U.S. patent application number 09/800159 was filed with the patent office on 2001-08-02 for method and apparatus for location and temperature specific drug action such as thrombolysis.
Invention is credited to Dobak, John D. III, Lasheras, Juan C..
Application Number | 20010011184 09/800159 |
Document ID | / |
Family ID | 27534970 |
Filed Date | 2001-08-02 |
United States Patent
Application |
20010011184 |
Kind Code |
A1 |
Dobak, John D. III ; et
al. |
August 2, 2001 |
Method and apparatus for location and temperature specific drug
action such as thrombolysis
Abstract
A method is provided of localizing a drug action where the drug
is present throughout a vascular system. The localization occurs to
within a volume of blood in a blood vessel, the vascular system
having an initial temperature substantially within a first
temperature range. A temperature-specific enzyme is delivered
throughout a vascular system including a volume of blood in a blood
vessel, the temperature-specific enzyme having a working
temperature within a prespecified temperature range that does not
substantially overlap the first temperature range. A heat transfer
element is delivered to a blood vessel in fluid communication with
the volume of blood. The temperature of the heat transfer element
is adjusted such that the volume of blood in the blood vessel is
heated or cooled to the prespecified temperature range. In this
way, the action of the temperature-specific enzyme is substantially
limited to the volume of blood heated or cooled. In an alternative
embodiment, the temperature-specific enzyme is localized to the
volume of blood in the blood vessel, and the heat transfer element
is disposed in fluid communication with the volume of blood in the
blood vessel. The enzyme localization may occur by way of direct
injection or by way of injection through a lumen of a catheter. The
injection lumen of the catheter may be disposed at least partially
adjacent or in combination with the heat transfer element and its
associated inlet and outlet lumens.
Inventors: |
Dobak, John D. III; (La
Jolla, CA) ; Lasheras, Juan C.; (La Jolla,
CA) |
Correspondence
Address: |
Mark Wieczorek
Del Mar Medical Technologies
Suite 106
6199 Cornerstone Court East
San Diego
CA
92121
US
|
Family ID: |
27534970 |
Appl. No.: |
09/800159 |
Filed: |
March 6, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09800159 |
Mar 6, 2001 |
|
|
|
09232177 |
Jan 15, 1999 |
|
|
|
6245095 |
|
|
|
|
09232177 |
Jan 15, 1999 |
|
|
|
09215039 |
Dec 16, 1998 |
|
|
|
09232177 |
Jan 15, 1999 |
|
|
|
09215040 |
Dec 16, 1998 |
|
|
|
09232177 |
Jan 15, 1999 |
|
|
|
09103342 |
Jun 23, 1998 |
|
|
|
6096068 |
|
|
|
|
09232177 |
Jan 15, 1999 |
|
|
|
09047012 |
Mar 24, 1998 |
|
|
|
5957963 |
|
|
|
|
09232177 |
Jan 15, 1999 |
|
|
|
09052545 |
Mar 31, 1998 |
|
|
|
6231595 |
|
|
|
|
Current U.S.
Class: |
607/105 ;
607/113 |
Current CPC
Class: |
A61F 2007/0056 20130101;
A61B 2018/0262 20130101; A61B 2018/0281 20130101; A61F 7/12
20130101; A61B 2018/0212 20130101; A61F 2007/126 20130101 |
Class at
Publication: |
607/105 ;
607/113 |
International
Class: |
A61F 007/00; A61F
007/12 |
Claims
What is claimed is:
1. A method of localizing a drug action, the drug present
throughout a vascular system, the localization occurring to within
a volume of blood in a blood vessel, the vascular system having an
initial temperature substantially within a first temperature range,
comprising: delivering a temperature-specific enzyme throughout a
vascular system including a volume of blood in a blood vessel, the
temperature-specific enzyme having a working temperature within a
prespecified temperature range that does not substantially overlap
the first temperature range; delivering a heat transfer element to
a blood vessel in fluid communication with the volume of blood; and
adjusting the temperature of the heat transfer element such that
the volume of blood in the blood vessel is heated or cooled to the
prespecified temperature range, such that the action of the
temperature-specific enzyme is substantially limited to the volume
of blood heated or cooled.
2. The method of claim 1, wherein the adjusting includes inducing
turbulence in the blood to enhance a heat transfer rate.
3. The method of claim 2, wherein the adjusting further includes
inducing turbulence in a working fluid flowing through the heat
transfer element.
4. A method for selective drug therapy by selective vessel
hypothermia in a vascular system having an average blood
temperature at a first temperature, comprising: introducing a
catheter having a heat transfer element into a blood vessel in
fluid communication with a blood vessel requiring drug therapy in a
vascular system having an average blood temperature at a first
temperature; cooling the heat transfer element by flowing a working
fluid through the heat transfer element; cooling the blood by
flowing the blood past the heat transfer element and inducing
mixing in the blood, such that the blood is cooled from the first
temperature to a prespecified temperature range; and delivering a
drug to the blood, the drug having a working temperature within the
prespecified temperature range.
5. A method for selective drug therapy by selective vessel
hyperthermia in a vascular system having an average blood
temperature at a first temperature, comprising: introducing a
catheter having a heat transfer element into a blood vessel in
fluid communication with a blood vessel requiring drug therapy in a
vascular system having an average blood temperature at a first
temperature; heating the heat transfer element by flowing a working
fluid through the heat transfer element; heating the blood by
flowing the blood past the heat transfer element and inducing
mixing in the blood, such that the blood is heated from the first
temperature to a prespecified temperature range; and delivering a
drug to the blood, the drug having a working temperature within the
prespecified temperature range.
6. A method of localizing a drug action to substantially within a
volume of blood in a blood vessel, the vascular system having an
initial temperature substantially within a first temperature range,
comprising: delivering a temperature-specific enzyme to a volume of
blood in a blood vessel, the temperature-specific enzyme having a
working temperature within a prespecified temperature range that
does not substantially overlap the first temperature range;
delivering a heat transfer element to a blood vessel in fluid
communication with the volume of blood; and adjusting the
temperature of the heat transfer element such that the volume of
blood in the blood vessel is heated or cooled to the prespecified
temperature range, such that the action of the temperature-specific
enzyme is substantially limited to the volume of blood heated or
cooled.
7. The method of claim 6, wherein the delivering includes injecting
the temperature-specific enzyme intravenously.
8. The method of claim 6, wherein the delivering includes injecting
the temperature-specific enzyme through a lumen adjacent the heat
transfer element.
9. The method of claim 6, wherein the delivering includes injecting
the temperature-specific enzyme through a tip of the heat transfer
element.
10. The method of claim 4, wherein the delivering includes
injecting the drug intravenously.
11. The method of claim 4, wherein the delivering includes
injecting the drug through a lumen adjacent the heat transfer
element.
12. The method of claim 4, wherein the delivering includes
injecting the drug through a tip of the heat transfer element.
13. The method of claim 5, wherein the delivering includes
injecting the drug intravenously.
14. The method of claim 5, wherein the delivering includes
injecting the drug through a lumen adjacent the heat transfer
element.
15. The method of claim 5, wherein the delivering includes
injecting the drug through a tip of the heat transfer element.
16. The method of claim 4, wherein the drug is a
neuroprotectant.
17. The method of claim 5, wherein the drug is a
neuroprotectant.
18. The method of claim 4, wherein the drug is tPA.
19. The method of claim 5, wherein the drug is tPA.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 09/232,177, filed Jan. 15, 1999, and entitled "Method and
Apparatus for Location and Temperature Specific Drug Action Such as
Thrombolysis", which is a continuation-in-part patent application
of co-pending U.S. patent application Ser. No. 09/215,039, filed
Dec. 16, 1998, and entitled "Method for Low Temperature
Thrombolysis and Low Temperature Thrombolytic Agent with Selective
Organ Temperature Control"; U.S. patent application Ser. No.
09/215,040, filed Dec. 16, 1998, and entitled "Method and Device
for Applications of Selective Organ Cooling"; U.S. patent
application Ser. No. 09/103,342, filed Jun. 23, 1998, and entitled
"Selective Organ Cooling Catheter and Method of Using the Same";
U.S. patent application Ser. No. 09/047,012, filed Mar. 24, 1998,
and entitled "Selective Organ Hypothermia Method and Apparatus";
and U.S. patent application Ser. No. 09/052,545, filed Mar. 31,
1998, and entitled "Circulating Fluid Hypothermia Method and
Apparatus".
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The present invention relates generally to the modification
and control of optimal temperatures for enzymes. More particularly,
the invention relates to the modification and control of optimal
temperatures for enzymes for use in treatments such as
thrombolysis.
[0005] 2. Background Information
[0006] Organs in the human body, such as the brain, kidney and
heart, are maintained at a constant temperature of approximately
37.degree. C. Hypothermia can be clinically defined as a core body
temperature of 35.degree. C. or less. Hypothermia is sometimes
characterized further according to its severity. A body core
temperature in the range of 33.degree. C. to 35.degree. C. is
described as mild hypothermia. A body temperature of 28.degree. C.
to 32.degree. C. is described as moderate hypothermia. A body core
temperature in the range of 24.degree. C. to 28.degree. C. is
described as severe hypothermia.
[0007] Hypothermia is uniquely effective in reducing brain injury
caused by a variety of neurological insults and may eventually play
an important role in emergency brain resuscitation. Experimental
evidence has demonstrated that cerebral cooling improves outcome
after global ischemia, focal ischemia, or traumatic brain injury.
For this reason, hypothermia may be induced in order to reduce the
effect of certain bodily injuries to the brain as well as other
organs.
[0008] Cerebral hypothermia has traditionally been accomplished
through whole body cooling to create a condition of total body
hypothermia in the range of 20.degree. C. to 30.degree. C. However,
the use of total body hypothermia risks certain deleterious
systematic vascular effects. For example, total body hypothermia
may cause severe derangement of the cardiovascular system,
including low cardiac output, elevated systematic resistance, and
ventricular fibrillation. Other side effects include renal failure,
disseminated intravascular coagulation, and electrolyte
disturbances. In addition to the undesirable side effects, total
body hypothermia is difficult to administer.
[0009] Catheters have been developed which are inserted into the
bloodstream of the patient in order to induce total body
hypothermia. For example, U.S. Pat. No. 3,425,419 to Dato describes
a method and apparatus of lowering and raising the temperature of
the human body. Dato induces moderate hypothermia in a patient
using a metallic catheter. The metallic catheter has an inner
passageway through which a fluid, such as water, can be circulated.
The catheter is inserted through the femoral vein and then through
the inferior vena cava as far as the right atrium and the superior
vena cava. The Dato catheter has an elongated cylindrical shape and
is constructed from stainless steel. By way of example, Dato
suggests the use of a catheter approximately 70 cm in length and
approximately 6 mm in diameter. However, use of the Dato device
implicates the negative effects of total body hypothermia described
above.
[0010] Due to the problems associated with total body hypothermia,
attempts have been made to provide more selective cooling. For
example, cooling helmets or head gear have been used in an attempt
to cool only the head rather than the patient's entire body.
However, such methods rely on conductive heat transfer through the
skull and into the brain. One drawback of using conductive heat
transfer is that the process of reducing the temperature of the
brain is prolonged. Also, it is difficult to precisely control the
temperature of the brain when using conduction due to the
temperature gradient that must be established externally in order
to sufficiently lower the internal temperature. In addition, when
using conduction to cool the brain, the face of the patient is also
subjected to severe hypothermia, increasing discomfort and the
likelihood of negative side effects. It is known that profound
cooling of the face can cause similar cardiovascular side effects
as total body cooling. From a practical standpoint, such devices
are cumbersome and may make continued treatment of the patient
difficult or impossible.
[0011] Selected organ hypothermia has been accomplished using
extracorporeal perfusion, as detailed by Arthur E. Schwartz, M.D.
et al., in Isolated Cerebral Hypothermia by Single Carotid Artery
Perfusion of Extracorporeally Cooled Blood in Baboons, which
appeared in Vol. 39, No. 3, NEUROSURGERY 577 (September, 1996). In
this study, blood was continually withdrawn from baboons through
the femoral artery. The blood was cooled by a water bath and then
infused through a common carotid artery with its external branches
occluded. Using this method, normal heart rhythm, systemic arterial
blood pressure and arterial blood gas values were maintained during
the hypothermia. This study showed that the brain could be
selectively cooled to temperatures of 20.degree. C. without
reducing the temperature of the entire body. However, external
circulation of blood is not a practical approach for treating
humans because the risk of infection, need for anticoagulation, and
risk of bleeding is too great. Further, this method requires
cannulation of two vessels making it more cumbersome to perform
particularly in emergency settings. Even more, percutaneous
cannulation of the carotid artery is difficult and potentially
fatal due to the associated arterial wall trauma. Finally, this
method would be ineffective to cool other organs, such as the
kidneys, because the feeding arteries cannot be directly cannulated
percutaneously.
[0012] Selective organ hypothermia has also been attempted by
perfusion of a cold solution such as saline or perflourocarbons.
This process is commonly used to protect the heart during heart
surgery and is referred to as cardioplegia. Perfusion of a cold
solution has a number of drawbacks, including a limited time of
administration due to excessive volume accumulation, cost, and
inconvenience of maintaining the perfusate and lack of
effectiveness due to the temperature dilution from the blood.
Temperature dilution by the blood is a particular problem in high
blood flow organs such as the brain.
[0013] Selective organ hypothermia is useful in limiting brain
injury after ischemia or traumatic brain injury, as noted above.
For example, neurons subjected to ischemia may die. Selective
cooling of these neurons, such as by nerve cooling, has been shown
to increase the survival rate. Hypothermic temperatures which may
be employed include, e.g., 20.degree. C. to 35.degree. C.
[0014] Ischemia is blockage of the arteries that supply blood to a
tissue. The blockage itself is referred to as a clot or thrombus
and results from the solidification of fibrinogen into fibrin. A
stroke is ischemia where the arteries to the brain are blocked. In
a stroke, the clot forms in the cerebral or pre-cerebral arteries.
This type of blockage may also be caused by a thrombus that breaks
free from the heart and flows into an artery through which it
cannot pass. In other words, the thrombus gets lodged in the
artery.
[0015] Clots can be treated in several ways. One way, fibrinolysis,
employs enzymes that lyse, or break up and dissolve, the clot.
Thrombolysis is fibrinolysis used to treat thrombosed vessels. The
enzymes that lyse clots are termed thrombolytics because thrombin
is the enzyme that coagulates fibrinogen. Streptokinase ("SK"),
urokinase ("UK"), and tissue plasminogen activator ("tPA") are
thrombolytics and are often used in this capacity. These enzymes
can be given as drugs by intravenous injection or by intra-arterial
delivery using a catheter with a fluid outlet port near or at the
site of the clot.
[0016] Drug administration is occasionally problematic as some
sensitive patients encounter adverse reactions to drugs. Moreover,
there is a risk of hemorrhage when these drugs are given
intravenously. There is a need for a method of lysing clots that
does not rely solely or partially on drug administration. There is
further a need for a method of lysing clots in which the effects of
ischemia on affected cells is minimized.
[0017] In some cases, of course, the extent or nature of the clot
indicates that drug therapies must be used. The effectiveness of
drug therapies is dependent on several factors, including the
temperature of the environment in which the drug acts. Thus, there
is further a need for a drug therapy which is effective to treat a
thrombus and which is also complementary to efforts to reduce
ischemia, especially when those efforts employ hypothermia.
BRIEF SUMMARY OF THE INVENTION
[0018] In one aspect, the invention relates to a method for
substantially reducing the size of a thrombus in a blood vessel.
The method includes delivering a heat transfer element to a blood
vessel in fluid communication with a thrombosed blood vessel. The
temperature of the heat transfer element is adjusted such that the
same is sufficient to remove heat from the flowing blood. Heat is
transferred from a volume of blood including the thrombus to the
heat transfer element. The resultant temperature of the volume may
be sufficient to substantially reduce the size of a thrombus. For
example, the resultant temperature of the volume may be
sufficiently high to substantially enhance plasminogen activation
near the thrombus.
[0019] Implementations of the invention may include one or more of
the following. The temperature of the blood may be adjusted by the
heat transfer element to a temperature of between about 30.degree.
C. and 32.degree. C. The temperature sufficient to substantially
reduce the size of a thrombus is also sufficient to substantially
reduce plasmin inhibitor activity near the thrombus. The
temperature of the heat transfer element may be raised from a
temperature sufficient to substantially reduce the size of the
thrombus to a temperature sufficient to substantially rewarm the
volume, and may further be cycled between these temperatures. In
this case, the temperature sufficient to reduce the size of the
thrombus is between about 25.degree. C. and 32.degree. C., and the
temperature sufficient to substantially rewarm the volume is
between about 34.degree. C. and 36.degree. C.
[0020] The delivering and adjusting may further include inserting
the heat transfer element into the vessel and cooling the heat
transfer element by delivering a working fluid to the heat transfer
element. The working fluid may be delivered at a temperature of
between about -3.degree. C. and 1.degree. C. The heat transfer
element may be inflated with the working fluid, which may be
delivered at a pressure of less than 5 atmospheres, such as about 1
to 5 atmospheres.
[0021] Turbulence may also be induced in the flowing blood or in
the working fluid. Regarding the former, turbulence may be induced
with a turbulence intensity of greater than about 0.05. Blood
turbulence may be induced in greater than 20% of the period of the
cardiac cycle within the carotid artery, such as during the entire
period of the cardiac cycle. To induce turbulence in the working
fluid, the inflating may include passing the working fluid through
a substantially helical-shaped structure. About 75 to 200 watts of
heat may be removed from the blood.
[0022] In another aspect, the invention relates to a method for
dissolving a blood clot. The method includes introducing a catheter
having a cooling element into a blood vessel in which a blood clot
has formed and disposing the cooling element within the blood
vessel such that blood flows past the cooling element to the blood
clot. At least a portion of the volume of blood surrounding the
blood clot is cooled. Free stream turbulence may be induced in
blood flowing over the catheter. The method thus reduces inhibition
of anti-clotting enzymes by the cooling.
[0023] In yet another aspect, the invention relates to a method of
altering the activity of an enzyme present in a flow of blood
relative to the activity of the enzyme at a normal blood
temperature. The method includes delivering a heat transfer element
to the blood flow upstream of the enzyme, adjusting the temperature
of the heat transfer element such that the temperature of the heat
transfer element is sufficient to alter the temperature of a local
portion of the blood flow including the enzyme, and transferring
heat between the portion of the blood flow and the heat transfer
element. The resultant temperature of the portion of the blood flow
is sufficient to substantially alter the enzyme activity within at
least the portion of the blood flow.
[0024] Implementations of the invention may include extending the
technique to stationary volumes of blood or tissue. The adjusting
may further include cooling the heat transfer element by delivering
a working fluid to the heat transfer element and inducing
turbulence within the working fluid or in the flow of blood.
[0025] In a further aspect, the invention is related to a method
for providing an optimal working temperature for a
temperature-specific enzyme with a drug in a blood vessel. The
method includes delivering a heat transfer element to a blood
vessel, the blood vessel containing a temperature-specific enzyme.
The temperature of the heat transfer element is adjusted such that
the temperature-specific enzyme is heated to a prespecified
temperature range within at least a portion of which the optimal
working temperature for a temperature-specific enzyme is attained.
The optimal working temperature in the blood vessel is
substantially different from the normal body temperature in the
blood vessel.
[0026] In another aspect, the invention is directed towards a
method for selective thrombolysis by selective vessel hypothermia.
The method includes introducing a catheter having a heat transfer
element into a blood vessel in fluid communication with a
thrombosed blood vessel. The heat transfer element is cooled by
flowing a working fluid through the heat transfer element. The
blood is cooled by flowing the blood past the heat transfer element
and inducing free stream turbulence in the blood, such that the
blood is cooled to a prespecified temperature range. A thrombolytic
drug is then delivered to the blood, the thrombolytic drug having a
working temperature within the prespecified temperature range.
[0027] Implementations of the invention may include one or more of
the following. The drug may be chosen from tPA, urokinase,
streptokinase, precursors of urokinase, and combinations thereof.
If the drug is tPA, the prespecified temperature range may be
between about 30.degree. C. to 32.degree. C. The blood may then be
rewarmed and cycled. If the thrombolytic drug is streptokinase, the
prespecified temperature range may between about 30.degree. C. and
32.degree. C., and the rewarming may raise the blood temperature to
about 37.degree. C.
[0028] If the thrombolytic drug is urokinase, the prespecified
temperature range may be below about 28.degree. C., and the
rewarming may raise the blood temperature to about 37.degree. C. If
the thrombolytic drug is a precursor to urokinase, the prespecified
temperature range may be below about 28.degree. C., and the
rewarming may raise the blood temperature to about 37.degree.
C.
[0029] In yet another aspect, the blood may be warmed instead of
cooled. In this case, if the drug is tPA, the prespecified
temperature range may be between about 37.degree. C. to 40.degree.
C.
[0030] In yet a further aspect, the invention is directed towards a
method of reducing certain deleterious and systemic effects of
thrombolytic drugs while allowing thrombolysis to effectively
proceed via selective vessel hypothermia. The method includes
introducing a catheter having a heat transfer element into a
thrombosed blood vessel or into a blood vessel in fluid
communication with a thrombosed blood vessel. The temperature of
the blood flowing through the blood vessel, prior to introduction
of the heat transfer element, and averaged over the body, is at a
first temperature or is alternatively within a first temperature
range. The heat transfer element is cooled by flowing a working
fluid through the heat transfer element. The blood is cooled by
flowing the blood past the cooled heat transfer element and by
inducing free stream turbulence in the blood, such that the blood
is cooled to a prespecified temperature range. The presence of the
free stream turbulence significantly enhances the heat transfer
rate. A drug is then delivered to the blood. The drug has a working
temperature within the prespecified temperature range. The drug is
substantially less active at the first temperature or within the
first temperature range. Alternatively, the drug has substantially
less activity at the first temperature or within the first
temperature range. Alternatively, the drug does not have a working
temperature at the first temperature or within the first
temperature range. The drug may be, e.g., a thrombolytic drug.
[0031] Advantages of the invention include one or more of the
following. Clot lysis may be achieved conveniently and selectively,
and may be induced without the need for additional anticoagulants.
The effects of ischemia are reduced during the procedure, reducing
damage to affected cells. In the case where drugs are administered
to further treat a thrombus, hypothermia may also be induced as a
complementary therapy to reduce the effects of ischemia and to
provide neural protection. In a case where temperature isoforms of
known drugs or enzymes are used to provide a therapy, the drug
action may be localized to a prespecified situs by selective
cooling. In other words, the drug only works at a particular
temperature, and the particular temperature is only achieved at the
working situs. In this way, procedures such as thrombolysis may be
achieved without adverse systemic effects.
[0032] The novel features of this invention, as well as the
invention itself, will be best understood from the attached
drawings, taken along with the following description, in which
similar reference characters refer to similar parts, and in
which:
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0033] FIG. 1 is an elevation view of a turbulence inducing heat
transfer element within an artery;
[0034] FIG. 2 is an elevation view of one embodiment of a heat
transfer element which may be employed according to the
invention;
[0035] FIG. 3 is longitudinal section view of the heat transfer
element of FIG. 2;
[0036] FIG. 4 is a transverse section view of the heat transfer
element of FIG. 2;
[0037] FIG. 5 is a perspective view of the heat transfer element of
FIG. 2 in use within a blood vessel;
[0038] FIG. 6 is a cut-away perspective view of an alternative
embodiment of a heat transfer element which may be employed
according to the invention;
[0039] FIG. 7 is a transverse section view of the heat transfer
element of FIG. 6; and
[0040] FIG. 8 is a schematic representation of the invention being
used in one embodiment to cool the brain of a patient.
DETAILED DESCRIPTION OF THE INVENTION
[0041] The temperature of a selected organ may be intravascularly
regulated by a heat transfer element placed in the organ's feeding
artery to absorb or deliver heat to or from the blood flowing into
the organ. While the method is described with respect to blood flow
into an organ, it is understood that heat transfer within a volume
of tissue is analogous. In the latter case, heat transfer is
predominantly by conduction.
[0042] The heat transfer may cause either a cooling or a heating of
the selected organ. A heat transfer element that selectively alters
the temperature of an organ should be capable of providing the
necessary heat transfer rate to produce the desired cooling or
heating effect within the organ to achieve a desired
temperature.
[0043] The heat transfer element should be small and flexible
enough to fit within the feeding artery while still allowing a
sufficient blood flow to reach the organ in order to avoid ischemic
organ damage. Feeding arteries, like the carotid artery, branch off
the aorta at various levels. Subsidiary arteries continue to branch
off these initial branches. For example, the internal carotid
artery branches off the common carotid artery near the angle of the
jaw. The heat transfer element is typically inserted into a
peripheral artery, such as the femoral artery, using a guide
catheter or guide wire, and accesses a feeding artery by initially
passing though a series of one or more of these branches. Thus, the
flexibility and size, e.g., the diameter, of the heat transfer
element are important characteristics. This flexibility is achieved
as is described in more detail below.
[0044] These points are illustrated using brain cooling as an
example. The common carotid artery supplies blood to the head and
brain. The internal carotid artery branches off the common carotid
artery to supply blood to the anterior cerebrum. The heat transfer
element may be placed into the common carotid artery or into both
the common carotid artery and the internal carotid artery.
[0045] The benefits of hypothermia described above are achieved
when the temperature of the blood flowing to the brain is reduced
to between 30.degree. C. and 32.degree. C. A typical brain has a
blood flow rate through each carotid artery (right and left) of
approximately 250-375 cubic centimeters per minute (cc/min). With
this flow rate, calculations show that the heat transfer element
should absorb approximately 75-175 watts of heat when placed in one
of the carotid arteries to induce the desired cooling effect.
Smaller organs may have less blood flow in their respective supply
arteries and may require less heat transfer, such as about 25
watts.
[0046] The method employs conductive and convective heat transfers.
Once the materials for the device and a working fluid are chosen,
the conductive heat transfers are solely dependent on the
temperature gradients. Convective heat transfers, by contrast, also
rely on the movement of fluid to transfer heat. Forced convection
results when the heat transfer surface is in contact with a fluid
whose motion is induced (or forced) by a pressure gradient, area
variation, or other such force. In the case of arterial flow, the
beating heart provides an oscillatory pressure gradient to force
the motion of the blood in contact with the heat transfer surface.
One of the aspects of the device uses turbulence to enhance this
forced convective heat transfer.
[0047] The rate of convective heat transfer Q is proportional to
the product of S , the area of the heat transfer element in direct
contact with the fluid, .DELTA.T=T.sub.b-T.sub.s, the temperature
differential between the surface temperature T.sub.s of the heat
transfer element and the free stream blood temperature T.sub.b, and
h.sub.c, the average convection heat transfer coefficient over the
heat transfer area. h.sub.c is sometimes called the "surface
coefficient of heat transfer" or the "convection heat transfer
coefficient".
[0048] The magnitude of the heat transfer rate Q to or from the
fluid flow can be increased through manipulation of the above three
parameters. Practical constraints limit the value of these
parameters and how much they can be manipulated. For example, the
internal diameter of the common carotid artery ranges from 6 to 8
mm. Thus, the heat transfer element residing therein may not be
much larger than 4 mm in diameter to avoid occluding the vessel.
The length of the heat transfer element should also be limited. For
placement within the internal and common carotid artery, the length
of the heat transfer element is limited to about 10 cm. This
estimate is based on the length of the common carotid artery, which
ranges from 8 to 12 cm.
[0049] Consequently, the value of the surface area S is limited by
the physical constraints imposed by the size of the artery into
which the device is placed. Surface features, such as fins, can be
used to increase the surface area of the heat transfer element,
however, these features alone cannot provide enough surface area
enhancement to meet the required heat transfer rate to effectively
cool the brain.
[0050] One may also attempt to vary the magnitude of the heat
transfer rate by varying .DELTA.T. The value of
.DELTA.T=T.sub.b-T.sub.s can be varied by varying the surface
temperature T.sub.s of the heat transfer element. The allowable
surface temperature of the heat transfer element is limited by the
characteristics of blood. The blood temperature is fixed at about
37.degree. C., and blood freezes at approximately 0.degree. C. When
the blood approaches freezing, ice emboli may form in the blood
which may lodge downstream, causing serious ischemic injury.
Furthermore, reducing the temperature of the blood also increases
its viscosity which results in a small decrease in the value of
h.sub.c. Increased viscosity of the blood may further result in an
increase in the pressure drop within the artery, thus compromising
the flow of blood to the brain. Given the above constraints, it is
advantageous to limit the surface temperature of the heat transfer
element to approximately 1.degree. C.-5.degree. C., thus resulting
in a maximum temperature differential between the blood stream and
the heat transfer element of approximately 32.degree. C.-36.degree.
C.
[0051] One may also attempt to vary the magnitude of the heat
transfer rate by varying h.sub.c. Fewer constraints are imposed on
the value of the convection heat transfer coefficient h.sub.c. The
mechanisms by which the value of h.sub.c may be increased are
complex. However, one way to increase h.sub.c for a fixed mean
value of the velocity is to increase the level of turbulent kinetic
energy in the fluid flow.
[0052] The heat transfer rate Q.sub.no-flow in the absence of fluid
flow is proportional to .DELTA.T, the temperature differential
between the surface temperature T.sub.s of the heat transfer
element and the free stream blood temperature T.sub.b times k, the
diffusion constant, and is inversely proportion to .delta., the
thickness of the boundary layer.
[0053] The magnitude of the enhancement in heat transfer by fluid
flow can be estimated by taking the ratio of the heat transfer rate
with fluid flow to the heat transfer rate in the absence of fluid
flow N=Q.sub.flow/Q.sub.no-flow=h.sub.c/(k/.delta.). This ratio is
called the Nusselt number ("Nu"). For convective heat transfer
between blood and the surface of the heat transfer element, Nusselt
numbers of 30-80 have been found to be appropriate for selective
cooling applications of various organs in the human body. Nusselt
numbers are generally dependent on several other numbers: the
Reynolds number, the Womersley number, and the Prandtl number.
[0054] Stirring-type mechanisms, which abruptly change the
direction of velocity vectors, may be utilized to induce turbulent
kinetic energy and increase the heat transfer rate. The level of
turbulence so created is characterized by the turbulence intensity
. Turbulence intensity is defined as the root mean square of the
fluctuating velocity divided by the mean velocity. Such mechanisms
can create high levels of turbulence intensity in the free stream,
thereby increasing the heat transfer rate. This turbulence
intensity should ideally be sustained for a significant portion of
the cardiac cycle, and should ideally be created throughout the
free stream and not just in the boundary layer.
[0055] Turbulence does occur for a short period in the cardiac
cycle anyway. In particular, the blood flow is turbulent during a
small portion of the descending systolic flow. This portion is less
than 20% of the period of the cardiac cycle. If a heat transfer
element is placed co-axially inside the artery, the heat transfer
rate will be enhanced during this short interval. For typical of
these fluctuations, the turbulence intensity is at least 0.05. In
other words, the instantaneous velocity fluctuations deviate from
the mean velocity by at least 5%. Although ideally turbulence is
created throughout the entire period of the cardiac cycle, the
benefits of turbulence are obtained if the turbulence is sustained
for 75%, 50% or even as low as 30% or 20% of the cardiac cycle.
[0056] One type of turbulence-inducing heat transfer element which
may be advantageously employed to provide heating or cooling of an
organ or volume is described in co-pending U.S. patent application
Ser. No. 09/103,342 to Dobak and Lasheras for a "Selective Organ
Cooling Catheter and Method of Using the Same," incorporated by
reference above. In that application, and as described below, the
heat transfer element is made of a high thermal conductivity
material, such as metal. The use of a highly thermally conductive
material increases the heat transfer rate for a given temperature
differential between the coolant within the heat transfer element
and the blood. This facilitates the use of a higher temperature
coolant within the heat transfer element, allowing safer coolants,
such as water, to be used. Highly thermally conductive materials,
such as metals, tend to be rigid. In that application, bellows
provided a high degree of articulation that compensated for the
intrinsic stiffness of the metal. The device size was minimized,
e.g., less than 4 mm, to prevent blockage of the blood flowing in
the artery. Therefore, the design of the heat transfer element
should facilitate flexibility in an inherently inflexible
material.
[0057] To create the desired level of turbulence intensity in the
blood free stream during the whole cardiac cycle, one embodiment of
the device uses a modular design. This design creates helical blood
flow and produces a high level of turbulence in the free stream by
periodically forcing abrupt changes in the direction of the helical
blood flow. FIG. 1 is a perspective view of such a turbulence
inducing heat transfer element within an artery. Turbulent flow
would be found at point 114, in the free stream area. The abrupt
changes in flow direction are achieved through the use of a series
of two or more heat transfer segments, each comprised of one or
more helical ridges. To affect the free stream, the depth of the
helical ridge is larger than the thickness of the boundary layer
which would develop if the heat transfer element had a smooth
cylindrical surface.
[0058] The use of periodic abrupt changes in the helical direction
of the blood flow in order to induce strong free stream turbulence
may be illustrated with reference to a common clothes washing
machine. The rotor of a washing machine spins initially in one
direction causing laminar flow. When the rotor abruptly reverses
direction, significant turbulent kinetic energy is created within
the entire wash basin as the changing currents cause random
turbulent motion within the clothes-water slurry.
[0059] FIG. 2 is an elevation view of one embodiment of a heat
transfer element 14. The heat transfer element 14 is comprised of a
series of elongated, articulated segments or modules 20, 22, 24.
Three such segments are shown in this embodiment, but two or more
such segments could be used. As seen in FIG. 2, a first elongated
heat transfer segment 20 is located at the proximal end of the heat
transfer element 14. A turbulence-inducing exterior surface of the
segment 20 comprises four parallel helical ridges 28 with four
parallel helical grooves 26 therebetween. One, two, three, or more
parallel helical ridges 28 could also be used. In this embodiment,
the helical ridges 28 and the helical grooves 26 of the heat
transfer segment 20 have a left hand twist, referred to herein as a
counter-clockwise spiral or helical rotation, as they proceed
toward the distal end of the heat transfer segment 20.
[0060] The first heat transfer segment 20 is coupled to a second
elongated heat transfer segment 22 by a first bellows section 25,
which provides flexibility and compressibility. The second heat
transfer segment 22 comprises one or more helical ridges 32 with
one or more helical grooves 30 therebetween. The ridges 32 and
grooves 30 have a right hand, or clockwise, twist as they proceed
toward the distal end of the heat transfer segment 22. The second
heat transfer segment 22 is coupled to a third elongated heat
transfer segment 24 by a second bellows section 27. The third heat
transfer segment 24 comprises one or more helical ridges 36 with
one or more helical grooves 34 therebetween. The helical ridge 36
and the helical groove 34 have a left hand, or counter-clockwise,
twist as they proceed toward the distal end of the heat transfer
segment 24. Thus, successive heat transfer segments 20, 22, 24 of
the heat transfer element 14 alternate between having clockwise and
counterclockwise helical twists. The actual left or right hand
twist of any particular segment is immaterial, as long as adjacent
segments have opposite helical twist.
[0061] In addition, the rounded contours of the ridges 28, 32, 36
also allow the heat transfer element 14 to maintain a relatively
atraumatic profile, thereby minimizing the possibility of damage to
the blood vessel wall. A heat transfer element may be comprised of
two, three, or more heat transfer segments.
[0062] The bellows sections 25, 27 are formed from seamless and
nonporous materials, such as metal, and therefore are impermeable
to gas, which can be particularly important, depending on the type
of working fluid which is cycled through the heat transfer element
14. The structure of the bellows sections 25, 27 allows them to
bend, extend and compress, which increases the flexibility of the
heat transfer element 14 so that it is more readily able to
navigate through blood vessels. The bellows sections 25, 27 also
provide for axial compression of the heat transfer element 14,
which can limit the trauma when the distal end of the heat transfer
element 14 abuts a blood vessel wall. The bellows sections 25, 27
are also able to tolerate cryogenic temperatures without a loss of
performance.
[0063] The exterior surfaces of the heat transfer element 14 can be
made from metal, and may comprise very high thermal conductivity
materials such as nickel, thereby facilitating heat transfer.
Alternatively, other metals such as stainless steel, titanium,
aluminum, silver, copper and the like, can be used, with or without
an appropriate coating or treatment to enhance biocompatibility or
inhibit clot formation. Suitable biocompatible coatings include,
e.g., gold, platinum or polymer paralyene. The heat transfer
element 14 may be manufactured by plating a thin layer of metal on
a mandrel that has the appropriate pattern. In this way, the heat
transfer element 14 may be manufactured inexpensively in large
quantities, which is an important feature in a disposable medical
device.
[0064] Because the heat transfer element 14 may dwell within the
blood vessel for extended periods of time, such as 24-48 hours or
even longer, it may be desirable to treat the surfaces of the heat
transfer element 14 to avoid clot formation. In particular, one may
wish to treat the bellows sections 25, 27 because stagnation of the
blood flow may occur in the convolutions, thus allowing clots to
form and cling to the surface to form a thrombus. One means by
which to prevent thrombus formation is to bind an antithrombogenic
agent to the surface of the heat transfer element 14. For example,
heparin is known to inhibit clot formation and is also known to be
useful as a biocoating. Alternatively, the surfaces of the heat
transfer element 14 may be bombarded with ions such as nitrogen.
Bombardment with nitrogen can harden and smooth the surface and,
thus prevent adherence of clotting factors to the surface.
[0065] FIG. 3 is a longitudinal sectional view of the heat transfer
element 14, taken along line 3-3 in FIG. 2. Some interior contours
are omitted for purposes of clarity. An inner tube 42 creates an
inner coaxial lumen 42 and an outer coaxial lumen 46 within the
heat transfer element 14. Once the heat transfer element 14 is in
place in the blood vessel, a working fluid such as saline or other
aqueous solution may be circulated through the heat transfer
element 14. Fluid flows up a supply catheter into the inner coaxial
lumen 40. At the distal end of the heat transfer element 14, the
working fluid exits the inner coaxial lumen 40 and enters the outer
lumen 46. As the working fluid flows through the outer lumen 46,
heat is transferred from the working fluid to the exterior surface
37 of the heat transfer element 14. Because the heat transfer
element 14 is constructed from a high conductivity material, the
temperature of its exterior surface 37 may reach very close to the
temperature of the working fluid. The tube 42 may be formed as an
insulating divider to thermally separate the inner lumen 40 from
the outer lumen 46. For example, insulation may be achieved by
creating longitudinal air channels in the wall of the insulating
tube 42. Alternatively, the insulating tube 42 may be constructed
of a non-thermally conductive material like polytetrafluoroethylene
or some other polymer.
[0066] It is important to note that the same mechanisms that govern
the heat transfer rate between the exterior surface 37 of the heat
transfer element 14 and the blood also govern the heat transfer
rate between the working fluid and the interior surface 38 of the
heat transfer element 14. The heat transfer characteristics of the
interior surface 38 are particularly important when using water,
saline or other fluid which remains a liquid as the coolant. Other
coolants such as freon undergo nucleate boiling and create
turbulence through a different mechanism. Saline is a safe coolant
because it is non-toxic, and leakage of saline does not result in a
gas embolism, which could occur with the use of boiling
refrigerants. Since turbulence in the coolant is enhanced by the
shape of the interior surface 38 of the heat transfer element 14,
the coolant can be delivered to the heat transfer element 14 at a
warmer temperature and still achieve the necessary heat transfer
rate.
[0067] This has a number of beneficial implications in the need for
insulation along the catheter shaft length. Due to the decreased
need for insulation, the catheter shaft diameter can be made
smaller. The enhanced heat transfer characteristics of the interior
surface of the heat transfer element 14 also allow the working
fluid to be delivered to the heat transfer element 14 at lower flow
rates and lower pressures. High pressures may make the heat
transfer element stiff and cause it to push against the wall of the
blood vessel, thereby shielding part of the exterior surface 37 of
the heat transfer element 14 from the blood. Because of the
increased heat transfer characteristics achieved by the alternating
helical ridges 28, 32, 36, the pressure of the working fluid may be
as low as 5 atmospheres, 3 atmospheres, 2 atmospheres or even less
than 1 atmosphere.
[0068] FIG. 4 is a transverse sectional view of the heat transfer
element 14, taken at a location denoted by the line 4-4 in FIG. 2.
FIG. 4 illustrates a five-lobed embodiment, whereas FIG. 2
illustrates a four-lobed embodiment. As mentioned earlier, any
number of lobes might be used. In FIG. 4, the coaxial construction
of the heat transfer element 14 is clearly shown. The inner coaxial
lumen 40 is defined by the insulating coaxial tube 42. The outer
lumen 46 is defined by the exterior surface of the insulating
coaxial tube 42 and the interior surface 38 of the heat transfer
element 14. In addition, the helical ridges 32 and helical grooves
30 may be seen in FIG. 4. As noted above, in the preferred
embodiment, the depth of the grooves, d.sub.i, is greater than the
boundary layer thickness which would have developed if a
cylindrical heat transfer element were introduced. For example, in
a heat transfer element 14 with a 4 mm outer diameter, the depth of
the invaginations, d.sub.i, may be approximately equal to 1 mm if
designed for use in the carotid artery. Although FIG. 4 shows four
ridges and four grooves, the number of ridges and grooves may vary.
Thus, heat transfer elements with 1, 2, 3, 4, 5, 6, 7, 8 or more
ridges are specifically contemplated.
[0069] FIG. 5 is a perspective view of a heat transfer element 14
in use within a blood vessel, showing only one helical lobe per
segment for purposes of clarity. Beginning from the proximal end of
the heat transfer element (not shown in FIG. 5), as the blood moves
forward during the systolic pulse, the first helical heat transfer
segment 20 induces a counter-clockwise rotational inertia to the
blood. As the blood reaches the second segment 22, the rotational
direction of the inertia is reversed, causing turbulence within the
blood. Further, as the blood reaches the third segment 24, the
rotational direction of the inertia is again reversed. The sudden
changes in flow direction actively reorient and randomize the
velocity vectors, thus ensuring turbulence throughout the
bloodstream. During turbulent flow, the velocity vectors of the
blood become more random and, in some cases, become perpendicular
to the axis of the artery. In addition, as the velocity of the
blood within the artery decreases and reverses direction during the
cardiac cycle, additional turbulence is induced and turbulent
motion is sustained throughout the duration of each pulse through
the same mechanisms described above.
[0070] Thus, a large portion of the volume of warm blood in the
vessel is actively brought in contact with the heat transfer
element 14, where it can be cooled by direct contact rather than
being cooled largely by conduction through adjacent laminar layers
of blood. As noted above, the depth of the grooves 26, 30, 34 (FIG.
2) is greater than the depth of the boundary layer which would
develop if a straight-walled heat transfer element were introduced
into the blood stream. In this way, free stream turbulence is
induced. In the preferred embodiment, in order to create the
desired level of turbulence in the entire blood stream during the
whole cardiac cycle, the heat transfer element 14 creates a
turbulence intensity greater than about 0.05. The turbulence
intensity may be greater than 0.05, 0.06, 0.07 or up to 0.10 or
0.20 or greater.
[0071] Referring back to FIG. 2, the heat transfer element 14 has
been designed to address all of the design criteria discussed
above. First, the heat transfer element 14 is flexible and is made
of a highly conductive material. The flexibility is provided by a
segmental distribution of bellows sections 25, 27 which provide an
articulating mechanism. Bellows have a known convoluted design
which provides flexibility. Second, the exterior surface area 37
has been increased through the use of helical ridges 28, 32, 36 and
helical grooves 26, 30, 34. The ridges also allow the heat transfer
element 14 to maintain a relatively atraumatic profile, thereby
minimizing the possibility of damage to the vessel wall. Third, the
heat transfer element 14 has been designed to promote turbulent
kinetic energy both internally and externally. The modular or
segmental design allows the direction of the invaginations to be
reversed between segments. The alternating helical rotations create
an alternating flow that results in mixing the blood in a manner
analogous to the mixing action created by the rotor of a washing
machine that switches directions back and forth. This mixing action
is intended to promote high level turbulent kinetic energy to
enhance the heat transfer rate. The alternating helical design also
causes beneficial mixing, or turbulent kinetic energy, of the
working fluid flowing internally.
[0072] FIG. 6 is a cut-away perspective view of an alternative
embodiment of a heat transfer element 50. An external surface 52 of
the heat transfer element 50 is covered with a series of axially
staggered protrusions 54. The staggered nature of the outer
protrusions 54 is readily seen with reference to FIG. 7 which is a
transverse cross-sectional view taken at a location denoted by the
line 7-7 in FIG. 6. In order to induce free stream turbulence, the
height, d.sub.p, of the staggered outer protrusions 54 is greater
than the thickness of the boundary layer which would develop if a
smooth heat transfer element had been introduced into the blood
stream. As the blood flows along the external surface 52, it
collides with one of the staggered protrusions 54 and a turbulent
wake flow is created behind the protrusion. As the blood divides
and swirls along side of the first staggered protrusion 54, its
turbulent wake encounters another staggered protrusion 54 within
its path preventing the re-lamination of the flow and creating yet
more turbulence. In this way, the velocity vectors are randomized
and turbulence is created not only in the boundary layer but
throughout the free stream. As is the case with the preferred
embodiment, this geometry also induces a turbulent effect on the
internal coolant flow.
[0073] A working fluid is circulated up through an inner coaxial
lumen 56 defined by an insulating coaxial tube 58 to a distal tip
of the heat transfer element 50. The working fluid then traverses
an outer coaxial lumen 60 in order to transfer heat to the exterior
surface 52 of the heat transfer element 50. The inside surface of
the heat transfer element 50 is similar to the exterior surface 52,
in order to induce turbulent flow of the working fluid. The inner
protrusions can be aligned with the outer protrusions 54, as shown
in FIG. 7, or they can be offset from the outer protrusions 54, as
shown in FIG. 6.
[0074] FIG. 8 is a schematic representation of the invention being
used to cool the brain of a patient. The selective organ
hypothermia apparatus shown in FIG. 8 includes a working fluid
supply 10, preferably supplying a chilled liquid such as water,
alcohol or a halogenated hydrocarbon, a supply catheter 12 and the
heat transfer element 14. The supply catheter 12 has a coaxial
construction. An inner coaxial lumen within the supply catheter 12
receives coolant from the working fluid supply 10. The coolant
travels the length of the supply catheter 12 to the heat transfer
element 14 which serves as the cooling tip of the catheter. At the
distal end of the heat transfer element 14, the coolant exits the
insulated interior lumen and traverses the length of the heat
transfer element 14 in order to decrease the temperature of the
heat transfer element 14. The coolant then traverses an outer lumen
of the supply catheter 12 so that it may be disposed of or
recirculated. The supply catheter 12 is a flexible catheter having
a diameter sufficiently small to allow its distal end to be
inserted percutaneously into an accessible artery such as the
femoral artery of a patient as shown in FIG. 8. The supply catheter
12 is sufficiently long to allow the heat transfer element 14 at
the distal end of the supply catheter 12 to be passed through the
vascular system of the patient and placed in the internal carotid
artery or other small artery. The method of inserting the catheter
into the patient and routing the heat transfer element 14 into a
selected artery is well known in the art.
[0075] Although the working fluid supply 10 is shown as an
exemplary cooling device, other devices and working fluids may be
used. For example, in order to provide cooling, freon,
perflourocarbon, water, or saline may be used, as well as other
such coolants.
[0076] The heat transfer element can absorb or provide over 75
Watts of heat to the blood stream and may absorb or provide as much
as 100 Watts, 150 Watts, 170 Watts or more. For example, a heat
transfer element with a diameter of 4 mm and a length of
approximately 10 cm using ordinary saline solution chilled so that
the surface temperature of the heat transfer element is
approximately 5.degree. C. and pressurized at 2 atmospheres can
absorb about 100 Watts of energy from the bloodstream. Smaller
geometry heat transfer elements may be developed for use with
smaller organs which provide 60 Watts, 50 Watts, 25 Watts or less
of heat transfer.
[0077] The practice of the present invention is illustrated in the
following non-limiting example.
Exemplary Procedure
[0078] 1. The patient is initially assessed, resuscitated, and
stabilized.
[0079] 2. The procedure is carried out in an angiography suite or
surgical suite equipped with flouroscopy.
[0080] 3. Because the catheter is placed into the common carotid
artery, it is important to determine the presence of stenotic
atheromatous lesions. A carotid duplex (doppler/ultrasound) scan
can quickly and non-invasively make this determinations. The ideal
location for placement of the catheter is in the left carotid so
this may be scanned first. If disease is present, then the right
carotid artery can be assessed. This test can be used to detect the
presence of proximal common carotid lesions by observing the slope
of the systolic upstroke and the shape of the pulsation. Although
these lesions are rare, they could inhibit the placement of the
catheter. Examination of the peak blood flow velocities in the
internal carotid can determine the presence of internal carotid
artery lesions. Although the catheter is placed proximally to such
lesions, the catheter may exacerbate the compromised blood flow
created by these lesions. Peak systolic velocities greater that 130
cm/sec and peak diastolic velocities greater than about 100 cm/sec
in the internal indicate the presence of at least 70% stenosis.
Stenosis of 70% or more may warrant the placement of a stent to
open up the internal artery diameter.
[0081] 4. The ultrasound can also be used to determine the vessel
diameter and the blood flow and the catheter with the appropriately
sized heat transfer element could be selected.
[0082] 5. After assessment of the arteries, the patients inguinal
region is sterilely prepped and infiltrated with lidocaine.
[0083] 6. The femoral artery is cannulated and a guide wire may be
inserted to the desired carotid artery. Placement of the guide wire
is confirmed with flouroscopy.
[0084] 7. An angiographic catheter can be fed over the wire and
contrast media injected into the artery to further to assess the
anatomy of the carotid.
[0085] 8. Alternatively, the femoral artery is cannulated and a
10-12.5 french (f) introducer sheath is placed.
[0086] 9. A guide catheter is placed into the desired common
carotid artery. If a guiding catheter is placed, it can be used to
deliver contrast media directly to further assess carotid
anatomy.
[0087] 10. A 10 f -12 f (3.3-4.0 mm) (approximate) cooling catheter
is subsequently filled with saline and all air bubbles are
removed.
[0088] 11. The cooling catheter is placed into the carotid artery
via the guiding catheter or over the guidewire. Placement is
confirmed with flouroscopy.
[0089] 12. Alternatively, the cooling catheter tip is shaped
(angled or curved approximately 45 degrees), and the cooling
catheter shaft has sufficient pushability and torqueability to be
placed in the carotid without the aid of a guide wire or guide
catheter.
[0090] 13. The cooling catheter is connected to a pump circuit also
filled with saline and free from air bubbles. The pump circuit has
a heat exchange section that is immersed into a water bath and
tubing that is connected to a peristaltic pump. The water bath is
chilled to approximately 0.degree. C.
[0091] 14. Cooling is initiated by starting the pump mechanism. The
saline within the cooling catheter is circulated at 5 cc/sec. The
saline travels through the heat exchanger in the chilled water bath
and is cooled to approximately 1.degree. C.
[0092] 15. It subsequently enters the cooling catheter where it is
delivered to the heat transfer element. The saline is warmed to
approximately 5-7.degree. C. as it travels along the inner lumen of
the catheter shaft to the end of the heat transfer element.
[0093] 16. The saline then flows back through the heat transfer
element in contact with the inner metallic surface. The saline is
further warmed in the heat transfer element to 12-15.degree. C, and
in the process, heat is absorbed from the blood, cooling the blood
to 30.degree. C. to 32.degree. C.
[0094] 17. The chilled blood then goes on to chill the brain. It is
estimated that 15-30 minutes will be required to cool the brain to
30 to 32.degree. C.
[0095] 18. The warmed saline travels back down the outer lumen of
the catheter shaft and back to the chilled water bath where it is
cooled to 1.degree. C.
[0096] 19. The pressure drops along the length of the circuit are
estimated to be 2-3 atmospheres.
[0097] 20. The cooling can be adjusted by increasing or decreasing
the flow rate of the saline. Monitoring of the temperature drop of
the saline along the heat transfer element will allow the flow to
be adjusted to maintain the desired cooling effect.
[0098] 21. The catheter is left in place to provide cooling for 12
to 24 hours.
[0099] 22. If desired, warm saline can be circulated to promote
warming of the brain at the end of the therapeutic cooling
period.
[0100] The above devices and techniques, including those disclosed
in the applications incorporated by reference above, provide
effective cooling or heating of a fluid such as blood. The heating
or cooling may occur either in the affected vessel or in a vessel
in fluid communication with the affected vessel. In this
disclosure, "fluid communication" between two vessels refers to a
situation where one vessel either feeds or is fed by the other. One
application of these devices and techniques is for clot lysis.
However, other types of enzyme activations may also be
advantageously induced. The method disclosed below is applicable to
other devices and techniques so long as they are also capable of
heating or cooling blood.
[0101] As noted above, enzymes have been delivered to patients in
drug or intravenous form for clot lysing. These enzymes are in
addition to naturally occurring enzymes already in the blood
plasma. The activity of enzymes is at least partially adjusted by
control of environmental temperature. A method according to an
embodiment of the invention selectively controls enzyme activity by
controlling the temperature of the environment of the enzyme. This
controlled enzyme activity allows selective thrombolysis by
selective vessel hypothermia in a manner described in more detail
below.
[0102] Several experimental procedures have been reported on
animals and clot preparations at various temperatures, as disclosed
below, and appropriate temperature regimes for thrombolysis may be
inferred with some accuracy. However, the mechanisms by which
enzyme environmental temperature controls thrombolysis are not yet
well characterized. Disclosed below are several suggested
mechanisms. These suggested mechanisms are conjecture, and should
not be construed as limiting, in any way, the method of the
invention.
[0103] The suggested mechanisms rely to a certain extent on the
known mechanisms for fibrinolysis. In particular, plasminogen is
the inert precursor of plasmin. Plasmin is an enzyme that lyses
clots, i.e., cleaves peptide bonds in fibrin. Plasminogen binds to
fibrin and, when activated by an appropriate enzyme, such as tPA,
UK, SK, etc., converts to plasmin. Plasminogen may also be
activated in solution. Inhibitors such as .alpha..sub.2-antiplasmin
moderate plasmin activity by inactivating plasmin released from a
fibrin surface almost instantaneously. .alpha..sub.2-antiplasmin
can even inactivate plasmin bound to a fibrin surface, but this
process requires about 10 seconds.
[0104] One suggested mechanism concerns the action of the
inhibitors. The activity of .alpha..sub.2-antiplasmin is lessened
at low temperatures and thus is less effective at inactivating
plasmin. In this case, more plasmin is available to lyse clots and
thus fibrinolysis is enhanced.
[0105] A related effect is due to the effect of plasmin levels on
plasminogen levels. Increased plasmin levels may lead to increased
plasminogen levels circulating in solution. Moreover, decreased
activity of .alpha..sub.2-antiplasmin also leads to increased
plasminogen levels because .alpha..sub.2-antiplasmin binds
plasminogen, and less .alpha..sub.2-antiplasmin means less of such
binding.
[0106] Increased plasminogen levels also suggests several other
mechanisms for clot lysing.
[0107] For example, plasmin cleaves single-chain urokinase
("scu-PA" or "pro-UK") to form UK, i.e., pro-UK is a precursor to
UK. Pro-UK, like tPA, cannot efficiently activate plasminogen in
solution, but it can readily activate plasminogen bound to fibrin.
Thus, increased plasminogen, together with the body's own UK or
tPA, or similar enzymes provided intravenously, may result in more
localized lysing of fibrin, e.g., directly at the clot situs.
[0108] Another suggested mechanism results from increased
plasminogen. UK can activate both plasminogen in solution and
plasminogen bound to fibrin. Thus, increased plasminogen levels,
together with the body's own UK, or that provided intravenously,
results in both localized lysing of fibrin and enhanced activation
of plasminogen in solution.
[0109] Another suggested mechanism results from the conjectured
bond of plasmin to fibrin. Plasmin may stay bound to fibrin for a
longer period in the hypothermic state. Thus, more time may be
available to lyse clots, increasing overall fibrinolysis.
[0110] The hypothermic temperatures at which increased fibrinolysis
occurs have not been fully explored. However, it has been shown
that clot samples have benefited from temperatures of, e.g.,
25.degree. C. or below. For human patients, it is believed that
temperatures of 30.degree. C. to 32.degree. C. may well be
appropriate and advantageously employed in the method of the
invention.
[0111] In a related embodiment of the invention, the method may
further employ a step of rewarming the cooled organ from the low
temperature of, e.g., 30.degree. C. The temperature range for
rewarming may be from about 20.degree. C. to 37.degree. C.
depending on the patient, the condition, the hypothermic
temperature, and so on. Rewarming has been shown to have a
beneficial effect in certain studies, perhaps by increasing the
rate at which clot lysis occurs. In another related embodiment of
the invention, the method may further employ temperature cycling
the blood in the vessel from a hypothermic temperature to a
rewarmed temperature. In this way, the rewarming temperature regime
is achieved repeatedly and thus so is the enhanced
fibrinolysis.
EXAMPLE ONE
[0112] (Non-drug)
[0113] Researchers have studied the effect of temperature on
fibrinolysis in the context of drug studies. As part of these
studies, control groups are investigated in which no drugs are
introduced. In one such investigation using clot samples, clot
lysis was investigated while varying clot temperatures in a range
of 25.degree. C. to 41.degree. C. In the absence of drugs, enhanced
clot lysis was seen at the lower part of the temperature range. It
is believed that this study can be extended to humans, and thus
fibrinolytic activity can be enhanced at lower temperatures.
EXAMPLE TWO
[0114] (Non-drug)
[0115] In another non-drug study of the effect of temperature on
fibrinolysis, clot lysis in dogs was investigated while varying
clot temperatures in a range of 20.degree. C. to 36.degree. C. The
dog's temperature was lowered from a normal temperature to a low
temperature. A gradual rewarming period followed the low
temperature period.
[0116] Enhanced clot lysis was observed at lower temperatures as
compared to higher temperatures. In particular, the maximum
fibrinolytic activity occurred in the early rewarming period, i.e.,
from 20.degree. C. to about 25.degree. C. It is believed that this
study can be extended to humans, and that fibrinolytic activity can
be enhanced at lower temperatures, especially during periods of
rewarming.
[0117] An advantage of all of these embodiments of the method is
that clot lysis can be achieved in a simple manner and without the
need for drugs. An additional advantage results from the reduced
temperature of the blood which helps to protect the cells from
ischemia at the same time lysis is occurring. Thus, clot lysis and
cooling occur simultaneously, providing an effective and aggressive
dual therapy. When dual therapies are employed, cooling catheters
may be inserted in both femoral arteries for transit to the brain.
One cooling catheter cools the brain, while the other cools the
blood in the artery leading to the clot. The latter provides the
beneficial effects noted above.
[0118] In some cases, of course, the nature or extent of the clot
is such that lysing may only occur with drug intervention. In these
cases, thrombolytic drugs, such as those disclosed above, may be
introduced to induce the fibrinolysis.
[0119] These drugs are effective at treating the thrombus. However,
it may also be advantageous to cool the brain as a separate
neuroprotective measure. The effectiveness of both therapies is
enhanced when applied as soon as possible. Thus, it is often
desirable to apply both therapies simultaneously. In this way,
hypothermia is induced as a neuroprotective measure, and may
further induce clot lysing per se in the manner described
above.
[0120] A difficulty with this approach is that the techniques are
interdependent. Drugs depend on enzymes for their activity, and
enzymes are temperature-dependent. In fact, past studies have
demonstrated that the enzyme activity of these specific
thrombolytic drugs on clot samples is temperature-dependent. In
other words, their effect on clot or thrombus lysis varies over a
temperature range. For typical temperature-specific enzymes, the
greatest activity occurs at an optimal temperature. The optimal
temperature may be about 37.degree. C. in the case of known
thrombolytics, as this is the normal human body temperature.
[0121] Enzyme activity drastically reduces above certain
temperatures as the enzyme denatures and becomes inactive. At the
opposite extreme, enzyme activity reduces below certain
temperatures as the enzyme lacks the energy necessary to couple to
a substrate. Therefore, when the brain or other tissue is at a
temperature different from normal body temperature, e.g., during
hypothermia, an isoform of the enzyme is preferably used which has
an optimal working temperature at the hypothermic body temperature.
In this disclosure, such an isoform which is effective at a
different temperature is said to have a "working temperature" at
the different temperature or within a range of different
temperatures.
[0122] In this disclosure, the term "isoform" of an enzyme is used
as follows. If a first enzyme catalyzes a reaction at a first
temperature, and a different enzyme catalyzes the same reaction at
a second temperature, then the different enzyme is an "isoform" of
the first enzyme within the meaning intended here.
[0123] For patients undergoing hypothermia, the physician may
preferably use a low-temperature isoform; for patients whose
temperatures have been raised, the physician may preferably use a
high-temperature isoform. The form of the enzyme will preferably
have an optimal activity curve at or near the desired temperature.
Known enzymes are described below, followed by a methodology for
choosing enzymes which are not yet known.
EXAMPLE THREE
[0124] (SK)
[0125] Researchers have investigated the effect of temperature on
the fibrinolytic activity of an SK mixture. In one such effort,
clots were treated with a mixture of plasminogen (2 mg) and SK (100
IU) in a total volume of 15 ml PBS. The temperature of the clots
was raised from 24.degree. C. to 37.degree. C. These researchers
found that heating enhanced the fibrinolytic activity. In other
words, heating from a hypothermic temperature to normal body
temperature increased clot lysing for clots treated with SK.
[0126] It is believed that such general trends may be extended to
patients without lack of accuracy. Patients may be provided with a
drug such as streptokinase and may undergo hypothermia using, e.g.,
one of the devices or methods described above. In particular, a
cooling catheter may be placed in an artery supplying blood to a
thrombosed vessel. The catheter may include a separate lumen
through which the SK mixture may be delivered. A coolant or working
fluid may be supplied to the cooling catheter, causing the same to
cool and to cool the blood adjacent a heat transfer element located
at a distal tip of the cooling catheter. This cooling step may
include the step of inducing turbulence in the blood flowing
through the vessel and/or in the working fluid. SK may be delivered
through the separate drug delivery lumen. The patient may then be
rewarmed as the SK is delivered. The rewarming step may be
accomplished by passing a warm saline solution as the working
fluid.
EXAMPLE FOUR
(tPA)
[0127] Researchers have also investigated the effect of temperature
on the fibrinolytic activity of tPA. Clots were treated with 2.5
.mu.g/ml tPA and incubated at various temperatures (e.g.,
37.degree. C., 25.degree. C., 10.degree. C., 0.degree. C., and
-8.degree. C.). Plasminogen activation was relatively high at low
temperatures (e.g., 0.degree. C. or -8.degree. C.) and was much
less at higher temperatures. In other words, these researchers
found that, for tPA, cooling to a hypothermic temperature from
normal body temperature increased fibrinolytic activity.
[0128] As above, it is believed that such trends may be extended to
patients without lack of accuracy. In this case, patients may be
provided with tPA and may undergo hypothermia using an above device
placed in an artery supplying blood to a thrombosed vessel. The
catheter may include a separate lumen through which tPA may be
delivered. A coolant or working fluid may be supplied to the
cooling catheter, causing the catheter and the adjacent blood to
cool. This cooling step may include the step of inducing turbulence
in the blood flowing in the vessel and/or in the working fluid. tPA
may be delivered through the separate drug delivery lumen. In this
case, the patient may not be rewarmed until the drug delivery is
complete, or until the thrombus is dissolved.
EXAMPLE FIVE
[0129] (tPA)
[0130] Researchers have further investigated the effect of
temperature on the fibrinolytic activity of tPA. Clots were treated
with tPA in concentrations of 0.3 .mu.g/ml, 1.0 .mu.g/ml, and 3.0
.mu.g/ml and incubated at various temperatures from 24.degree. C.
to 40.degree. C. The amount of clot lysis correlated with
temperature at all concentrations. However, contrary to the results
indicated in Example Four, the amount of clot lysis at lower
temperatures was less than that at higher temperatures. It is
conjectured that heating may have enhanced the activation of
plasminogen by the tPA, and that such heating may have a similar
effect in patients. This general enhancement has also been seen in
UK and SK systems.
[0131] Further research is clearly necessary to determine the
optimal procedure. In any case, an embodiment of the method of the
invention may be employed to advantageously perform either heating
or cooling in an improved way. To enhance the activation of
plasminogen by tPA, a warm saline solution may be provided in a
catheter of the type described above. The warm saline solution
transfers heat to the blood at a heat transfer element. An
appropriate temperature range for the warm saline solution at a
point within the heat transfer element may be about 38.degree. C.
to 74.degree. C.
EXAMPLE SIX
[0132] (UK)
[0133] Researchers have also investigated the effect of temperature
on the fibrinolytic activity of UK. In one such effort, clots were
treated with a mixture of UK at temperatures of 4.degree. C. and
28.degree. C. A certain amount of fibrinolytic activity was induced
by the introduction of the UK to the clots. Heating to 28.degree.
C. caused a second phase of activation, resulting in complete
conversion of all plasminogen to plasmin, and thus increased
fibrinolytic activity. In other words, heating from a very low
temperature (4.degree. C.) to a hypothermic temperature (28.degree.
C.) increased clot lysing. As above, it is believed that such
trends may be extended to patients. As may be noted, this Example
may be analogous to that of Example Three because of the rewarming
step; a similar procedure may be employed to perform the procedure
on patients.
[0134] The above examples indicate how drugs may be combined with
temperature-altering devices as, e.g. are disclosed above, to
provide simultaneous cooling and thrombolysis. This combination
provides a power dual therapy which may be advantageously employed
to aggressively treat stroke and other similar body insults. When
dual therapies are employed, a cooling catheter may be inserted in
one femoral artery for transit to the brain for neural protection.
Of course, a heating catheter would be employed if a temperature
rise were desired. Another catheter may provide the drug delivery.
Alternatively, the heating or cooling catheter may have disposed
therein a lumen for drug delivery. For example, the lumen may be
coaxial with the catheter and may be disposed along the centerline
of the catheter and heat transfer element. Alternatively, the lumen
may be disposed along one portion of the wall of the outlet lumen.
The drug delivery lumen may have an outlet at a tip of the heat
transfer element. Examples of such catheters are disclosed in U.S.
patent application Ser. No. 09/215,040, filed Dec. 16, 1998, and
entitled "Method and Device for Applications of Selective Organ
Cooling", the entirety of which is incorporated by reference
herein. These drug delivery catheters are particularly useful in
dispensing the drug or enzyme regionally, into a blood vessel
containing the thrombus or into a blood vessel in fluid
communication with the thrombosed blood vessel.
[0135] The above examples have used known drugs. However, for all
of the above and for similar techniques, an appropriate isoform of
an enzyme may be employed to allow enzymatic activity at
temperatures other than normal body temperature. One way to choose
appropriate isoforms for these enzymes is by searching for the same
in cold climates. For example, SK is a bacterial enzyme. Bacteria
live in many different temperature environments. It is common to
find or select an enzyme for a certain process or temperature by
finding bacteria that live in environments having the desired
temperature.
[0136] As another example, the polymerase chain reaction is a
polynucleotide amplification process that requires an enzyme
capable of surviving high temperatures. These enzymes were located
in bacteria living in hot springs and thermal vents on the sea
floor. Therefore, it is likely that certain bacteria that live in
room temperature environments or arctic-like environments will have
enzymes similar to those desired, i.e., SK that can survive
hypothermic environments.
[0137] tPA and UK, on the other hand, are recombinant forms of
human enzymes. As such, tPA and UK could be genetically altered to
maintain their activity at lower temperatures. For example, the
protein backbone could be changed to yield higher tPA or UK
activity at lower temperatures.
[0138] Such "temperature-specific" enzymes or drugs may be
advantageously used to localize the effect of the enzymes or drugs.
Some enzymes or drugs are considered to have risks associated with
their use due to total body effects. For example, some thrombolytic
drugs are provided only sparingly because of the risk of
hemorrhage. This risk is present because current drugs are active
at a working temperature which is within the blood temperature
range of the vascular system, and because the drugs pervade the
entire vascular system. The blood temperature range of the vascular
system is referred to here as being within a first temperature
range and as having an average temperature at a first temperature.
Drugs provided to lyse thrombi also reduce clotting throughout the
vascular system, increasing the risk of hemorrhage. Of course, such
effects are not limited to thrombolytic drugs.
[0139] The invention provides a way to reduce such total body
risks. As discussed above, an appropriate isoform of an enzyme may
be employed to allow enzymatic activity at temperatures other than
within a normal body temperature range, e.g., the first temperature
range described above. In other words, for cooling, an enzyme may
be found with a working temperature range at a hypothermic
temperature. Such an enzyme may not work within the above-described
first temperature range. For example, a thrombolytic isoform may
lyse clots where the blood temperature is hypothermic but may not
produce fibrinolytic effects where the blood temperature is not
hypothermic.
[0140] This type of drug or enzyme may be advantageously used in
the present invention. For example, a heat transfer element may be
placed in the vasculature upstream of a vicinity in which a clot
has formed. The heat transfer element may be used to cool the blood
flowing to the vicinity so that the blood in the vicinity achieves
a hypothermic temperature. An isoform of a thrombolytic drug may be
delivered to the vicinity, the isoform having a working temperature
at the hypothermic temperature. The isoform of the thrombolytic
drug may then act to lyse the clot. The thrombolytic drug does not
produce fibrinolytic activity in portions of the vasculature that
are not at the hypothermic temperature, i.e., the rest of the body.
An advantage to this method is that even very strong thrombolytics
may be used to effectively lyse clots, with significantly less
concern about the above-described fibrinolytic side effects
throughout the remainder of the body.
[0141] While the method of the invention has been described with
respect to specific devices and techniques which may be used to
cool blood, other techniques or devices may also be employed. The
embodiments of the method of the invention may advantageously
employ the turbulence inducing devices and techniques disclosed
above to enhance the heat transfer and thus the heating or cooling
of the blood.
[0142] Furthermore, the invention has been described predominantly
with respect to a particular lysing system: the lysing of a blood
clot in a blood vessel such as is caused by stroke or myocardial
infarction. However, the methods of the invention can be equally
applied to altering the activity of any enzyme relative to its
activity at normal temperatures. Furthermore, the invention may be
applied to cooling solids, such as volumes of tissue, rather than
blood flows or static volumes of blood. Moreover, the invention can
be applied to heating blood or tissue, especially when such heating
advantageously enhances desired activity in a specific enzyme.
[0143] The invention has also been described with respect to
certain drug therapies. It will be clear to one of skill in the art
that various other drugs may be employed in the method of the
invention, so long as they have characteristics similar to those
described above. Accordingly, the invention is limited only by the
scope of the appended claims.
* * * * *