
target organ or area can occur. Hence inducing "selective
hypothermia" refers to inducing hypothermia in a target organ or
organs to a greater extent or substantially greater extent than in
non-target organs. For example, selective hypothermia may be
induced in the brain or head of a subject by selectively cooling
blood vessels that perfuse that organ as well as selectively
cooling anatomic structures that are contiguous with that organ.
Selective hypothermia need not be absolutely selective, and some
cooling of other organs (or the entire body) can occur. In
particular examples, selective hypothermia reduces the temperature
of the target organ (such as the brain) by at least 25%, 50%, or
75% more than the reduction of overall core body temperature.
Inducing "non-selective hypothermia" refers to a generalized
cooling of the body that is not specifically targeted to any
particular organ (such as the brain). However, even with
"non-selective" cooling some preferential cooling of a particular
organ can occur.
[0045] A "non-nebulized" liquid is one that is not turned into a
fine spray or atomized. The non-nebulized liquid therefore emerges
in a continuous liquid stream instead of discontinuous droplets
from a catheter. The continuous or coherent liquid flow provides
superior turbulent flow that is not achieved by droplets, as well
as greater flow rates (with consequently greater cooling rates) can
be achieved by using non-nebulized introduction of cooling liquid
into the aerodigestive tract.
[0046] "Turbulent flow" of liquid is agitated flow that is not
strictly laminar. Turbulent flow helps disrupt liquid barriers and
increases heat transfer as compared to laminar flow.
[0047] "Upper aerodigestive tract" refers to the portion of the
aerodigestive tract above the esophagus. The "upper airway" refers
to the air passageways above the trachea, which includes the nasal
and oral cavities, as well as the pharynx.
[0048] References to "introducing a catheter" are understood to
refer to introducing one or more catheters. For example,
introducing a catheter into the nasal cavity can refer to
introducing a catheter into each nostril so that there are two
catheters in the nasal cavities.
DETAILED DESCRIPTION
[0049] A therapeutic system and method are disclosed for cooling
the brain, spinal cord, or more generally the body of a subject to
clinically beneficial temperatures that help preserve tissue
function (such as brain function) following potentially
tissue-damaging events, such as hypoxia (as can occur following
cardiac arrest or respiratory failure), neurovascular events (such
as a stroke), direct trauma (such as a closed head injury or spinal
contusion) or perinatal insults (such as difficult deliveries).
However, the treatment can be used for any person at risk of tissue
injury or inflammation damage from a traumatic or other medical
incident. The therapeutic method can be initiated prior to arrival
at a medical center, but it is also suitable for in-hospital
use.
[0050] The therapeutic method may be continued for hours or days as
clinically needed and can be used with other methods of brain or
body cooling. The therapeutic method can also be used as a bridge
to concomitant therapies such as thrombolysis or thrombectomy for
treating stroke and cardiopulmonary bypass for treating cardiac
arrest. In the event of cardiac arrest, brain cooling may be
initiated before or after spontaneous circulation is reestablished,
and even when spontaneous circulation cannot be reestablished prior
to presentation at a medical center.
[0051] In some embodiments of the new method the brain is cooled
(either separately or in combination) by two functional mechanisms:
direct head cooling and cooling of blood that is delivered to the
brain. The head is directly cooled externally by immersing it
completely or partially in a container through which cold liquid
circulates or by applying a turbulent flow of cold liquid
externally against the head. Direct cooling of the inferior surface
of the brain and brain stem are achieved by infusing cold liquid
into the upper aerodigestive tract using catheters placed in the
upper airway (for example into the nasal cavity, nasopharynx, oral
cavity, oropharynx and/or hypopharynx). By establishing a
continuous flow and exchange of liquid between the upper
aerodigestive tract and the cool liquid (such as cooling liquid
circulating around the head or present in a reservoir that does not
immerse the head), a highly effective and more rapid internal
cooling of the nasopharyngeal cavity, upper airway or aerodigestive
tract occurs.
[0052] Cooling the upper aerodigestive tract and scalp causes blood
delivered to the brain to be cooled as it flows through the
arteries of the neck and head. Optional additional cooling of the
upper chest is achieved by delivering cold liquid into the
esophagus via a catheter inserted through the mouth with the tip
positioned in the esophagus, for example the mid-esophagus.
Alternatively, multiple outlet ports (either from a single or
multiple catheters) can deliver even higher flows of cooling liquid
in the esophagus. The outlet ports in the esophageal catheter(s)
deliver the cold liquid into the proximal, and/or mid and/or distal
esophagus, and/or the stomach.
[0053] In certain embodiments, the cool liquid circulating from the
esophagus and upper airway/aerodigestive tract exits the mouth and
mixes with the liquid surrounding the scalp, whence it is withdrawn
from the container, optionally cooled and returned to the
container, for example through liquid delivery catheters (such as
the catheters in the nose, mouth and esophagus). Cooled liquid can
be cooled and/or stored in a reservoir external to the head
receptacle. In yet other illustrated embodiments described in
greater detail below, the liquid can be cooled in the head
receptacle without withdrawing it from the receptacle (the
receptacle is the reservoir), by adding ice or other cold items to
the liquid. In yet other embodiments, the cool liquid that
passively flows out of the mouth and nose is returned to a cooling
reservoir by the action of gravity, for example by passing through
a liquid permeable net that support the head, or a drain in the
receptacle that leads to the reservoir.
[0054] The initial temperature of the liquid is in the range of -30
to +30.degree. C., for example -30 to +10.degree. C. Optimal
temperature may vary during treatment but is believed to be in the
range of -20 to +10.degree. C. Alternatively, the liquid is
maintained at a temperature (such as a substantially fixed
temperature) of less than +30.degree. C., and in some embodiments
less than +10.degree. C., or even less than -10.degree. C. (such as
a temperature of about -17.degree. C.). The liquid can be
maintained at any constant temperature (for example within a range
of .+-.2.degree. C.) by circulating it between the
receptacle/reservoir and a separate heat exchanger cooling unit,
adding additional cool liquid as required or by adding cold objects
to the reservoir of liquid. Alternatively the temperature is
maintained by adding ice (including dry ice) or other cool objects
at a specific temperature to the liquid.
[0055] Turbulent flow of the liquid over the surfaces of the scalp
is achieved, for example, by constantly withdrawing the liquid to
be cooled, and reintroducing the cooled liquid under pressure into
the head receptacle, for example through a tube directed at the
head. However other means of liquid agitation within the head
receptacle may also be used. Turbulent flow over internal and
external body surfaces improves heat transfer by reducing the depth
of the boundary layer of immobile cool liquid. Hair may be removed
if it has an insulating effect that interferes with effective rapid
heat exchange.
[0056] One aspect of the cooling method is illustrated in FIG. 1A,
which schematically shows the placement of irrigation catheters
that deliver a flow of cooling liquid to structures that
substantially selectively cool the brain 10 in the head 12 of a
subject 14, as opposed to generalized induction of hypothermia
throughout the body of subject 14. The sectional view shows (moving
anterior to posterior) the nose 16 with nasal cavities 18 (only one
shown) and nasopharynx 20. The bottom wall of nasal cavity 18 is
defined by the palate, which is divided into the anterior hard
palate 22 and posterior soft palate 24. Mouth 26 defines an
entrance to oral cavity 28 which leads to a posterior oropharynx
30. Inferior to oropharynx 30 is hypopharynx 32 that is bounded
anteriorly by epiglottis 34 and leads inferiorly to the anteriorly
situated trachea 36 and posteriorly situated esophagus 38.
[0057] Targeted cooling of the brain is achieved by introducing a
continuous or coherent flow of liquid that circulates through the
upper airway, which is above the level of the trachea and
esophagus, and includes the nasal and oral cavities 18, 28,
nasopharynx 20, oropharynx 30, and hypopharynx 32. FIG. 1A provides
an example of how to provide this continuous flow by introducing
nasal catheters 40 into the nasal cavities and an oral catheter 42
into the oral cavity of subject 14. First and second nasal
catheters 40 (only one is shown in FIG. 1A) are inserted into each
nostril of nose 16 and advanced until the distal open delivery tip
44 is positioned in the nasal cavity above the hard palate 22
(although it can alternatively be positioned above either hard
palate 22, soft palate 24, or even in nasopharynx 20). Oral
catheter 42 is similarly inserted into the oral cavity 24 with the
open delivery tip 46 advanced toward and positioned slightly beyond
and below soft palate 24 with open delivery tip 46 positioned in
oropharynx 32. To help isolate the lungs from the upper airway and
aerodigestive tract, an endotracheal tube 48 is shown inserted
through mouth 26 and hypopharynx 32 into trachea 36. An optional
inflatable peripheral cuff 50 is shown in its expanded condition
occluding the lumen of trachea 36.
[0058] The illustrated catheters 40, 42, 48 are single or multiple
lumen catheters. The bores of catheters 40, 42 are of a sufficient
size to permit a flow of a continuous or coherent column of cooling
liquid through the catheters and out of open tips 44, 46 to
establish the coherent flow of liquid that substantially fills the
upper airway. One or more fronto-tempero-parietal catheters 52 are
schematically shown in FIG. 1A positioned to direct a turbulent
flow of cooling liquid against the anterior portion of head 12, for
example against the fronto-parietal portions of the head, such as
against the forehead or side of the head. One or more posterior
catheters 54 are also situated to direct a turbulent flow of
cooling liquid against a posterior portion of head 12, for example
against the occipital portion of head 12. Catheters 52 have open
tips 56 oriented within 1-5 cm of the surface of the head, and
catheters 54 have open tips 58 similarly situation within 1-5 cm of
the head surface.
[0059] Although not shown in the schematic illustration of FIG. 1A,
each of the catheters is adapted for operative connection to a
source of liquid for introduction through the catheter. Catheters
40, 42, 52, 54 are adapted for connection to a sufficient supply of
cooling liquid of a temperature adequate to lower the brain to a
targeted temperature (such as 33.degree. C. or less), or by a
targeted change in temperature within a set period of time (such as
5.degree. C. within 30 minutes or less). Endotracheal tube 48 is
adapted for operative connection to a ventilator or other source of
respirable gas that can be introduced under pressure for mechanical
ventilation of the lungs (not shown). Although the illustrated
catheters are shown having end openings for discharging the liquid
from the catheter into the aerodigestive tract, the catheters can
instead be provided with multiple side holes in the distal 5-10 cm
of the catheter to allow liquid to be discharged laterally from the
catheter instead of (or in addition to) discharge from the tip.
Lateral discharge helps promote turbulent flow within the
aerodigestive tract.
[0060] Cooling liquid is introduced through tips 44, 46, 56, 58 of
tubes 40, 42, 52, 54 as shown by arrows in FIG. 1A. In disclosed
examples, the flow rate of the introduced liquid totals at least 5
L/min total from the combined flow of tubes 40, 42 that are
situated internally (i.e. excluding external tubes 52, 54), but the
combined flow rate from the internal tubes can be much higher, for
example 5-50 L/min as described in greater detail below. The large
volume of cooling liquid circulates through the upper
airway/aerodigestive tract above the level of the esophagus and
trachea, to at least partially fill the upper airway with the
cooling liquid and assure substantial contact between the cooling
liquid and the exposed surfaces of the upper aerodigestive
tract/airway. In some embodiments, the upper airway and upper
aerodigestive tract are substantially completely filled with the
cooling liquid.
[0061] Many of the surfaces of the upper aerodigestive tract are
irregular (such as the richly vascularized nasal turbinates) and
the flow of liquid that bathes and moves along the irregular
surfaces of the airway provides superior heat exchange to cool the
airway. The turbulence induced by a large flow of liquid being
introduced into the confined space of the upper aerodigestive tract
and returning outside of any catheters or tubes through the airway
itself further disrupts any insulative areas as the circulating
liquid moves toward the mouth and nose. Liquid passively moves out
of the mouth and nose as new cooling liquid replaced is in the
upper airway to continuously replenish the cooling effect of the
liquid.
[0062] FIG. 1B shows a variation of the method illustrated in FIG.
1B, wherein like parts have been given like reference numbers to
those found in FIG. 1A. However, an esophageal tube 60 has
additionally been inserted through mouth 26 into esophagus 38.
Esophageal tube 60 has a distal balloon 62 that is shown in an
inflated condition in the proximal or middle portion of esophagus
38 to substantially seal the esophagus beyond the balloon to the
entry of cooling liquid into it. Esophageal tube 60 can be
operatively connected to a source of cooling liquid (not shown) to
introduce a flow of liquid under pressure that moves through the
lumen of the catheter and emerges through side port 64 to thereby
serve as an additional source of cooling liquid circulating through
the upper airway.
[0063] The methods of cooling described in FIG. 1A and FIG. 1B are
examples of "selective" cooling of the head and the brain in that
cooling of those structures proceeds faster than cooling of other
parts of the body. However a certain amount of non-selective
cooling will also occur as well because the blood that perfuses the
tissue of the scalp and upper aerodigestive tract will be cooled
and returned to the heart thereby somewhat lowering systemic
arterial blood temperature.
[0064] FIG. 2A illustrates a non-selective cooling method for
inducing non-selective hypothermia in a subject 70 by generally
cooling the body of the subject without specifically targeting the
brain. FIG. 2A schematically shows the subject's brain 72, within
head 74. One of the two lungs 76 is illustrated in the chest of
subject 70, as is the position of heart 78. The subject's nasal
cavity 80 and oral cavity 82 communicate with esophagus 84 and
stomach 86, and trachea 87 that communicates with lung 76. No tubes
are placed in nasal cavity 80, but an endotracheal tube 88 is
positioned in trachea 87 with an optional inflated cuff 90 to
isolate the lungs from the flow of cooling liquid in the upper
aerodigestive tract. The esophagus and stomach are cooled by three
esophageal tubes, namely an upper esophageal cooling tube 92
positioned with a single outlet in the upper esophagus, a middle
esophageal cooling tube 94 positioned with a single outlet in the
mid esophagus, and a gastric tube 96 positioned with a single
outlet in the stomach for cooling the stomach. Although three tubes
are illustrated in this example, a single multi-lumen tube with
multiple outlet ports could alternatively be used. As previously
described, side ports instead of end openings could also be used to
increase turbulent flow.
[0065] Cooling liquid is introduced through all three tubes at the
different levels of the digestive tract to provide primary cooling
of the esophagus and stomach as the cool liquid returns from the
stomach and esophagus. The cool liquid in the stomach contacts the
rugae that greatly increase the surface area across which heat
exchange with the blood can occur. Cooling liquid in the esophagus
and stomach is also in close anatomic proximity to the inferior
vena cava 98, superior vena cava (not shown), descending aorta 100,
and aortic arch 102 to cool the blood therein as it moves through
body, and particularly as it the blood moves through the structures
of the mediastinum.
[0066] Although FIG. 2A only shows tubes inserted in the esophagus
and stomach, it will be understood that cooling of the entire
aerodigestive tract can occur by retroflow of cool liquid through
the aerodigestive tract to the mouth and nose. In addition,
irrigation catheters can be inserted in the mouth and nose as in
FIG. 1A to further increase the flow of cooling liquid through the
aerodigestive tract.
[0067] External liquid application tubes 104, 106 are positioned to
apply a turbulent flow of liquid externally to the head of the
subject. Tube 104 is positioned to flow liquid against the frontal
area of the head (for example against the forehead) and tube 106 is
positioned to provide turbulent flow in the occipital region.
[0068] FIG. 2B illustrates that that the mediastinum is an anatomic
compartment that is somewhat insulated and therefore retains the
cooling effect of the liquid introduced through the esophageal
tubes. The mediastium contains the heart, the great vessels of the
heart, esophagus, and trachea, and is insulated laterally by the
air-filled lungs and inferiorly by the stomach.
[0069] All of the cardiac output passes through the veins of the
mediastinum. Internal cooling of the mediastinum can be
accomplished by cooling the entire aerodigestive tract, from the
nares to the pyloris (excluding lungs). The mediastinum is
insulated from heat from the rest of the body by the lungs, larynx
and stomach. The lateral aspects of the mediastinum are bordered by
the lungs which of low mass and kept cool by the normal function of
ventilation. The inferior aspect of the mediastinum is cooled by
cooling the stomach and the superior aspect of the mediastinum, the
neck, is cooled by cooling the upper airway. Insulation of the
mediastinum enables cooling of the venous blood in the vena cava
more efficiently than if similar cooling were to be performed on
the vena cava within the abdomen. If vena cava cooling were
attempted in the abdomen, heat from the surrounding organs would
also be delivered to the vena cava and significantly impede
cooling.
[0070] FIG. 3 provides an example of a more detailed brain cooling
device 110 for carrying out the selective cooling method, wherein a
container 112 encloses a head 114 of a subject 116 who is in a
supine position (with the face up). Head 114 can be partially or
totally immersed in cool liquid 118, but the illustrated embodiment
shows total immersion of the head and face. The illustrated
container 112 is a rectangular or square box having a solid flat
bottom wall 120, three solid upright side walls 122 (only one is
shown in FIG. 1), and open top face 124. Side walls 122 are
connected to bottom wall 120 and each other with liquid tight
seals. The bottom wall 120 and three solid upright side walls 122
and the upright solid wall 126 that receives the neck may, for
example, be preformed out of contiguous material, as in a seamless
unitary piece of molded plastic. Open top face 124 defines a square
or rectangular opening large enough to provide access to the entire
face. An upright side wall 126 defines a neck receiving opening
that contains an annular flexible seal 128 to inhibit flow of
liquid from container 112. An overflow trough 130 may extend along
the bottom edge of face 126 to collect liquid that leaks through
the seal, and re-circulate it to the container by a recirculation
pump (recirculation tubing not shown). In the illustrated example,
the dimensions of the container are 35 cm for length, width and
height for an adult sized box and 20 cm on all sides for a device
to be used for infants.
[0071] The reservoir of cool liquid 118 can substantially fill
container 112. The liquid in the box has a top liquid level 132
that in the illustrated embodiment is within 2-10 cm of the top
edge of the box, such that the liquid completely submerges head 114
below liquid level 132. With the liquid at this level, both the
nose 134 and mouth 136 of subject 116 are completely covered with
liquid, and the upper airways can passively fill with liquid from
the container in addition to being actively filled with liquid
pumped into the airway, as described below. The area around the
head and in the upper airways is therefore a substantially
uninterrupted continuum of cooling liquid that establishes
efficient thermal exchange with the anatomic structures that come
into contact with the continuum of liquid.
[0072] Device 110 is provided with a cooling means for controlling
the temperature of the liquid in container 112. The cooling means
can take many forms, such as making the container itself a
refrigeration unit, adding cool objects (such as ice) to the
liquid, and using endothermic chemical reactions (such as ammonium
nitrate in water) in the walls of the container to cool them.
However, in a particularly illustrated embodiment liquid in
container 112 is cooled externally to the container by pumping it
from the container to a heat exchanger 144 where it is cooled, and
then pumping it back to the container. The heat exchanger can be of
any type, such as a shell and tube heat exchanger, a plate heat
exchanger, a regenerative heat exchanger, an adiabatic wheel heat
exchanger, a fluid heat exchanger, or a dynamic scraped surface
heat exchanger. Additional information about such devices is
readily available, for example in Sadik Kakac and Hongtan Liu Heat
Exchangers: Selection, Rating and Thermal Design, 2nd Edition, CRC
Press (2002)(ISBN 0849309026).
[0073] FIG. 3 shows an intake conduit 140 that extends from
container 112 to a liquid pump 142. A heat exchanger 144 is in
series with pump 142, and an outlet conduit 146 extends from heat
exchanger 144 and communicates with an elongated distribution
conduit 148 that provides multiple catheter connection outlets.
Although the illustrated embodiment shows a single pump, more than
one pump can be used. The pump can also be manually operated (for
example by manually rotating or reciprocating a pump handle) or
non-manually operated (for example by actuating an electrically
operated pump).
[0074] Liquid circulation conduits of various lengths are connected
to the outlets on distribution conduit 148 and extend through the
open top face 124 of container 112. Four of them are liquid
circulation tubes 150, 152, 154, 156 which ensure turbulent flow of
liquid to the scalp and face. Tubes 150 and 156 are long tubes that
reach almost to the bottom of container 112 for deep recirculation
of liquid, while tubes 152, 154 are shorter and extend only into
the top portion of container 112 to provide more superficial
recirculation of liquid in the container. Another of the liquid
circulation conduits is a first liquid delivery catheter 158 for
delivering cool liquid to the nasal cavity 160 of the subject, and
it is of sufficient length to extend from distribution conduit 148
to a distance of about three to six cm into the nasal cavity of a
head 114 in container 112, with the outlet of catheter directed at
nasopharynx 161. Another of the conduits is a second liquid
delivery catheter 162 for delivering cool liquid to the oral cavity
164 of the subject. Catheter 162 is of sufficient length to extend
a distance of about six to twelve cm into oral cavity 164 with its
outlet directed at oropharynx 168.
[0075] A third liquid delivery catheter 166 is similar to a
nasogastric tube, and extends from distribution conduit 148 and is
of sufficient length to reach into oral cavity 164, through
oropharynx 168, hypopharynx 170 and into esophagus 172. Typically,
catheter 166 is of a sufficient length for it to extend 25 to 30 cm
past the lips. Catheter 166 is a multi-lumen catheter provided with
a balloon tip 174 that is selectively inflatable, for example using
a source of pressurized air such as a syringe (not shown) that
introduces the air through one of the lumens to the balloon tip
174. Another lumen of catheter 166 opens to a side port 176 that
communicates with distribution conduit 148 for delivering cool
liquid into the proximal esophagus. Side port 176 is proximal to
balloon tip 174, so that when balloon tip 174 is inflated the
liquid delivered into esophagus 172 will not flow into the distal
gastrointestinal tract (such as the stomach), but will instead move
in a proximal direction through the upper airways and eventually
circulate to and rejoin the reservoir of liquid in container
112.
[0076] The disclosed brain cooling system also employs an optional
multi-lumen endotracheal tube 180 having a conventional coupling
collar 182 for connection to a source of ventilation (not shown).
Suitable sources of ventilation include any device for introducing
under positive pressure a non-toxic fluid (such as a gas) with
oxygen in it. Examples of such sources include a manual ventilation
bag or a mechanical ventilator that communicate with the primary
lumen of tube 180 for delivering the gas into the lower airways and
lungs. Endotracheal tube 180 includes a conventional distal cuff
184 that can be selectively inflated after insertion by introducing
fluid under pressure (such as gas from a syringe) through a
secondary lumen of tube 180 to secure the tube in place within the
trachea 186, provide an effective seal between tube 180 and the
walls of the trachea that improves the efficiency of ventilation,
and inhibit the entry of liquid from the upper airway into the
lower airways and lungs.
[0077] Although the illustrated embodiment of endotracheal tube 180
in FIG. 3 includes cuff 184, the cuff is not always required to
substantially seal the airway, for example in small or pediatric
subjects in whom the endotracheal tube itself is large enough to
effectively occlude passage of liquid between tube 180 and the
walls of trachea 186. In the illustrated embodiment (FIG. 3) a
suction port 188 is located on the side of tube 180, proximal to
cuff 184. Port 188 communicates with a tertiary lumen in tube 180
and is connected to a source of negative pressure (not shown) that
withdraws liquid from the trachea. The removed liquid can be
recirculated into the reservoir of liquid 118 in container 112.
[0078] In use, head 114 of subject 116 in need of brain cooling is
placed in container 112 by inserting head 114 through flexible seal
128. A more liquid-resistant seal with the neck is provided by
placing a thickened liquid-resistant emulsion or gel (such as
petroleum jelly) externally in a continuous ring around the neck. A
soft, liquid-resistant foam strip is also placed around the neck
and may be layered to achieve a desired thickness. Flexible seal
128 achieves a tightness around the neck that is sufficient to
provide a substantially liquid-tight seal but not so tight to
obstruct arterial or venous flow of blood through the neck. In some
embodiments, a plastic liner (not shown) is also placed in
container 112 around head 114 to provide an additional barrier to
loss of liquid from container 112.
[0079] The subject 116 may optionally be prepared for the brain
cooling procedure by removing hair from the head, for example by
cutting the hair or shaving the head to improve conductive loss of
heat externally from head 114 to surrounding cool liquid 118. If
the subject is conscious, sedation may also be administered (for
example intravenously administering a benzodiazepine or narcotic)
to lower the level of consciousness and/or induce transient amnesia
about the procedure. Once the subject's shaved head 114 is
positioned within container 112, unobstructed access to the
interior of the container is provided by the completely open top
face 124 of container 112. Deep circulation tubes 150 and 156 are
positioned around head 114 with their outlets proximal to bottom
wall 120. Superficial circulation tubes 152, 154 are positioned
above head 14 with the outlets of tubes 152, 154 directed at the
face and scalp of subject 116. Catheter 158 is lubricated in a
conventional fashion and inserted through a nostril to a distance
of three to six cm into nasal cavity 160 so that the tip of
catheter 158 is adjacent the vascularized surfaces of the turbinate
mucosa and near the cribiform plate of the ethmoid bone that
supports the inferior surface of the cerebral cortex, with the
outlet of catheter 158 directed at nasopharynx 161. Esophageal
catheter 166 is inserted through the mouth (to a distance of 25 to
30 cm past the lips) into the proximal esophagus 172, and once it
is in position cuff 174 is inflated. Endotracheal tube 180 is
inserted into trachea 186 and cuff 184 inflated. The tertiary lumen
of endotracheal tube 180 is connected to suction.
[0080] Pre-cooled liquid that is already at the desired temperature
is introduced into container 112 until the liquid level 132 is
above the intake level of intake conduit 140. Liquid is circulated
by activating pump 142 which draws liquid from container 112 though
conduit 140 and propels it under pressure, for example a pressure
of about out 20-60 cm H.sub.2O through heat exchanger 144, outlet
conduit 146 and into distribution conduit 148. The liquid is then
distributed among the outlets through the series of conduits that
lead to container 112. Turbulent flow is induced in container 112
around the head by introduction of cool liquid through circulation
tubes 150, 152, 154 and 156. This turbulent flow helps disrupt
convection boundaries that would otherwise form at the surface of
the head or face.
[0081] Pump 142 also circulates the cool liquid through tube 158
into the nasal cavity, through tube 162 into the oral cavity, and
through tube 166 and out of port 176 to introduce cool liquid into
the proximal esophagus. The liquid introduced through the tubes
merges with cool liquid that passively enters from the reservoir of
liquid in surrounding container 112 to substantially fill the upper
airways with a turbulent flow of cool liquid that is in an
uninterrupted liquid continuum with the reservoir of cool liquid
around head 114. A continuous recirculation of liquid from the
upper airways to the reservoir of liquid around the head and back
into the upper airway occurs, and the liquid may also be
continuously cooled to maintain it at a desired temperature that
induces rapid cooling of the brain to a desired therapeutic
temperature.
[0082] As previously noted, the neck of the subject rests in an
opening through one wall of the container. The opening is provided
with a sealing means, such as a circumferential flexible sealing
material that circumscribes the neck to help provide a more
liquid-tight seal. The liquid-tight seal around the neck can
include a thickened liquid-resistant emulsion or gel (such as
petroleum jelly) that is applied to the skin to make a continuous
ring around the neck. A soft liquid-resistant foam strip may be
placed around the entire circumference of the neck (for example
over the gel) and may be layered to achieve a desired thickness.
Finally, the flexible sealing material is tightened around the neck
to a pressure sufficient to provide a substantially liquid tight
seal but not tight enough to obstruct arterial or venous blood flow
in the neck.
[0083] In one embodiment, the neck-receiving opening is a "U"
shaped opening in the side wall 126 of container 112, and the width
of the "U" is wider than the neck. Attached to the inner edges of
the opening is a liquid-resistant flexible material (such as rubber
or vinyl). At least 2 inches of free material extends from the
inferior aspect of the defect and sufficient material extends from
each lateral aspect of the defect to cross completely to the other
side of the opening. To finish the seal around the neck, the excess
material superior to the anterior surface of the neck is held
together by clips. The excess material from both sides is wrapped
around each other before being temporarily clipped together.
[0084] FIG. 4 shows a shaded area that corresponds to the upper
airway that is filled with cool liquid, and this area includes the
nasal cavity, nasopharynx, oral cavity, oropharynx, and
hypopharynx. The upper airway is defined by the walls of the
pharynx that are laterally flanked in close association on either
side by major blood vessels that perfuse the brain. As shown in
FIG. 4, these blood vessels include common carotid artery 202 and
internal carotid artery 204, which in turn supplies anterior
cerebral artery (not shown) and middle cerebral artery 206. Another
blood vessel in close anatomic association to the upper airway
includes the vertebral artery 208, which is a branch of the
subclavian artery and that in turn forms the basilar artery 210
that supplies blood to the vertebrobasilar system. The blood
flowing through the arteries of the neck are conductively cooled by
their close association with the cool liquid that fills the upper
airway, and this cooled blood quickly lowers the temperature of the
brain as the blood perfuses it.
[0085] Further cooling of the blood that perfuses the brain is
achieved by the introduction of cool liquid into the proximal
esophagus where the cool liquid comes into closer contact with
mediastinal and lower neck structures, including the common carotid
artery 202.
[0086] In this novel therapy, cooling of the blood starts in the
aortic arch if there is cold liquid flow in the esophagus and
continues throughout the length of the common and internal carotid
arteries which are in close proximity to the upper airway filled
with circulating cold liquid. The posterior circulation (vertebral
and basilar arteries) is also cooled. Cooling continues in the
Circle of Willis itself which is separated from the upper airway by
a thin layer of soft tissue and bone. Direct cooling of the scalp
and upper airway also results in a temperature gradient within the
brain, with surface temperatures colder than deep in the brain.
This gradient is offset by flowing blood since the cerebral
arteries traverse long distances along the relatively cooler
surface of the brain before delivering cooled blood to deeper brain
structures.
[0087] Using the disclosed method, focal or isolated cooling of the
head/and or brain is achieved without the adverse physiological and
medical consequences or technical difficulties of cooling the
entire body or large portions of it. Brain cooling can continue for
a sufficient period of time to avoid damage to the brain, and this
period can extend for minutes, hours, days or weeks. In some
embodiments, the cooling continues for at least 24 hours, at least
48 hours, at least one week or longer. The period of time during
which cooling is continued is determined by the condition of the
patient and the clinical judgment of medical personnel. The
temperature of the cool liquid can be changed over time in
accordance with therapeutic needs. For example, the liquid may
initially be cooled to 10.degree. C. or less (for example less than
zero .degree. C.) to induce rapid brain cooling and inhibit the
development of brain edema, adverse metabolic changes or
reperfusion injury. After the first few hours or even days of use,
the temperature of the liquid can be increased, for example to
20-30.degree. C., to cool the brain with a lesser risk of
hypothermic damage to soft tissues.
[0088] This method can produce cerebral cooling in an estimated
5-15 minutes compared to 3-5 hours demonstrated in human studies
with many other prior art hypothermic treatments. Therapy may be
started in the field (outside a hospital setting) to accelerate the
initiation of treatment and reduce the elapsed time to achieving
the temperature goal following the onset of illness. The devices
and methods can be used by someone having only basic emergency
medical skills, such as the ability to place the catheters and
insert an endotracheal tube. The simplicity of the method will also
allow for rapid application of treatment in a broad array of
clinical situations. The cool liquid can be significantly cooler
than ice water used in previous human studies and most animal
studies, thereby providing a large temperature gradient that
promotes deeper and more rapid brain cooling.
[0089] Combining the scalp, upper airway and cerebral blood cooling
provides rapid and effective cerebral cooling. The method is
particularly effective because it cools all of these structures
using a common pool of circulating cold liquid. This method of
aggressive local cooling is believed to be effective at rapidly
cooling the brain even in the absence of spontaneous circulation,
although circulating blood is believed to further accelerate the
cooling. The disclosed method also permits deeper levels of
hypothermia to be achieved, which may help to realize the possible
benefits of "suspended animation." This treatment also leaves open
the possibility of salvaging life and neurological function even in
those who do not achieve restoration of spontaneous circulation in
the field. After arrival at an appropriately equipped medical
center, whole body and brain blood flow can be reinstituted using
cardiopulmonary bypass while more aggressive and time consuming
attempts to restore and maintain spontaneous circulation are
explored. If the brain is cooled, greater neurological recovery can
be achieved even if the restoration of circulation is significantly
delayed.
[0090] The circulation of cool liquid around the head is also
believed to be more effective than the static application of a cold
source (such as a cold pack or skull cap). Factors that
functionally insulate the scalp from local hypothermia treatment
include scalp hair, the boundary layer effect, and layers of
material and air between a cold helmet and the scalp. The direct
contact of scalp structures with the circulating liquid helps avoid
these problems.
[0091] Direct cooling of the inferior surface of the brain is
believed to occur more rapidly than scalp cooling due to thinner
boundary layers of bone and soft tissue. Bone between the upper
airway and the brain is approximately half as thick as bone in the
scalp and the soft tissue layer is 1/4 the thickness of the
scalp.
[0092] An additional example of a device suitable for use with
either selective or non-selective cooling is shown in FIGS. 5A-5C.
The device is a head cooling box 220 having a rectangular base 222,
a rectangular rear wall 224, two opposing side walls 226, and a
front wall 228. Each of walls 224 and 226 are sufficiently high to
extend above the head 230 of a subject within the box, even when
the head is tilted with the head in extension as in FIGS. 5A-5C.
However front wall 228 has a cut-out support portion 232 (FIG. 5A)
for receiving the neck of the subject.
[0093] Spaced from and parallel to the outer walls of box 220 are a
set of inner walls that form a head receptacle 234 that is
sufficiently large to receive the head 230 as shown in FIGS. 5A-5C,
with the neck of the subject resting on support portion 232.
Between the head receptacle and the outer walls the box forms a
reservoir 238 that partially or completely surrounds receptacle 234
for storing a sufficient volume of cool liquid to circulate through
the subject and to be applied externally against the scalp.
Reservoir 238 extends behind and below receptacle 234 and
communicates with receptacle 234 via one or more openings that form
drains 240, 242, and 244. In the illustrated embodiment, drain 240
is in a rear wall, drain 242 in a bottom wall, and drain 244 in a
front wall of receptacle 234. An upper port 246 extends through
rear wall 224 near the top of box 220, and a lower port 248 extends
through rear wall 224 near base 222 of box 220.
[0094] In use, the head 230 of a subject in need of treatment is
placed in box 220 with the neck in cut-out portion 232 and the head
tilted back in extension. Cool liquid is introduced into reservoir
238 to provide a large volume of cool liquid that can then be
circulated though irrigation catheters (not shown) into the
aerodigestive tract of the subject as described earlier. The cool
liquid is initially delivered into reservoir 238 through upper port
246, and is subsequently withdrawn through lower port 248 and
returned through drains 240 and/or 242 and/or 244 after coming into
contact with the subject. As liquid is introduced into the
aerodigestive tract, it flows into and through the aerodigestive
tract until it eventually passively exits the mouth and nose of the
subject without being suctioned or removed through a catheter or
other tubing. As the liquid emerges from the mouth and nose, it
collects in receptacle 234 around head 230 to further cool the head
externally to lower brain temperature and drains into reservoir 238
via drains 240-244. The rate at which liquid can return from
receptacle 234 to reservoir 238 through one of more of the drains
is adjusted by the degree to which the drains are opened, and the
position and number of open drains. In the illustrated embodiment
of FIG. 5C, bottom drain 242 is open while side drains 240, 244 are
closed so that liquid in receptacle 234 passively flows under the
influence of gravity into the underlying portion of the reservoir,
as shown by the arrow 250. Adjusting the rate a which liquid drains
from receptacle 234, relative to the rate at which liquid enters
the receptacle, determines the level of liquid in receptacle
234.
[0095] In the illustrated embodiment of FIG. 5C, the liquid level
in surrounding reservoir 230 is lower than the level of bottom
drain 240, which permits drainage through bottom drain 242.
However, in those instances in which a larger volume of cool liquid
is provided in surrounding reservoir 238, the liquid is still
maintained at a level below side drains 240, 244 which are open
(while bottom drain 242 is closed).
[0096] An alternative embodiment is shown in FIGS. 5D and 5E, in
which corresponding parts from FIGS. 5A-5C are given like reference
numbers. This embodiment differs from the prior version, however,
in that the front wall 228 has a height adjustment member 252 that
fits on front wall 228 and can be moved toward and away from base
222 to adjust the height of the support for the neck of a subject.
Adjustment member 252 is capped with a cushion 254 for protection
of the neck of the subject and allows for a variable amount of neck
extension. The top of reservoir 238 is also covered by a lid 256
that pivots at hinge 258 to open and close reservoir 238. The
reservoir may be opened, for example, to add ice or other cold
objects to reservoir 238 when cooling of liquid within it is
desired.
[0097] Yet another embodiment of the box is illustrated in FIG. 5F
wherein the box 220 forms the reservoir for holding cold liquid,
and the front wall of the box is of a reduced height or has a
cut-out portion for receiving the head with the neck supported on
cushion 254 of height adjustment member 252. However the head
receptacle is formed by a liquid permeable net 260 that covers
receptacle 238 for holding the head of the subject during
hypothermic treatment. Net 260 is secured along one edge to front
wall 228 below the level of padding 254 and along an opposite edge
to rear wall 224 at the top of box 220. Net 260 therefore forms a
liquid permeable support sling for the head of a subject, so that
as liquid flows through then out of the aerodigestive tract, the
liquid spills on to and through net 260 to be returned to
underlying reservoir 238.
[0098] In the embodiment of FIG. 6A, the cooling device is in the
form of a backboard 270 that contains both a head receptacle 272
and a reservoir 274 for holding a supply of cool liquid. Receptacle
272 and reservoir 274 are in a side-by-side relationship with one
another instead of the reservoir surrounding the receptacle as in
previously described embodiments. Backboard 270 has a flat
rectangular base 276 that is large enough to accommodate upon it
the upper portion of a body, for example from the waist or
mid-thorax to the top of the head. A top surface of backboard 270
is formed by a flat body support 278 that is spaced from and held
parallel to base 276 by opposing sidewalls 271 (only one of which
is shown in phantom), an upright bottom wall 280, and an inclined
top wall 282 that separates reservoir 274 from receptacle 272.
Sidewalls 271 are of the same height as the top of receptacle 272
to thereby also form the sidewalls of receptacle 272.
[0099] Inclined wall 282 slopes from body support surface 278 down
to bottom surface 280 of receptacle 272. A drain 284 is provided
through inclined wall 282 near the junction of wall 282 with
support surface 278 to drain liquid from receptacle 272 back into
reservoir 274 when the level of liquid in receptacle 272 rises
above the level of liquid in reservoir 274, as illustrated by the
arrow through drain 284 in FIG. 6A. A cushioned neck support 286 is
positioned on body support 278 near inclined wall 282 to protect
and assist with the extension of the neck of a subject placed on
backboard 270.
[0100] In use, a subject is placed face-up on backboard 270 with
the neck extended and the head in receptacle 272. The desired
irrigation catheters are inserted in the aerodigestive tract of the
subject (not shown) and liquid from reservoir 274 is pumped through
the catheters into the aerodigestive tract for cooling the patient.
The irrigation liquid then flows out of the nose and mouth of the
subject and collects in reservoir 272 to be returned to reservoir
274 though drain 284. Backboard support 278 is preferably thermally
conductive (for example made of metal) so that the cool liquid in
the backboard also cools the body of the subject directly. This
direct cooling of the subject's back is particularly advantageous
for providing cooling of the spine in patients who may have
incurred a spinal cord injury that could benefit from such cooling
to reduce inflammation and swelling.
[0101] Another embodiment of the backboard cooling device is shown
in FIG. 6B, which is similar to the embodiment of FIG. 6A except
that body support surface 278' is inclined upwardly to lift the
shoulders and neck of the subject. Raising the upper torso in this
fashion helps protect the airway and inhibit the entry of liquid
into it. It also appropriately positions the head for intubation of
the patient and introduction of the irrigation catheters in the
aerodigestive tract. The backboard cooling device of FIG. 6B is
also shown placed under the back of a patient who is lying face up
on a stretcher 288, so that the cooling method can be performed on
the subject either in a hospital on en route (for example while in
an ambulance or in transit to a hospital).
[0102] The embodiment of FIG. 7 illustrates an embodiment of the
cooling device that is suitable for treating a subject who has had
potential spine injuries and requires stabilization of the spine to
avoid additional injury, such as damage to the spinal cord. This
embodiment includes a large rectangular tub 290 that is longer and
wider than a flat body support board 292 that is suspended above or
within tub 290. Support board 292 has lateral extensions that form
right and left arm support members 294, 296 and a superior
extension that forms a head support 298. In use, tub 290 is filled
with liquid 300 that contains sufficient ice 302 to cool it to a
desired temperature. Tub 290 therefore provides an underlying large
reservoir of cool liquid for introduction through irrigation tubes
(not shown) into the aerodigestive tract of a subject placed on
support board 292. A patient (not shown) can be positioned supine
on support board 292 with the head turned to the side so that
internally circulated liquid (and/or any liquid sprayed on the
head) can return passively to tube 290 to be cooled there for
recirculation to the patient.
[0103] FIG. 8 illustrates a mobile version of the cooling device in
which a subject 302 is lying supine on a stretcher 304 that is
supported by wheels 306 for transportation of the subject on the
stretcher. A separate reservoir 308 is supported on a cart 310
having an adjustable height, and which is also supported on wheels
312 for movement with the stretcher. Reservoir 308 is a large
capacity tank that has a cut-out or reduced height portion 311 in
which the neck 314 is placed so that the head 316 of the patient
can be tilted back and into reservoir 308. A backboard is placed
under the back of the patient to support the back and head. The
backboard is an angled member that includes several sections: a
flat back support 318 for horizontal placement on stretcher 304, an
inclined neck support 320 that fits into reservoir 308 through the
neck-receiving portion of the reservoir, and a flat head support
322 that is secured to neck support 320 and held substantially
parallel to back support 318. Head support 322 mates with a series
of ratchets or support grooves 324 on neck support 320 so that the
position of head support 322 can be adjusted along neck support 320
while maintaining the substantially parallel relationship between
head support 322 and back support 318.
[0104] In use, the subject 302 is placed supine on stretcher 304
with back support 318 under the back of the subject, the neck
positioned in cut-out portion 311, and head 316 tilted back over
the top edge of stretcher 304 with head 316 in reservoir 308 which
also serves as the receptacle for holding the head. The position of
head support 322 is adjusted to support the crown of head 316 at a
desired depth within reservoir 308. Reservoir 308 contains cool
liquid 326 up to a level that covers the crown of head 316 to
provide external cooling of the head (or below the head if scalp
cooling is not desired). As described in connection with other
embodiments, irrigation catheters (not shown) are inserted in the
subject 302 and cooling liquid 326 is pumped from reservoir 308
into the aerodigestive tract of the subject to achieve the desired
rate and degree of cooling. Since both the reservoir and stretcher
are on wheels, they are transported in tandem to administer the
hypothermia therapy to the subject during transport.
[0105] Additional details about the disclosed method and device are
provided in the following Examples.
Example 1
Temperature of the Liquid
[0106] Since permanent brain injury is a major cause of death and
disability, more effective methods of brain cooling will benefit a
subject's overall medical recovery even if these treatments risk
transient damage to other tissue beds. While frost-bite can
sometimes occur at temperatures less than 0.degree. C.,
perfluorocarbon (PFC) and other liquids at temperatures used herein
are believed to be more beneficial than harmful in this method. For
example, household freezers maintain their contents at -17.degree.
C. and food (such as ice cream) is consumed at this temperature
without damage to the mouth or esophagus. Likewise, cold items from
a freezer can be placed on damaged skin to reduce swelling (ice
packs to traumatized areas) without unacceptable risk of tissue
necrosis.
[0107] The esophagus and upper airway are resilient to a variety of
damaging stimuli, such as acid reflux, toxic injections, radiation
and chemotherapy. The lungs, upper airways and skin have been
exposed to 0-4.degree. C. water/saline in cold water drowning
without significant sequela. The lung has been infused with large
volumes of 4.degree. C. PFC without significant adverse effects, so
cold biocompatible liquids that may inadvertently enter the lungs
is unlikely to be harmful.
[0108] Beneficial results of brain cooling can be seen, for
example, with cerebral cooling to approximately 33.degree. C.
However, the brain can tolerate much lower temperatures. Animals
have had their brains cooled to 10-26.degree. C. and subsequently
recovered without significant neurological damage. Humans have been
found at 26.degree. C. and subsequently recovered without
significant neurological damage. Based on this information, it is
believed that the disclosed hypothermic treatment can be used with
an acceptable therapeutic risk if the cooled liquid is at a
temperature below about 30 or 32.degree. C., and above -20.degree.
C., for example above -10 degrees, zero degrees, 10 degrees or 20
degrees. Brief skin and upper airway exposures to liquid with
temperature between -30 to -20.degree. C. may also carry an
acceptable risk of soft tissue injury. Therapeutic risks of cold
damage to soft tissue can also be reduced by inducing the
hypothermic cooling at a lower temperature and then gradually
increasing the temperature as the risk of soft tissue damage
increases and the risk of permanent brain damage decreases.
Example 2
Precooling the Brain
[0109] The disclosed brain cooling method has been described in
connection with the treatment of cardiac arrest, stroke, brain
injury and other conditions. However, the method can also be used
prophylactically, for example to prepare a patient for
cardiovascular surgery in which the patient is placed on a
heart-lung bypass machine. Prior studies have shown good outcomes
of cardiac surgery performed on humans externally cooled to
25.degree. C. with ice baths. Such patients have had encouraging
outcomes after circulatory arrest that lasted for 30 to 77 minutes
that was not supported by hear-lung bypass or other means. Adverse
neurological outcomes were observed only in 3.8% of surviving
patients, predominantly in those with arrest times longer than 30
min. The brain cooling method of the present invention can be
substituted for the external cooling with ice baths during such
procedures.
[0110] While "suspending" cerebral metabolism may explain the
protective effect of hypothermia, the temperature of the brain at
the time that cerebral blood flow is restored may also be an
important variable. This hypothesis is consistent with
reperfusion-injury theory. Neurological function may be better in
patients who have perfusion reinstated after cerebral cooling
rather than before cerebral cooling.
Example 3
Clinical Indications
[0111] A variety of clinical conditions can be treated with the
methods and devices disclosed herein. In some embodiments, the
method involves determining whether a subject has a condition that
would benefit from treatment with the cooling method and then
treating the subject with the method once it has been determined
that the subject has that condition. In addition, the method
includes determining whether the condition would benefit from
relatively selective cooling of the brain or non-selective cooling,
then administering that type of cooling (or a combination thereof).
Examples of such conditions, and a treatment that can be initiated
in response to finding that condition, are shown in the following
Table 1.
TABLE-US-00001 TABLE 1 Clinical Indications for Cooling, and Types
of Cooling Selective cooling (targets cooling primarily the head
and brain) Anoxic encephalopathy Cardiac arrest Hemorrhagic shock
Sepsis Neonatal anoxic encephalopathy Stroke Embolic Hemorrhagic
Head trauma Closed Open Neurosurgery Cerebral aneurism repair
Hematoma evacuation Resection of abnormal tissue or tumor
Cardiovascular surgery CABG (Coronary Arterial Bypass Surgery)
Valve surgery CEA (Carotid Endarterectomy) Aortic aneurism repair
Pulmonary arterial embolectomy High risk general surgery Procedures
with risk of diminished oxygen or blood flow to brain from Hypoxia
Hypotension Systemic or cerebral embolization SIRS (systemic
inflammatory response syndrome) Status epilepticus Fever associated
with: Systemic infection Stroke Seizures Malignant hyperthermia
Neuroleptic syndrome Encephalitis Infectious Toxic Metabolic
Meningitis Prevention of hospital acquired pneumonia Non-selective
cooling (also targets cooling organs outside of the head) Early
stage of brain cooling Spinal cord Injury Ischemia Myocardial
infarction Cardiogenic shock SIRS (systemic inflammatory response
syndrome) Septic shock Hemorrhagic shock, large volume transfusion
Anaphylactic shock Acute lung injury ARDS (adult respiratory
distress syndrome) Aspiration Pneumonia TRALI (transfusion related
acute lung injury)
[0112] Treating Stroke:
[0113] Many animal studies have shown that cerebral cooling results
in improved neurological function and reduced volume of infarct
after stroke. Cerebral cooling appears to be beneficial even if
initiated hours following the onset of the stroke, however more
benefit is obtained if therapeutically effective hypothermia is
promptly induced and maintained in accordance with the methods
disclosed herein. Cerebral cooling can be used as a primary therapy
for stroke, and can also be used as a bridging therapy before
attempting cerebral revascularization.
[0114] Cerebral revascularization is performed as a standard
treatment for embolic strokes. Thrombolytics are routinely used to
treat embolic stroke in patients who present to a medical center
within 3 hours of initial symptoms. The mechanical removal of
cerebral vascular embolism (embolectomy) has been shown to improve
neurological function in humans after stroke even if
revascularization is delayed until up to 8 hours after the onset of
the stroke. Timely revascularization is also combined with the
disclosed methods of rapid induction of cerebral cooling to
significantly improve neurological outcome after stroke.
[0115] Fevers: High fevers are commonly seen in infection, stroke,
seizures trauma and adverse drug reactions. Fevers are associated
with significantly worse neurological outcomes. Current methods of
cooling are often not able to prevent or blunt fevers even when
patients are closely monitored in intensive care settings. Fevers
often present rapidly (spike) and often last for only 1-2 hours,
and current methods of cooling are not able to lower temperatures
significantly in this short amount of time even when the brain is
normothermic and would be expected to take even longer to cool the
brain during fever. The methods disclosed herein are capable of
reducing cerebral temperatures to <33.degree. C. in 5-15 minutes
even in the face of fever to rapidly blunt fevers and reduce damage
to vulnerable organs such as the brain, lungs and kidneys. Rapid
interruption of fever spikes is also believed to improve outcomes
in systemic inflammatory conditions such as septic shock and acute
lung injury.
[0116] Surgical Procedures:
[0117] Brain damage is also a risk associated with neurosurgical,
cardiovascular and other surgical procedures. Cognitive and
behavioral changes are common after CABG (coronary arterial bypass
surgery). Episodic hypotension and hypoxia are common occurrences
in such high risk surgical procedures. Surgical interruption of
cerebral blood flow is also required for cerebral aneurism repair
and CEA (carotid endarterectomy) which can induce transient or
permanent neurological damage. Cerebral hypothermia is believed to
reduce the effects of surgically related brain damage from
intraoperative hypotension, hypoxia, interruption of cerebral blood
flow (emboli, vascular clamping) or inflammation. Brain cooling
before injury results in better outcomes than if cooling is
initiated after injury, therefore to prevent or minimize surgery
related brain injury cooling is preferably completed before the
initiation of surgery, for example between the induction of
anesthesia and the beginning of surgery. Cooling can be maintained
during surgery and the recovery period.
[0118] Myocardial Infarction and Ischemia:
[0119] The disclosed rapid induction of therapeutic hypothermia is
also believed to be advantageous in subjects who have had a
myocardial infarction (MI) whether or not blood flow is
reestablished to the affected area. If perfusion is not
reestablished, cooling is believed to limit the volume of dead
tissue by salvaging the areas with collateral circulation and
partial perfusion. Cooling the heart and systemic arterial blood
before perfusion is reestablished is believed to decrease
reperfusion injury, which may be the primary cause of permanent
myocardial damage after MI. In some embodiments of the method,
cooling is therefore initiated before revascularization and is
continued during and after coronary instrumentation or
thrombolysis. Rapidly induced hypothermia cools the heart in a
clinically desirable amount of time while reperfusion efforts are
underway. Rapid myocardial cooling occurs because cooled blood
occupies all four chambers of the heart, cooled systemic arterial
blood supplies the myocardium, and the outer surfaces of the heart
are directly cooled by the cold liquid in the esophagus and the
stomach.
[0120] The disclosed cooling methods are safe for use during
treatment for acute MI. Cardiac arrhythmias are common after MI and
systemic hypothermia increases the risk. It is therefore possible
that electrical cardioversion will be required to offset such heart
rhythm abnormalities, however cardioversion can be performed safely
since the chest and torso will be dry and the device is
electrically isolated.
[0121] Cooling of the Spinal Cord or Body to Diminish
Inflammation:
[0122] The disclosed method can also be used for non-specific
cooling of organs other than the brain. For example, irrigating the
oropharyngeal cavities and esophagus with cool water can be used to
cool the entire neck or back and adjacent structures, such as the
spine and spinal cord (such as the cervical spine) in a trauma
victim with a neck or back injury. Such cooling will diminish
residual adverse neurological sequelae. Although the spinal cord is
thinner than the brain, it is surrounded by more insulating tissue
and bone. These insulating features can be overcome, however, by
cooling the blood that is perfusing the spinal cord and its
surrounding structures. The regioslective features of the disclosed
method can be used to enhance treatment of particular types of
injuries, or maximize the cooling of specifically affected
areas.
[0123] Generalized cooling of the spinal cord can be achieved by
rapid and significant cooling of the brain, which lowers the
temperature of the cerebrospinal fluid (CSF) that circulates around
the spinal cord. The introduction of cool liquid through the tubes
in the mouth and esophagus will introduce a high volume of
turbulent flow against tissues that are very near the brainstem,
which can also be helpful in cases of basilar stroke or other
injuries to the brainstem. In addition, the cooling of blood
returning from the head (for example via the jugular veins) in turn
cools the blood in the heart that is subsequently pumped through
the aorta and to the vertebral arteries that perfuse the spinal
cord. Cooling of the mediastinum by introducing cool liquid into
the esophagus and the stomach will cool the blood returning to the
heart via the superior and inferior vena cava. This cooled blood
will then be pumped to the spinal cord. The overall reduction in
body temperature achieved by lowering the temperature of aortic
blood also helps reduce the inflammatory response and minimize
permanent neurological damage that may otherwise occur to neuron
bodies from damage to its neurons.
[0124] Although regioselective cooling of the upper aerodigestive
tract will target cooling directly to the cervical spine, more
generalized cooling can be used to minimize systemic inflammatory
effects of trauma to the brain or non-brain structures (such as
spinal cord injury or other types of trauma, such as multiple
fractures). Complete submersion of the head accompanied by cooling
irrigation of the entire aerodigestive tract (but not the lungs)
will maximize total body cooling and accelerate induction of
protective cooling to minimize the inflammatory response. For
example, placement of irrigation tubes into the nasopharynx,
oropharynx, and esophagus (and optionally the stomach) will rapidly
induce widespread body cooling.
[0125] In cases of potential spinal injury, care must of course be
taken to stabilize the spine during the induction of rapid brain
and/or body cooling. Devices and methods that avoid extension of
the neck are preferred in such circumstances.
[0126] The disclosed methods cool the spinal cord at all levels
relatively rapidly because the cord is thin and of low mass.
Cooling of the upper cord is enhanced because it is bathed with
cold cerebrospinal fluid (CSF) from the cranium and direct cooling
from the upper airway. Cervical spine cooling is targeted for
33.degree. C. within 15-30 or 15-20 minutes of initiating
cooling.
[0127] Lung Cooling:
[0128] Inflammation associated with lung injury, such as the adult
respiratory distress syndrome (ARDS) has been extremely difficult
to prevent and treat. Broad anti-inflammatory modulation with
steroids has had mixed results and is not recommended for
early-stage ARDS. The only targeted anti-inflammatory therapy for
sepsis that has come to market is so toxic that it is
contraindicated in patient with isolated ARDS and no other organ
failure; the morbidity and mortality associated with the drug is
greater than that of ARDS alone. In contrast, systemic hypothermia
causes less toxicity while demonstrating broad anti-inflammatory
properties. Prior studies have shown that cooling in ARDS provides
a 33% reduction in predicted mortality when body temperature is
reduced to 33.degree. C. in severe ARDS otherwise refractory to
non-cooling treatments.
[0129] The lungs cool more quickly than most other organs
(including the brain) when the non-selective cooling methods
disclosed herein are used. The lungs have the greatest ratio of
blood flow to organ mass in the body and the full cardiac output
runs through them. The lungs are also insulated by air in the
airspaces, which compose the majority of the lung's volume, and
have a low metabolic rate.
[0130] Avoiding Hospital Acquired Pneumonia:
[0131] Hospital acquired pneumonia, particularly for a patient
receiving mechanical ventilation, is caused by translocation of
bacteria from the upper airway to the lung. Currently, prevention
of ventilator associated pneumonia relies on attempts to disinfect
the upper airway using an antibacterial mouth wash applied twice
daily in combination with frequent oral care. However, the
disclosed cooling is believed to lower the incidence of ventilator
associated pneumonia by reducing the number of viable bacteria in
the upper airway by washing away bacteria with the large volume of
cooling liquid that passes through the upper airway. The
temperature of the cooling liquid renders the bacteria inert and
can even kill many species. In addition, cooling liquid that
contains propylene glycol further reduces the number of viable
bacteria because propylene glycol has broad antibacterial
properties.
Example 4
Inhibiting Flow of Cool Liquid into Lungs
[0132] Maintaining the lungs free of the cooling liquid avoids loss
of the liquid from the upper airway and helps maintain more
effective gas transport in the lungs. A variety of techniques are
disclosed as means for inhibiting the entry of the cool liquid into
the lungs.
[0133] For example, the subject's head and neck may be extended
unless contraindicated (for example when cervical spine damage is
suspected). Head and neck extension reduces the risk of cold liquid
entering the lung by elevating the level of the entrance of the
trachea (the larynx) compared to the level of the liquid.
[0134] Alternatively, the subject is placed in the Trendelenburg
position with the head lower than the chest. This position reduces
reduce the risk of cold fluid entering the lung by elevating the
level of the entire trachea and lungs compared to the level of the
liquid.
[0135] Another possibility is to elevate the subject's chest on a
firm (possibly padded) board approximately 10 to 30 cm thick. The
chest elevation raises the level of the entire trachea and lungs
compared to the level of the liquid. In some embodiments the board
will have a defect in the midline of the cephalad portion to allow
the neck to hyperextend without impingement on the board. The board
may also extend under the head at a thickness of 2 to 6 cm,
positioned under the box to support the box. The board is firm
enough to support CPR.
[0136] As shown in the detailed embodiments of the method, a
multi-lumen endotracheal tube with an inflatable balloon cuff (or
for infants without a cuff) may also function to keep cold liquid
from entering the lungs. In some embodiments, the cuff can comprise
an ultrathin high volume cuff. The pressure in the cuff can be, in
some embodiments, greater than about 30 cm H.sub.2O.
[0137] The endotracheal tube may also contain a third lumen with
the distal opening immediately proximal (above) the inflatable
balloon cuff and with the proximal end connected to suction. This
third lumen will remove liquid proximal to the balloon cuff,
reducing the amount of liquid that would need to be blocked by the
balloon cuff.
[0138] Active removal of liquid from the pharynx can be provided to
further restrict fluid entry into the subject's lungs. For example,
tubing under a negative pressure can be provided with an open end
or port located in the oropharynx or hypopharynx. In this manner,
fluid can be actively removed from the pharynx and returned to the
reservoir. The negative pressure in the tubing can be accomplished,
for example, by using a suction device such as a suction pump or
other such device.
[0139] Similarly, active removal of liquid from the trachea can be
provided to further restrict fluid entry into the subject's lungs.
Such subglottic suction can be achieved via a lumen on a cuff (as
described above) positioned in the trachea or by providing an open
end or port of a tube in the trachea (e.g., above an endotracheal
tube cuff). The tubing can be under negative pressure to pull
liquid into the opening or port to remove liquid from the trachea.
The removal of fluid from the trachea can be intermittent or
continuous. The rate of fluid removal can be monitored to determine
the amount of fluid being delivered to the trachea. If the rate is
too high measures can be taken to reduce fluid in the trachea, such
as increasing the suction pressure, extending the period of use of
a suction pump configured to remove fluid from the trachea, and/or
decreasing the flow of fluid into the aerodigestive tract (and, in
particular, in the area of the trachea).
[0140] In other embodiments, a modified laryngeal mask airway (LMA)
can be provided to restrict fluid from entering the subject's
lungs. The LMA can have an inner diameter greater than an outer
diameter of an endotracheal tube (ETT) positioned in the trachea. A
portion of the LMA can be removed so that the LMA can slide over an
existing ETT. The portion that is removed can be, for example, a
portion of the perforated membrane in a central region of the LMA.
In use, the LMA circumferential cuff can be inflated so that the
circumferential cuff seals the larynx off from the pharynx. In some
embodiments, a suction tube can be provided to remove fluid around
the mask. If desired, the suction tube can be attached to the mask.
Once the LMA is in position, the ETT or other suction tube can be
removed from the opening in the LMA, leaving the LMA in place.
Example 5
Liquid Flow and Temperature
[0141] The total amount of liquid introduced into the cool liquid
reservoir can be varied according to the needs of the patient. As
already noted, the cool liquid can be introduced at a depth that
covers the entire head and face. Another option is to keep the
liquid level below the level of the endotracheal balloon. The pump
flow (from one or more pumps) can be adjusted to provide overall
liquid flow in the range of 0.5 to 50 or 60 L/minute to the
internal catheters (not including the catheters provided for
directing a turbulent flow of cooling liquid against the scalp of
other structure that does not involve insertion of a catheter into
the mouth or nose). In certain examples this flow is at least 10
L/min. The total flow is typically delivered through 1-6 (such as
2-6) or more catheters. The position of inflow and outflow
catheters can be changed over time if needed to provide or maintain
liquid flow over the scalp and in the upper airway.
[0142] Non-limiting examples of flow rates for particular
nasal-oral cooling are 0.5-6 L/min flow in the nose alone. In other
examples, the flow rate in the nose can be at least 2 L/min, such
as 2-20 L/min. Esophageal flow rates can be independent of other
flow rates, and, in some embodiments can be between about 0.5-6
L/min flow in the esophagus alone. In other examples, the flow rate
in the esophagus can be at least 5 L/min, such as 5-20 L/min. The
maximum flow rates selected should not exceed those that are
considered are safe and well-tolerated by the patient.
[0143] In certain embodiments, flow can be adjusted to be 0.5-10
L/min into the upper airway and 1-20 L/min on the scalp for adults,
less for children and infants. A particular reservoir (such as a
box in which the head is partially or totally immersed) has a total
volume of about 40 liters if the box is about 35 cm on all sides.
In such particular embodiments, 5 to 15 or 20 total liters of cold
fluid are present in the reservoir, for example about 10 liters.
The contents of the reservoir can be circulated about twice a
minute, or more, to achieve a desired degree of turbulence that
enhances head cooling. To maintain high flow cooling at a low
temperature, even larger reservoirs of cooled liquid can be
employed, such as reservoirs that contain 20 or more liters (for
example at least 30 or 40 liters) of the cooling liquid at the
desired temperature (for example, less than 5.degree. C., 0.degree.
C., or -5.degree. C.).
[0144] To achieve optimal cooling, different flow rates of cooling
liquid can be introduced through different catheters that are used
in the method. Optimal flow may differ for different tubes,
clinical indications and patients but non-limiting examples of flow
rates for selected internal tubes include:
[0145] Nose tube(s)--6 L/minute (combined, right+left nasal cavity
at 3 L/min each)
[0146] Mouth tube--8 L/min
[0147] Upper esophagus--8 L/min
[0148] Lower esophagus--8 L/min
[0149] Stomach--12 L/min
[0150] Total Flow Rate--42 L/min
[0151] An alternative combination of flow rates is illustrated by
this example:
[0152] Nose tubes(s)--6 L/min (3 L/min each nostril)
[0153] Oral and esophagus--12 L/min combined (from a single
pump)
[0154] Total Flow Rate--18 L/min
[0155] An example of a rate of external flow of cooling liquid
against the scalp is 20 L/min.
[0156] In other non-limiting examples, when cooling only the upper
airway (all exposed external structures of the aerodigestive tract
above the trachea and esophagus), a minimum of 10 L/min total flow
can be provided through two nasal catheters and one oral catheter.
In an example that also includes irrigating the upper esophagus,
lower esophagus and stomach, the total flow can be about 30
L/min.
[0157] In other examples, the flow per catheter can be about 2
L/min. For instance, when irrigating above the esophagus with three
catheters (one each in nostril and one in the mouth) then the flow
above the esophagus can be about 6 L/min (2 nasal and 1 oral
catheter). This is a higher flow rate than in prior methods of
cooling. Then when adding catheters (or lumens) to introduce
cooling liquid at three ports below the entrance to the esophagus
(for example, two in the esophagus and one in the stomach) an
additional 6 L/min would be introduced into the aerodigestive tract
for a total of 12 L/min.
[0158] In other embodiments, because of the cumulative effect of
adding multiple irrigating catheters, the flow rates associated
with each catheter can be relatively low, such as about 0.5
L/min.
[0159] In another example, if cooling liquid is only introduced
into the nose using 2 L/min in each nostril, then the total flow
rate of cooling liquid into the aerodigestive tract (in this case
the upper airway) is 4 L/min.
[0160] The temperature of the liquid in the container can be
adjusted by various cooling means over time, for example by any one
or combination of the following methods: [0161] adding cold liquid
to the reservoir to increase the volume of liquid in the box [0162]
removing an aliquot of warmer liquid and replacing it with colder
liquid [0163] placing inert cold objects within the reservoir
[0164] placing frozen water (water ice) or CO2 (dry ice) within the
reservoir (as used herein, "ice" refers generically to a solid
phase of a non-metallic substance that is a liquid or gas at room
temperature) [0165] placing a heat exchanger in series with the
reservoir and the pump
[0166] Additional air may be added to the balloons of the
endotracheal tube and the esophageal catheter to compensate for
volume loss in the balloon as the air within the balloon is
cooled.
[0167] The initial temperature of the liquid is in the range of -30
to +30.degree. C. Optimal temperature may vary during treatment but
is believed to be in the range of -20 to +10.degree. C.
[0168] The ideal cooling liquid is biologically compatible (for
example nontoxic) and has a melting point in the range of -50 to
+10.degree. C. and a boiling point of greater than 50.degree. C.
Examples of liquids meeting these are listed in Example 12. Liquids
can be combined or used in series during the treatment.
[0169] Although various flow rates are described herein, it should
be understood that many of the general advantages of the disclosed
embodiments can be achieved using either high or low flow rates. By
irrigating various portions of the upper aerodigestive tract
(excluding the lungs and intestines), the cold fluid in the
aerodigestive tract can extract heat from the perivascular tissue
(tissue surounding the arteries of the head, neck and mediastinum),
which in turn extracts heat from the blood in the carotid and
vertebral arteries. The cold blood then extracts heat from the
brain and returns to the body having been warmed by passage through
the brain. This chain of events means that extracting a joule of
energy from the patient's brain and into the aerodigestive tract
fluid involves several interacting transport processes. Without
being bound by theory, it is believed that the convective transfer
of heat into the forced flowing cooling fluid in the aerodigestive
tract will be much faster than conduction through the perivascular
tissue of the patient. As a result, increasing the length and/or
area of the cooled region in the manners described herein is
particularly helpful to improve cooling of the brain.
[0170] As discussed above, in some embodiments, increased flow
rates may improve cooling of the brain; however, it should be
understood that the systems described herein can function
effectively with both high and low flow rates when the free-flowing
liquid is introduced to the larger cooling regions as disclosed
herein. In addition, by increasing the length and/or areas of
cooling as described herein, the regions of cold tissue created
around the aerodigestive tract can overlap a greater portion of the
key arteries that supply blood to the brain, thereby creating a
longer zone for the blood to cool on its way to the brain.
Example 6
Multistage Cooling (Induction and Maintenance)
[0171] The cooling methods disclosed herein can be used for
multi-stage treatments, for example using induction and maintenance
regimens. In certain examples, the induction stage can take 15
minutes to an hour, followed by a maintenance phase that can last
greater than 12 hours, for example, 12-48 hours, such as up to a
week or more. Different issues related to side effects arise during
such long duration treatment, for example chemical or thermal
toxicity of the liquid caused by sustained exposure to the cooled
tissues of the aerodigestive tract. To address these issues,
different liquids and temperatures can be used in the induction and
maintenance phases of the treatment. For example, lower liquid
temperatures will be used in the induction phase to achieve more
rapid cooling, while higher liquid temperatures can be used in the
maintenance phase. In one example, the temperature of the cooling
liquid during the induction phase is -30 to 5.degree. C., while the
liquid temperature in the maintenance phase is 5 to 30.degree. C.
Liquid flow rates are also varied depending on the stage of
treatment. For example, higher flow rates can be used during
induction to achieve more rapid cooling, while lower flow rates can
be used during maintenance for a more prolonged period of time.
[0172] In one example, a liquid temperature below 0.degree. C. is
used for the induction phase to achieve more rapid cooling (for
example during the first 30 minutes to one hour of cooling).
Temperatures below 0.degree. C. are achievable with liquids such as
propylene glycol cooled with ice. After cooling induction, higher
temperatures (above 0.degree. C.) are used for maintenance. Such
temperatures are readily achieved with cooled water.
[0173] Given the urgency of cooling the subject quickly to achieve
maximal benefit from the procedure, less controlled conditions may
be used during rapid induction, for example in the field (such as
in an ambulance) before a subject is brought to a hospital. Hence
the subject's head may be partially or completely immersed in a
container of ice water by emergency medical technicians who have
been sent to retrieve a patient who may benefit from the treatment.
The liquid in the container can also be used to supply the
irrigation fluid for the aerodigestive tract at a less controlled
temperature than would be achieved in the more controlled
in-patient setting (as in an intensive care unit).
[0174] Different body regions can also be cooled in different
stages of the treatment. Portions of the head and aerodigestive
tract that are suitable for irrigation with turbulent cold liquid
include external structures such as the scalp and face, and
internal structures of the aerodigestive tract such as the
naso-pharynx (through nose tubes), the oro-hypopharynx (through a
mouth tube), the esophagus (through one or more esophageal tubes),
and the stomach (through a stomach tube). During induction, when
rapid cooling of the brain and/or body is desired, all regions may
be used for cooling unless otherwise contraindicated.
Alternatively, during induction catheters can be placed in all
these locations except the stomach. During maintenance treatment,
any combination of the external and internal structures can be used
to achieve desired degrees of targeted or non-targeted cooling.
[0175] As discussed above multi-stage cooling can include an
initial induction cooling stage and later maintenance cooling
stage. In some instances, these stages (or a portion of each stage)
can take place at different locations. For example, a subject may
begin the induction stage at a first location (e.g., outside of a
hospital setting such as in an ambulance, at the place of injury,
etc.) and the induction stage can be continued or the maintenance
stage begun at a second location (e.g., at a hospital).
Accordingly, it can be useful to provide a system wherein various
elements (such as the tubing, pump, etc.) are capable of being
transferred with the subject from the first location to the second
location. At subsequent locations, such elements can be
reconnected, if necessary, to systems and cooling fluids provided
at the subsequent location.
[0176] In one embodiment, the aerodigestive tract and/or upper
airway can be cooled while the subject's head is at least partially
submerged in a reservoir during an induction stage. Then, during
transfer of the subject to the section location, the subject's head
can be removed from the reservoir and the cooling of the
aerodigestive tract and/or upper airway can be continued without
external cooling of the head by submersion in a reservoir. In this
case, the cooling liquid can be delivered and recirculated from the
original reservoir (from which the subject's head was removed) or,
if desired, the cooling liquid can be delivered and recirculated
from a different external reservoir.
[0177] In another embodiment, the reservoir that supplies the
cooling liquid to the aerodigestive tract and/or upper airway can
be separate from the reservoir that supplies the cooling liquid
that cools the external surface of the subject's head. In this
manner, the subject can be readily transitioned from an induction
stage in which an external surface of the subject's head is cooled
along with the cooling of the aerodigestive tract and/or the upper
airway to a maintenance stage where only the aerodigestive tract
and/or the upper airway is cooled.
[0178] Although multistage cooling is described, it should be
understood that the systems and methods described herein can be
performed separately. Thus, for example, if desired, the upper
airway and/or aerodigestive tract can be cooled without providing
any external cooling (e.g., to an external surface of the
head).
Example 7
Selective and Non-Selective Cooling
[0179] The disclosed method and device can be used to
preferentially or selectively cool the brain ("selective mode") or
to cool the entire body ("non-selective mode").
[0180] In the selective mode, the aerodigestive regions to be
cooled by applying cooling liquid are only the nasopharynx and
oropharynx; in some embodiments the cooling liquid is also
introduced into the upper esophagus. Liquid may optionally be
inhibited from entering the lower esophagus and the stomach by
placing an esophageal balloon that obstructs the lower esophagus.
However, in some embodiments of selective cooling the esophagus is
not mechanically obstructed.
[0181] In non-selective mode, the following regions are cooled:
scalp, face, nasopharynx, oropharynx, and portions of the
gastrointestinal tract, such as one or more or all of the upper
esophagus, lower esophagus, and stomach.
[0182] Selective cooling allows for lower temperatures in the brain
with less cooling of the body core and therefore less systemic
toxicity. In animal models, brain temperatures of 15.degree. C.
have been shown to be very well tolerated and therapeutic, while
core body temperatures of <30.degree. C. are associated with
increased risk of cardiac arrhythmia, pneumonia and electrolyte
shifts. Cooling "overshoot" does not appear to have any adverse
effects in the brain.
[0183] Non-selective cooling is used to reduce the effects of
inflammation and ischemia throughout the body. Many diseases or
conditions are driven by inflammation: reperfusion injury after
organ ischemia, septic shock, trauma and allergic reactions.
Cooling has a potent broad non-selective anti-inflammatory effect
and is currently being studied as a treatment for some of these
conditions.
[0184] Cooling outside of the cranium is accomplished by cooling
the arterial blood supplying the organs or structures of interest,
or the body in general. Experimental data from use of the disclosed
device and method have demonstrated significant cooling of the
aortic blood, at approximately the same rate and depth as that of
the brain, even without cooling the lower esophagus or stomach.
Arterial blood temperature (measured in the aorta) is decreased by
profoundly cooling the blood returning to the heart from the head
and neck. Cooling of the face and scalp cools the blood delivered
to the extracranial structures of the head via the external carotid
artery. In addition, cooling of the tissue surrounding the upper
aerodigestive tract (above the esophagus) also adds to the coolness
of the returning jugular venous blood. Cooling of every possible
surface of the head and the entire upper airway provides effective
non-selective cooling.
[0185] Cooling structures below the upper aerodigestive tract, such
as the lower esophagus and stomach, increases the rate of systemic
arterial blood cooling. Cooling of the entire mediastinum can be
achieved by cooling the full length of the esophagus as well as the
stomach. The proximity of the esophagus to the superior vena cava,
right atrium and inferior vena cava allows for cooling of blood
coming from all areas of the body. Therefore, cooling of the entire
esophagus and the stomach allows for more rapid cooling of systemic
arterial blood by cooling all venous blood as it returns to the
heart.
[0186] Although some currently available hypothermia devices rely
on non-selective cooling, they are unable to provide non-selective
cooling at therapeutically beneficial rates. The methods and
devices disclosed herein are optimally able to achieve a
therapeutic target temperature in the brain within 5-10 minutes,
but optimal cooling of most of the non-brain organs is expected to
require more time. The rate and depth of cooling of an organ will
depend on multiple factors, including the organ's mass, metabolic
activity, rate of blood flow and cold induced vasoconstriction in
addition to the temperature of the blood perfusing the organ. This
amount of time is still much less than that required by
state-of-the-art devices, which require 3-6 hours.
[0187] The methods and devices disclosed herein are also capable of
delivering a rapid "burst" of hypothermia to affected organs (such
as the brain) early in the course of treatment. Rapid induction of
hypothermia allows for a more definitive reduction of inflammation
at the beginning of the inflammatory cascade, which is believed to
significantly enhance the effectiveness of treatment. Early
temperatures in target organs could briefly be obtained that are
far lower than what would be considered toxic if maintained
throughout the body for a prolonged period of time.
[0188] Any "overshoot" of systemic cooling can be rapidly
corrected. Since continuation of cooling requires continued use of
the device, merely discontinuing or diminishing treatment will
result in an increase in body temperature. This rapid reversibility
contrasts to other state-of-the-art devices which require warming
of the entire mass of the body if the core body temperature
decreases to an unwanted level. Warming the entire mass of the body
is a slow process.
[0189] In certain embodiments of the method, therapeutic
hypothermia is induced non-selectively followed by selective
cooling (for example of the brain to result in very rapid cooling
of the brain). Delivery of warm blood from the body via the carotid
and vertebral arteries normally counteracts cerebral cooling.
However non-selective cooling results in a rapid decrease in
systemic arterial blood temperature, resulting in cooler blood
entering the carotid and vertebral circulations in the upper chest
and allowing for an even lower temperature of blood as it enters
the brain. Non-selective cooling also decreases the minimum plateau
temperature achieved in the brain. The minimum temperature of the
brain is a balance between the amount of heat delivered to the head
from the body and the amount of cold delivered by the device. Since
non-selective cooling decreases systemic arterial blood
temperature, less heat is delivered to the head and lower brain
temperatures are possible, and are more rapidly achieved.
[0190] After the brain has reached its goal temperature (predicted
by non-invasive measurements) cooling can be switched from
non-selective cooling to selective head cooling. This change helps
avoid adverse reactions from body core hypothermia. After selective
cooling is initiated, body warming can be initiated to slow or
reverse the temperature decline for the body core.
Example 8
Emergency Cooling with Rapid Induction
[0191] An advantage of the disclosed methods and devices is that
they are capable of inducing rapid cooling of the brain and/or
other organs and/or the entire body. Such rapid cooling has been
found particularly beneficial in the avoidance of permanent tissue
damage and the promotion of full functional recovery. Certain
embodiments of the invention are therefore designed for use by
emergency medical technicians in the field, for example in
ambulances transporting patients to a hospital.
[0192] A cooling unit (such as a small freezer) may be placed in an
ambulance, and the unit contains 5-50 liters of a cooling liquid
(such as 20% propylene glycol in water). If the technicians find a
subject who has a condition that would benefit from brain and or
body cooling (as detailed in other sections of this specification),
then rapid field-induction of brain or body cooling can be achieved
by quickly immersing the head of the patient in cooling liquid. To
simplify use of the device in the field, ice can be placed in the
liquid to maintain it at the desired temperature. The iced liquid
in which the head is submerged also serves as a reservoir of
cooling liquid that can be directed in a turbulent flow externally
against the head, and/or used as an irrigating fluid for
introduction into the aerodigestive tract. This simple version of
the device will not require any electrical cooling devices, and
cooling can be maintained by ice cooled liquid alone for the
duration of transportation of the patient to the hospital.
[0193] When used in the field, and to simplify the technique for
rapid induction and ease of transportation, the cooling of the
aerodigestive tract may be carried out without external application
of cooling liquid to the head, as would occur in partial or total
immersion of the head. However, the cooling liquid may optionally
be applied externally to the head to further accelerate rapidity of
therapeutic hypothermic induction.
Example 9
Pump Embodiments
[0194] Although only one pump is shown in FIG. 3 to drive liquid
externally over the head and internally through the upper airway,
multiple pumps can instead be incorporated into the system. For
example a first pump would draw liquid 118 from the reservoir in
container 112 through a first inlet conduit to the first pump and
pump the liquid back through a first return conduit into container
112 externally over the head. A second pump would draw liquid from
the same reservoir through a second inlet conduit to a second pump
and pump the liquid back through a second return conduit to the
upper airway catheters. An advantage of the separate pumps is that
the flow of liquid can be separately regulated for external
delivery around the head and internal delivery into the upper
airway. This is a particular advantage when the caliber of the
upper airway catheters is different than the conduit for external
delivery of the liquid, and the internal resistance of the external
and internal delivery systems differs.
[0195] In other embodiments of the method that use multiple
catheters, each catheter can be associated with a separate pump.
Alternatively, a separate pump can provide liquid flow to all
catheters in a particular anatomic regions, such as all the
external catheters, all the internal catheters, all the catheters
in the upper airway, all the catheters in the gastrointestinal
tract (esophagus and/or stomach), etc.
[0196] The pump or pumps may be either manually operated or
non-manually powered, for example by electricity. A hand or foot
powered pump is particularly useful for field operation outside a
hospital or ambulance where a source of electricity may not be
readily available. Once the patient is transported to an ambulance
or hospital, the pump can be connected to a source of electrical
energy and automated pumping initiated and continued for a
sustained period of time.
[0197] Batteries can also be used to power the pump for field
operation.
[0198] The pump or pumps can include one or more filter mechanisms
to remove any undesirable materials from the liquid as it is
circulated out of the subject. Such undesirable materials can
include, for example, microbes or other loose matter present in the
area of the body where the cooling liquid is introduced. Such
undesirable materials can be picked up and carried out of the body
as the cooling liquid is discharged from the body. The filter
mechanism can remove such materials from the cooling liquid and the
pump can reintroduce the filtered cooling liquid into the body. As
described in more detail in Example 12 below, by filtering the
circulated cooling liquid in this manner, the cooling liquid can
help sanitize the treated portions of the subject (e.g., the upper
airway and/or aerodigestive tract).
Example 10
Esophageal Tubes
[0199] A variety of specialized multi-lumen esophageal tubes can be
provided to deliver the high flow of cooling liquid to the
aerodigestive tract in those embodiments that employ esophageal
irrigation. For example, a double or triple coaxial tube may be
employed.
[0200] In the triple coaxial tube, the inner lumen is the longest
and acts as a nasogastric tube hooked up to suction, for example to
remove cooling and other liquids from the stomach if desired.
Alternatively, the long inner lumen can be used to deliver cooling
liquid to the stomach. The middle lumen delivers cooling liquid and
may have multiple side ports for omni-directional delivery of the
cooling liquids in multiple different directions and at different
levels of the esophagus. The outer lumen can selectively remove
cooling liquid from the esophagus if desired. However, lamellar
flow of returning liquid moving along the wall of the esophagus
toward the mouth is helpful in achieving heat transfer to the
liquid, hence suctioning of return liquid is not normally used
absent special circumstances.
[0201] Alternatively, multiple parallel tubes of different lengths
are used to introduce flow into the esophagus. The longest tube is
positioned with its tip in the stomach, and may serve to either
introduce cooling liquid or suction cooling liquid from the
stomach. This tube has an inflatable balloon around the tube about
10 cm from the distal end of the tube. The balloon can selectively
be inflated in the distal esophagus if it is desired to isolate the
stomach from the flow of liquid in the esophagus so that the
cooling liquid is directed more selectively to the esophagus. The
mid-length tube is of a sufficient length to be positioned with its
tip about 3 cm proximal to the balloon on the first tube; the
mid-length tube has multiple side ports for the delivery of the
cooling liquid. The short tube is positioned with its tip in the
hypopharynx; this tube has multiple side ports along its length for
about 5 cm for omnidirectional delivery or removal of cooling
liquid in the hypopharynx.
Example 11
Mouth and/or Nose Drainage
[0202] An advantage of certain embodiments of the device and method
is that the cooling liquid is capable of draining passively through
the mouth and/or nose without application of suction. Removal of
liquid through the mouth and/or nose avoids removal through suction
tubes placed in the aerodigestive tract, and therefore provides
flow of the cool return liquid over the large surface area of the
tissues of the aerodigestive tract to maximize heat exchange
between the tissues and the liquid. Drainage of the liquid through
the mouth and/or nose can be achieved with the head entirely
submerged in the cooling liquid, partially submerged in it, or not
submerged at all.
[0203] In some illustrated embodiments, liquid that drains out of
the mouth collects in a reservoir around the head. However, the
draining liquid can also collect in a reservoir that is below or
beside the head. For example, the head may be supported by a
permeable support surface having an opening or openings through
which liquid returns to the reservoir. The draining liquid can then
be cooled and returned to the aerodigestive tract for continued
cooling of the tissues.
[0204] In one example, the head may be turned to the side so that
liquid will pour out one side of mouth, which will help avoid
contacting the cool liquid with the face and help keep liquid out
of the lungs by lowering the level of liquid in the upper airway.
The head can be gently restrained to keep the head turned to its
side, and the corner of the mouth may be pulled down to encourage
egress of liquid from the mouth. In some embodiments a drainage
tube can be place in the mouth to further reduce the level of
liquid in the mouth.
[0205] If desirable, oral and/or nasal barriers can be provided to
restrict or prevent the exit of cooling fluid from the subject's
body (e.g., from the upper airway and/or aerodigestive tract). Such
barriers can be useful for keeping the field (e.g., the head, bed,
etc.) dry during long-term use of the devices disclosed herein.
[0206] Nasal plugging can ensure that returning fluid exit the body
via the mouth and can comprise, for example, partial or full rings
made of a soft shape-holding material that can wrap around any
tubes that are inserted in the nose. Each ring can fit tightly
around the tubing and also fit tightly along the mucus membrane of
the interior surface of the flares. The rings can be supplied
separately from the nasal tubing for attachment by a user.
[0207] Alternatively, such rings can be manufactured or sold in a
condition where they are already attached to nasal cooling tube(s).
In some embodiments, the ring or other such plugging member can be
fixed relative to the nasal cooling tube(s) to ensure that the tip
of the nasal cooling tube is not inserted too far into the pharynx.
Such rings can also help to keep the tubing in proper placement
during an operation and/or any situation where the position or
location of the subject's body may be altered or adjusted.
[0208] Oral barriers can comprise semi-permeable or solid, soft,
shape-holding substances that are placed between the teeth/gums and
the lips/buccal mucosa. This barrier can prevent cooling fluid from
leaving the mouth at undesired locations. For example, if a mouth
gutter is being used on one side of the mouth, the oral barrier can
be placed on the opposite side of the mouth to direct fluid flow
towards the gutter. In another example, the entire mouth could be
covered with the oral barrier. In such a case, defects within the
barrier can permit some fluid to escape there-through and/or can
permit a tube to be placed through the barrier at those areas.
[0209] The oral barriers described herein can be rigid or pliable.
A pliable barrier can allow for bulging which would indicate higher
fluid pressures in the upper airway and could be used as an
indicator to the user of the pressure of the fluid in the airway.
The barrier can extend into the mouth in multiple directions to
ensure that, when pressure increases and the diameter of the oral
opening increases, the barrier remains generally in place and does
not allow fluid to pass between the barrier and the lips.
[0210] In some embodiments, the barrier can be connected to a mouth
gutter (or funnel) type device to allow for drainage of the fluid
from the mouth. The gutter or funnel can be open to the air or
sealed tightly with the oral barrier.
Example 12
Cooling Liquids
[0211] A variety of biologically compatible cooling liquids can be
used, either alone or in combination, in the disclosed methods and
devices. A biologically compatible liquid is one that is either
non-toxic, or that has levels of toxicity that are acceptable in
view of the problem being treated. Some toxicities are minor (such
as skin irritation that can be caused by glycerol), and others are
more significant (such as causing electrolyte abnormalities) but
can be medically managed. As long as the toxicity presented by use
of the liquid is acceptable in the clinical circumstances in which
it is used, the liquid is biologically compatible. Any liquid that
causes a severe permanent injury or is incompatible with life is
not considered biologically compatible. Liquids that may not be
biologically compatible at high concentrations can in some
instances be made biologically compatible by adding a diluent (such
as water).
[0212] Examples of biologically compatible liquids are listed in
Table 2.
[0213] Cooling liquids particularly useful in the methods disclosed
herein have high heat transferability. Gases are not suitable for
this purpose because they do not transfer heat at the rate
envisioned by the disclosed methods. The optimal temperature for a
particular liquid is often the lowest temperature that can be
achieved without freezing, and with an acceptable degree of
viscosity. Since liquids usually become more viscous as they are
cooled, there is an optimal balance of temperature and viscosity.
For example, the liquid is cooled until it reaches a viscosity of 5
to 10 times the viscosity of water at 0.degree. C.
[0214] Colder cooling liquids increase the rate of brain and/or
body cooling, however the rate of cooling is balanced with the
potential tissue damaging effect of the cold liquid. However,
animal (including human) tissue can tolerate surprisingly low
temperatures, at least for limited periods of time. Items from food
freezers (-17.degree. C.) are routinely placed on skin after trauma
to reduce swelling, which illustrates the ability of skin to
tolerate such low temperatures. The mucous membranes (such as those
found in the aerodigestive tract) also tolerate low temperatures,
as illustrated by the fact that items from food freezers
(-17.degree. C.) are routinely eaten.
[0215] Mixtures of liquids are particularly contemplated as useful
in the disclosed methods. For example, mixtures that take advantage
of interactions with water can be used. A water/propylene glycol
mixture is a preferred liquid for induction because it can be
cooled to temperatures below 0.degree. C. A water/saline cooling
liquid will likely be used as maintenance liquid to maintain a
temperature above 0.degree. C. for 12-48 hours because of its low
toxicity. Saline solution has a lowered freezing point, and is
easily washed off the patient, staff and equipment.
[0216] Examples of cooling liquids include those shown in Table
2.
TABLE-US-00002 TABLE 2 Cooling Liquids Water-based Propylene glycol
(5-25% in water) Ethanol (5-25% in water) Glycerol/glycerine (5-25%
in water) Dextrose (5-25% in water) Glucose (5-25% in water)
Sucrose (5-25% in water) Sodium chloride (0.45-5% in water) Calcium
chloride (1-25% in water) Sodium bicarbonate (0.45-5% in water)
Oils High-oleic safflower oil Corn oil Castor oil Perfluorocarbons
Perfluorohexane Perfluoroheptane Perfluorooctane Additives
(optional) Detergents (trace)
[0217] Trace quantities of detergents such as sodium laurel
sulfate, sodium laureth sulfate, etc can be added to the cooling
liquid to solubilize debris and bodily fluids (blood, mucus, hair,
sweat) and inhibit pump/tubing obstructions.
[0218] As mentioned above, a particularly preferred cooling liquid
for the induction phase is propylene glycol (PG). The PG is cooled
to -10 to -20.degree. C., and is used during induction for 30-60
minutes. This temperature is achievable because PG 40% in water has
freezing point of -22.degree. C. PG is in an FDA classification of
"generally recognized as safe" and has very low ingestion toxicity.
For example, PG is found in high concentrations in foods and
cosmetics; the average adult in the United States consumes 2.5
grams/day of PG in food. PG is a common ingredient in mouthwash,
and is the main ingredient in many oral and intravenous
medications. It causes minimal skin and eye irritation, and is used
in many topical medications and personal care products. PG has been
nebulized and inhaled for treatment of chronic lung disease. It is
easily flushed off mucous membranes and skin by water or saline, so
this induction liquid can easily be removed by flushing with
saline, water of other liquid that is used in a subsequent
maintenance phase of treatment.
[0219] Other characteristics of PG that make it very suitable as a
cooling liquid are its high specific heat (which is close to water
and better than ethylene glycol), a viscosity only slightly higher
than water, a surface tension lower than water (when mixed with
water), compatibility with many types of flexible tubing and pumps,
very low flammability, and no special disposal needs.
[0220] A particularly suitable cooling liquid for maintenance of
hypothermia is saline solution, such as 0.9% saline solution. An
optimal temperature range for maintenance liquid is +5 to
+20.degree. C., and an example of a maintenance period would be
12-48 hours. Use of saline maintenance solution for this sustained
period of time is particularly suitable because it is considered a
"physiologic" fluid. Saline solution during maintenance therapy
also avoids dermal and enteral absorption of propylene glycol
during long-term use.
[0221] Glycerol is a particularly useful cooling liquid component,
because when added to water it has a low surface tension. Salt in
water (saline solution) has no effect on viscosity and does not
decrease surface tension. Sugar solution increase viscosity of the
liquid, while ethanol decreases surface tension (but must be
treated with caution because of its flammability). Calcium chloride
slightly increases the viscosity of a solution, and it used in low
concentrations because it can be an irritant at very high
concentrations.
[0222] The cooling liquids described herein can also function to at
least partially sanitize the areas of the body into which they are
introduced, including, for example, upper airway and/or
aerodigestive tract. Sanitization of the upper airway and/or
aerodigestive tract can be useful to reduce the incidence of some
complications that are associated with intubation and/or ventilator
support. For example, patients who are intubated and receiving
mechanical ventilatory support can suffer from ventilator
associated pneumonia (VAP). VAP is a relatively common complication
that can extend the number of days on the ventilator, the length of
stay in the ICU, and increase the risk of death of the patient. The
incidence of VAP can, in some cases, be reduced by utilizing or
providing various methods described herein including, for example,
specialized endotracheal tube (ETT) cuffs, subglottic suction above
the ETT cuff, an upright posture and partial sterilization
(sanitizing) of the aerodigestive tract using antimicrobial
solutions applied to the mouth. Such methods can be supplemented
and/or replaced by the utilization of the sanitizing fluids and
methods described herein.
[0223] The methods and cooling liquids described herein can
sanitize the various areas of the body into which they are
introduced (e.g., the upper airways and/or aerodigestive tract) in
one or more of the following ways. Mechanical sanitization of these
areas can be achieved by debridement of microbes from these areas,
sheer forces achieved by the flowing fluid, and by removing
superstructures or biofilms that can enhance microbe viability in
these areas. The sheer forces introduced by the free-flowing
cooling liquid as that liquid travels in the body and through the
pump and filter systems can further physically stress microbes,
thereby killing them and/or reducing their pathogenicity.
[0224] In addition, the large volume of cooling liquid can dilute
the bacterial concentrations in the areas in the body into which
the cooling liquid is introduced, which can further reduce the
pathogenicity of surviving microbes. Similarly, by removing,
reducing, and/or diluting the nutrients available to the microbes
(such as those present in the mucosa), the number and pathogenicity
of microbes can be even further reduced by the introduction of the
cooling liquids disclosed herein.
[0225] Accordingly, the exchange and circulation of cooling liquid
can remove mucus, biofilms, and bacterial superstructures
mechanically, essentially washing them out of the aerodigestive
tract. Once they are removed from the aerodigestive tract (or other
areas) and are suspended in the cold fluid they can be removed from
the fluid by filtering as described above. Even if not removed by
filtering, however, such microbes will be greatly diluted in the
reservoir of cooling fluid.
[0226] The temperature of the cooling liquids can also play a role
since the temperature is preferably sufficiently low to kill
microbes and/or otherwise reduced the energy stores and/or
pathogenicity of the microbes. Also, microbe adaption to
"cold-shock" can take time (e.g., hours) and generally requires
large energy expenditures by the microbes. Accordingly, by removing
or damaging microbes by filtering them out the body within minutes,
the systems and methods described herein can kill or damage
microbes before they have time to adjust to the cooler
temperature.
[0227] The cooling liquid can also include biochemical agents that
can further stress, kill, and/or reduce the pathogenicity of
microbes in the body. For example, hypertonic or hypotonic fluid,
pH adjustments to the cooling liquid, detergents, and/or
antibiotics can be provided in the cooling liquid to further damage
and/or disrupt microbe function. Examples of antimicrobials that
can be included in the cooling fluid are Tobramycin (currently used
in eye drops and nebulized lung treatment), Nystatin (currently
used in oral rinses), and Chlorhexadine (currently used in oral
treatments for patients on ventilators).
[0228] The addition of detergents can increase the rate and
proportion of microbe death and/or reduced pathogenicity by causing
additional damage to the cell membrane while under the stresses of
cold, depleted energy reserves and sheer forces described
above.
[0229] The addition of salts and/or sugars can also have an
additional microbe effect, including, for example, killing and
decreasing pathogenicity. Salts and sugars that can be included in
the cooling liquid include, for example, sodium chloride (e.g.,
preferably about 0.45-15% by weight in a water-based solution, and
more preferably about 0.45-5%), sodium bicarbonate (e.g.,
preferably about 0.45-15% by weight in a water-based solution, and
more preferably about 0.45-5%), calcium chloride, propylene glycol
(PG) (e.g., preferably about 1-50% by weight in a water-based
solution, and more preferably about 5-25%), dextrose (e.g.,
preferably about 1-50% by weight in a water-based solution, and
more preferably about 5-25%), glucose (e.g., preferably about 1-50%
by weight in a water-based solution, and more preferably about
5-25%), sucrose (e.g., preferably about 1-50% by weight in a
water-based solution, and more preferably about 5-25%), and
glycerin (e.g., preferably about 1-50% by weight in a water-based
solution, and more preferably about 5-25%).
[0230] Accordingly, the risk of pneumonia or other complications
associated with microbes or other elements entering into the lungs
can be lessened by the reduction of microbes by the cooling liquid
as described herein. By this reduction of microbes, even if the
patient were to aspirate any cooling liquid into the lungs, the
amount and/or pathogenicity of the microbes will not likely exceed
an infective threshold.
Comparative Data
[0231] Comparative studies have been performed to compare cooling
induced by the method as described by Brown et al., Profound
Selective Cerebral Hypothermia in Dogs by Naso-Oral Perfusion and
Head Immersion, Surgical Forum 15:413-415, 1964 (Example 14);
improved cooling with liquid at 0.degree. C. and scalp, nasal, oral
and upper esophageal cooling (Example 15); cooling liquid at
-15.degree. C. using scalp nasal and oral cooling (Example 16).
Example 13
Surgical Preparation of the Animal
[0232] A 98 kg adult female sheep was maintained under surgical
plane anesthesia until euthanized. The sheep was subjected to 3
methods of cerebral hypothermia and outcome was measured by the
rate and magnitude of cooling of the superficial cortex of the
brain and of the systemic arterial blood. Temperatures were
recorded every minute in superficial cerebral cortex, in arterial
blood in the abdominal aorta, in the peri-carotid tissue of the
neck, in the rectum (core temperature), and in the device
reservoir. Monitoring was performed by continuous ECG, continuous
pulse oxymetry, continuous arterial blood pressure, and continuous
end-tidal CO2.
[0233] During surgical preparation, the sheep was intubated orally
with a standard cuffed endotracheal tube (ETT) and mechanically
ventilated with 100% oxygen and minute ventilation titrated to an
end-tidal CO2 of 35 Torr. Tracheostomy was performed and a cuffed
tube was placed with the tip in the lower trachea. Esophagostomy
was performed and a cuffed tube was placed with the tip in the mid
esophagus and the proximal end to gravity. Arterial and venous
catheters were placed in the right groin.
[0234] The left mid neck was dissected, a temperature probe was
placed lateral to the carotid artery and the site closed at the
levels of the fascia and the skin. The scalp was dissected in the
left upper parietal region, and a 10 mm burr hole was created
through 22 mm of skull. The dura and superficial brain were incised
and a temperature probe was placed with tip 7 mm below the surface
of the cerebral cortex. The burr hole was sealed with dental
cement. The site was closed at the levels of the fascia and the
skin and covered with petroleum jelly.
[0235] Catheters were obtained for use in the following examples.
The catheters had the following inner diameter (ID) and outer
diameter (OD):
[0236] intake tubes--from reservoir to each of the 3 pumps
[0237] ID=1/2 inch
[0238] OD=3/4 inch
[0239] scalp tubes
[0240] ID=1/2 inch
[0241] OD=3/4 inch
[0242] nasal and oral and esophageal tubes
[0243] ID= 5/16 inch
[0244] OD= 7/16 inch
Example 14
Trial 1
Selective Cooling with Low Flow Cooling Liquid from Catheters
Inserted Only Into Nostrils (Brown et al. Method)
[0245] One tube was placed in each nasal cavity by inserting the
tip of the tube 5 cm beyond each nares.
[0246] A box open at the top acted as a reservoir for cooling
liquid. The reservoir was filled with water with ice at 0.degree.
C. A pump withdrew liquid from the reservoir at L/min, introduced
it through the tubes into the nasal cavities. The liquid returned
passively back to the reservoir via the nose and mouth. At the
start of cooling the head was submerged in the reservoir by tilting
the surgical table head-down, removing the headrest from the table
and extending the neck. At the same time the nasal tubes were
connected to the outflow tube of the pump. Cooling was discontinued
after 30 minutes, the pump stopped, the head removed from the
reservoir and the sheep rewarmed using a warm saline IV infusion
and external warming of the trunk. Nasal tubes were left in place
and disconnected from the pump.
[0247] Cooling was performed for 31 minutes, then rewarming was
initiated. The data that was obtained is shown in Table 3.
TABLE-US-00003 TABLE 3 Selective Cooling with Low Flow Cooling
Liquid only into Nasopharynx Temperature (deg C.) Time (min) Brain
Peri-carotid Aorta Bath Core 0 38.1 37.8 37.7 1.3 38.1 1 38.1 37.8
37.6 1.2 38.1 2 37.8 37.7 37.1 1.5 38.1 3 37.4 37.7 36.8 1.7 38 4
37.1 37.7 36.6 2.1 37.9 5 36.7 37.4 36.3 2.2 37.8 6 36.3 37.4 36.2
2.5 37.8 7 35.9 37.1 35.9 2.5 37.7 8 35.9 36.8 35.9 2.7 37.5 9 35.9
36.8 35.4 2.8 37.4 10 35.6 36.5 35.3 2.9 37.3 11 35.3 36.4 35.3 3
37.2 12 35.3 36.2 35.3 3.1 37.1 13 35 36.2 35.4 3.2 37.1 14 35 35.9
35.4 3.2 37.1 15 34.8 35.9 35.3 3.4 37 16 34.8 5.9 35.1 3.4 36.9 17
34.8 35.7 35 3.7 36.8 18 34.6 35.7 34.5 3.7 36.8 19 34.3 35.4 34.5
3.7 36.6 20 34.3 35.4 34.7 3.8 36.5 21 33.9 35.4 34.7 3.9 36.5 22
33.9 35.3 34.6 4 36.4 23 33.9 35.3 34.1 4.2 36.4 24 33.9 35.1 34.1
4.2 36.3 25 33.9 35.1 34.1 4.4 36.2 26 33.7 35.1 34.1 4.5 36.1 27
33.4 34.9 34 4.5 36 28 33.4 34.9 34.1 4.7 35.9 29 33.4 34.7 34.1
4.8 35.8 30 33.4 34.7 34.2 4.8 35.8
Example 15
Trial 2
[0248] Selective Brain Cooling
[0249] After rewarming the animal from the trial described in
Example 14, an oral tube was placed with the tip at the base of the
tongue and an esophageal tube was placed with the tip in the upper
esophagus. Two additional tubes were placed in the liquid
reservoir. When the head was submerged in the reservoir their tips
were 4 cm from and pointed towards the right and left parietal
scalp. A box open at the top acted as a reservoir for cooling
liquid. The reservoir was filled with water with ice at 0.degree.
C. At the start of cooling the head was submerged by tilting the
surgical table head-down, removing the headrest from the table and
extending the neck. Three pumps (1, 2, and 3) were used. The two
nasal tubes were connected to the outflow tube of pump 1, oral tube
to pump 2, esophageal tube to pump 2 and the two scalp tubes to
pump 3. Pumps withdrew cool liquid from the reservoir at 6 L/min
for pump 1, and 12 L/min each for pumps 2 and 3. Cooling was
discontinued after 21 minutes, the pumps stopped, the head removed
from the reservoir and the sheep rewarmed using a warm saline IV
infusion and external warming of the trunk.
[0250] Data obtained from the method is shown in Table 4.
TABLE-US-00004 TABLE 4 Selective Brain Cooling Temperature (deg C.)
Time (min) Brain Peri-carotid Aorta Bath Core 0 36.8 36.4 35.5 1.2
36.2 1 35.8 36.4 35.6 1.3 36.2 2 3 4 35.9 27.2 34.1 3.4 36 5 35.5
24 33.7 3.8 35.9 6 34.8 21.9 33.2 3.9 35.7 7 34.4 20.7 32.8 3.9
35.5 8 33.6 19.8 32.5 4 35.3 9 33.3 21.1 32.4 4.2 35.2 10 32.9 22
32.2 4.6 35 11 32.3 21.2 31.9 4.8 34.8 12 32 20.2 31.6 5 34.7 13
31.7 19.7 31.3 5.3 34.5 14 31.3 19.3 31.1 5.6 34.3 15 31.3 19.3
30.9 5.7 34.1 16 30.9 18.9 30.7 5.9 33.9 17 18 19 30.3 22.3 30.5
6.7 33.5 20 30 20.1 30.4 7.1 33.3 21 30 19.6 30.2 7.3 33.2
Example 16
Trial 3
Propylene Glycol as Cooling Liquid (Trial 3)
Continued Cooling after Animal Euthanized (Trial 4)
[0251] After rewarming the animal from Trial 2 (Example 15), the
esophageal tube was withdrawn and replaced with a second oral tube,
so that there were two oral tubes both having their tips positioned
at the base of the tongue. Both nasal and both scalp tubes remained
in place. A box open at the top acted as a reservoir for cooling
liquid. The reservoir was filled with a 1:1 mixture of propylene
glycol and water at -15.degree. C. Pumps withdrew fluid from the
reservoir at 1 L/min for pump 1, and 3 L/min for pump 2 and 5 L/min
for pump 3 for a total of 9 L/min through the internally placed
catheters. At the start of cooling the head was submerged by
tilting the surgical table head-down, removing the headrest from
the table and extending the neck. At the same time the nasal tubes
were connected to the outflow tube of pump 1, oral tubes to pump 2,
and the scalp tubes to pump 3. Pumps withdrew liquid from the
reservoir at 1 L/min for pump 1, at 3 L/min for pump 2 and 5 L/min
for pump 3 for a total of 4 L/min through the internally placed
catheters and 5 L/min of liquid was directed at the scalp.
[0252] The sheep was euthanized after 14 minutes and cooling
proceeded for another 22 minutes.
[0253] The results of the cooling with propylene glycol are shown
in the Table 5. Measurements after death are presented in bold
italics.
TABLE-US-00005 TABLE 5 Propylene Glycol as Cooling Liquid with
Continued Cooling after Animal Death Temperature (deg C.) Time
(min) Brain Peri-carotid Aorta Bath Core 0 34.6 34.7 33.9 -12.9
34.2 1 34.6 34.7 33.9 -11.6 34.2 2 34.3 31.7 33.2 -11.1 34.1 3 33.9
27.6 32.7 -9.3 34 4 33.4 25.4 32.4 -7.8 33.8 5 33.1 24.7 32.1 -5.9
33.6 6 32.6 25.1 31.8 -3.8 33.4 7 32.2 22.5 31.3 -2 33.2 8 31.8
23.1 31.3 0 32.9 9 31.8 22.4 31.1 0 32.7 10 31.4 21.9 31 0 32.5 11
31.1 21.6 31 1 32.3 12 31.1 21.6 30.9 1.4 32.3 13 30.8 21.4 30.8
2.3 32 14 30.8 21.5 30 2.8 31.9
Example 17
Comparison of Aortic Blood Cooling using Nasal vs. Aerodigestive
Cooling
[0254] Aortic blood temperature data in the following table
illustrates the superior rate of systemic blood cooling achieved by
introducing the higher flow of liquid into multiple sites along the
aerodigestive tract and the scalp. Cooling would be accelerated
even more if lower esophageal and stomach catheters were added, and
cooling liquid introduced into the aerodigestive tract through them
as well. Cooling liquid is also accelerated by using cooling liquid
colder than 0.degree. C.
TABLE-US-00006 TABLE 6 Aortic Blood Temperature nasal + oral +
upper time (min) esophageal + scalp nasal + scalp 0 35.5 37.7 1
35.6 37.6 2 37.1 3 36.8 4 34.1 36.6 5 33.7 36.3 6 33.2 36.2 7 32.8
35.9 8 32.5 35.9 9 32.4 35.4 10 32.2 35.3 11 31.9 35.3 12 31.6 35.3
13 31.3 35.4 14 31.1 35.4 15 30.9 35.3 16 30.7 35.1 17 35 18 34.5
19 30.5 34.5 20 30.4 34.7 21 30.2 34.7 22 34.6 23 34.1 24 34.1 25
34.1 26 34.1 27 34 28 34.1 29 34.1 30 34.2
[0255] With regard to Examples 13 to 16, using pure water as the
cooling liquid, the addition of esophageal and oral irrigation and
turbulent scalp flow to nasal irrigation more than doubled the rate
of cerebral temperature drop from 30 min to 13 min for a 5.degree.
C. drop in brain temp. A temperature drop of 5.degree. C. in 13
minutes is a remarkable rate of cooling. Head cooling still has an
effect even without a pulse. After death of the animal, the core
body and aortic temperature actually increased but brain temp
continued to decrease. Hence the cooling liquid has a direct effect
on the brain, in addition to the effect of cooling blood in the
vessels that perfuse the brain.
[0256] Brain temperature also decreased significantly in Trial 3
despite two departures from optimal operating conditions. First,
the esophageal tube was not optimally placed because the tip
remained in the oropharynx in Trial 3 and served as a second oral
tube. Second, the high viscosity of the 50% propylene glycol in
water cooling liquid resulted in decreased flow rates of liquid
into the aerodigestive tract. A much deeper and more rapid
temperature drop would be expected with 20% PG and bath temperature
of -10.degree. C. because the viscosity would be lower and the flow
rates of the liquid in the aerodigestive tract would be
greater.
[0257] Nonetheless, the blood temperature achieved by adding
aerodigestive cooling to scalp cooling is substantially lower than
cooling merely the nasal cavity and scalp. Nasal+scalp cooling
reached a minimum temperature of only 34.degree. C. and
equilibrated, while the addition of aerodigestive cooling achieved
a blood temperature of 30.degree. C. and was still decreasing when
the experiment ended. This is a substantial difference; without
aerodigestive cooling the total temperature drop was 4.7.degree.
C., while with aerodigestive cooling the temperature was
3.4.degree. C. cooler in less time and had still not
equilibrated.
[0258] In Example 16 (Trial 3) with propylene glycol, brain
temperature reached a brain temperature of about 28.degree. C. in
32 minutes, even though the experimental subject had been dead for
about half that cooling time. Previously published reports have
reported reaching temperatures of only about 33.4.degree. C. in 30
minutes. Hence the aerodigestive cooling method is capable to
cooling about twice as quickly in the critical first 30 minutes
during which therapeutic hypothermia is being initiated.
[0259] The addition of esophageal flow helped increase the rate and
depth of cooling. There did not appear to be any significant loss
of cooling liquid into the stomach from the tube placed in the
esophagus. Greater esophageal distension from even higher
esophageal flow rates would be expected to increase the surface
area of the esophagus, and provide a greater esophageal surface
area for heat transfer to occur.
[0260] Since the sheep (98 kg) was larger than a typical human
adult (60-70 kg), had a skull much thicker than a human skull, and
possessed an effective boundary of fur despite close shearing, the
rate and depth of direct brain cooling provided by scalp cooling is
expected to be greater in humans. However, the inventor has
demonstrated a much more rapid rate of cooling is possible using
aerodigestive cooling as opposed to nasal cooling alone.
[0261] In some embodiments of the method in which more focal
hypothermia is desired (for example selective cooling of the brain)
the body can be warmed, for example by wrapping the trunk and
extremities in heating blankets. The cooling methods disclosed
herein cool much more rapidly and deeply than previous methods by
cooling a combination of surfaces, and/or using very high rates of
flow of cooling liquid. The method is also versatile in that it can
be used for substantially specific cooling of the brain alone or
less specific cooling of the brain and other organs, either in or
remote from a hospital setting or in transit between those sites.
The method is capable of deeply cooling about 15% of cardiac blood
flow (the blood flow to the head), is non-invasive to the extent
that liquid is only introduced into the aerodigestive tract, and
can combine internal and external cooling.
[0262] All regions cooled are integrated by combining all return
liquid from the body, mixing and redelivering liquid to the body.
The return of cooling liquid from the body in the experiments was
passive, which allows for much higher flow of cooling liquid out of
the nose and mouth, and in turn provides more rapid cooling. The
simplicity of the equipment for carrying out the method allows for
rapid implementation and broad applicability, so that more people
can benefit from the simple sophistication of the approach. The
simplicity of design, in which the method can be performed without
inserting catheters into organs (such as the brain) leaves vital
organs intact and allows more people to benefit from its use. The
method and device can be used inside or outside a medical facility
so that patients do not have to wait until they reach the emergency
room to be treated. The method is suitable for use by less trained
medical personnel (such as EMTs) without having to wait for a
surgeon to arrive to perform invasive surgical maneuvers (such as
introducing cooling catheters into the brain or blood vessels).
[0263] The brain can also be maintained significantly colder than
the rest of the body during selective cooling, which maximizing
brain benefit and minimizes body side effects. Rapid cooling can be
induced much faster and attain much lower brain temperatures than
with conventional induction of therapeutic hypothermia using prior
art methods. In some examples, the temperature in the cerebral
cortex is lowered to 33.degree. C. in 5-15 minutes, or 28.degree.
C. in 10-20 minutes, or 25.degree. C. in 15-30 minutes. In other
examples, the temperature in systemic arterial blood is lowered to
33.degree. C. in 5-15 minutes, to 28.degree. C. in 15-30 minutes,
or to 25.degree. C. in 20-40 minutes.
[0264] A variety of different catheters/tubes can be used in the
devices. Specific, non-limiting examples of particular catheter
sizes are given in Example 13. Examples of ranges of catheter sizes
are 5/16 to 1/4 inches ID for the scalp tube, 3/16 to 6/16.sup.th
inches for the esophageal and stomach tubes, 3/16 to 1/2 inches for
the mouth tube, and 2/16 to 6/16.sup.th inches for the nose
tubes.
[0265] The method is also capable of rapidly inducing cooling by
using "stored cold" for the induction phase in the form of ice
water or pre-cooled liquids that are available for emergency use,
for example during the first 30 minutes of cooling. The temperature
of the cooling liquid is also quite low, and using cooling liquids
that are available at sub-zero temperatures to increase the rate
and depth of cooling. The volumes of cool liquid available in the
reservoir help maintain a sufficient supply for continued high
volume flow of cooling liquid.
[0266] Organs are cooled by cooling the blood that supplies the
organs, so that the disclosed methods do not require total body or
even regional cooling to be effective. For example, if cooling of
the cervical spinal cord is desired, this low mass region is
rapidly cooled without waiting for the much more massive contents
of the abdomen to be cooled.
[0267] The disclosed methods cool the head, neck and mediastinum
using simple but effective techniques to maximize heat transfer.
Selective cooling rapidly and deeply cools arterial blood delivered
to the brain via the carotid and vertebral arteries. Non-selective
cooling is capable of cooling venous blood returning to the heart,
and therefore the systemic arterial blood. The venous blood is
cooled in two regions, the neck and the mediastinum. The
temperature of the blood draining from the neck is very low, in
time approaching the temperature of the cold liquid bath that
bathes it. This is due to cooling of the blood in the head and neck
at the capillary level (most profound in the tissue beds in
proximity to the skin and mucus membranes that are in direct
contact with the cooling fluid) in addition to cooling of the blood
in the jugular veins via cold fluid in the upper airway. About 15%
of the cardiac output will be cooled in this very efficient
manner.
[0268] The esophagus traverses the entire mediastinum and is in
close proximity to the inferior vena cava, superior vena cava and
the heart. The vena cava carries the entire cardiac output back to
the heart. It is thin walled and lies in very close proximity to
the esophagus, allowing for very efficient heat transfer with the
esophagus. The stomach is in close proximity to the inferior vena
cava as well as the inferior surface of the heart.
[0269] Direct contact of cooling liquids with the aerodigestive
tract (as opposed to placing the liquid in a container within the
tract) allows for the full surface area of the aerodigestive tract
(from nares to pyloris) to be used for heat exchange. The cooling
liquid enters irregular areas of the surface that balloons or rigid
devices would not reach. Examples of such irregular surfaces that
are bathed with the cooling liquid are the nasal trabeculae,
tonsils, and larynx.
[0270] In addition to the high flow of cool liquid through the
aerodigestive tract, turbulent flow of the cooling liquid (both
externally against the face and scalp and internally in the
aerodigestive tract) contributes to heat exchange. For example, a
thick layer of stagnant liquid at the outer aspects of the
esophageal lumen could cause the flow of cool liquid to flow down
only a central core that reduces heat exchange. Turbulence of flow
is increased by having multiple points of liquid delivery (multiple
catheters and each catheter can have side holes), high flow rates,
crossed currents of liquid flow (liquid is pushed into the body and
generally directed towards the feet but changes direction and is
expelled out the mouth and nose), encountering irregular surfaces
in the aerodigestive tract (not smoothed over by a bag or balloon)
and the presence of multiple delivery tubes along the path of
liquid exit.
[0271] Another advantage of the method is that it is capable of
providing the internal delivery of the cool liquid to the
aerodigestive tract without immersing other parts of the body (such
as the chest, extremeties or even in the head in some embodiments)
in cooling liquid. Hence it is possible to perform other
interventions on the patient that would not be possible in other
types of induced hypothermia. Examples of such interventions
include electrical cardioversion (applying electrical energy to the
heart to change or initiate its rhythm), electrocardiography
(obtaining diagnostic signals from the heart by applying external
electrodes to the body, including the thorax), or performing
cardiac or neurovascular surgery (such as angioplasty or
stenting).
[0272] Although the methods and devices have been described in
association with certain theories of their operation, the invention
is not to be limited by those theories. To the extent that the
invention can be understood in terms of the described structures
and methods, the claims do not incorporate theories of operation
unless the claims clearly indicate otherwise.
[0273] In view of the many possible embodiments to which the
principles of the disclosed invention may be applied, it should be
recognized that the illustrated embodiments are only preferred
examples of the invention and should not be taken as limiting the
scope of the invention. Rather, the scope of the invention is
defined by the following claims. I therefore claim as my invention
all that comes within the scope and spirit of these claims.
* * * * *