Patent Abstract:
Methods for (a) preventing hypoxic damage to a potentially transplantable organ or tissue prior to explanation of that organ or tissue from the body of a mammalian transplant donor and (b) preventing rejection of a transplanted organ or tissue in a human or veterinary transplant recipient. The methods comprise placing a heat exchange apparatus in the vasculature of the donor or recipient and using that heat exchange apparatus to cool at least a portion of the body of the donor or recipient to a temperature below normothermia (e.g. below normothermia and sometimes between about 30° C. and about 36° C.).

Full Description:
FIELD OF THE INVENTION  
       [0001]     This invention relates generally to methods for human or veterinary medical treatment and more particularly to a) the endovascular application of hypothermia to beating heart donors prior to harvesting of organ(s) and/or tissue(s) for transplantation to avoid hypoxic damage to the organ(s) and/or tissue(s) and b) the endovascular (e.g., intravascular) application of hypothermia to transplant recipients during and/or after transplantation of organ(s) and/or tissue(s) to reduce acute inflammatory response and help avoid acute transplant rejection and/or other complications.  
       BACKGROUND OF THE INVENTION  
       [0002]     In the early days of organ transplantation, all cadaveric (non-living) organ donors were pronounced dead by loss of heart function or “cardiac death” criteria. However, in the late 1960&#39;s and early 1970&#39;s “brain death” criteria were developed that allowed organs to be harvested from donors who&#39;s hearts were still beating but who had been pronounced dead based on the irreversible cessation of all brain activity. Additionally, it was learned that organ transplantation was more successful in cases where the donor&#39;s respiration and circulation were supported by artificial means (e.g., the use of mechanical ventilation and the administration of pharmacologic or mechanical support of cardiac activity) after brain death had occurred until the organs could be removed for transplantation. This “beating heart donor” technique enables oxygenated blood to continue to flow through the organs until immediately before they are harvested from the donor, thereby enhancing the organs&#39; viability.  
         [0003]     Every day, approximately ten people die in the United States while awaiting an organ transplant, simply because suitable donor organs are not available for them in time. Various approaches have been proposed for making transplantable organs more readily available to patients in need of transplants. For example, research is underway to develop genetically or immunologically modified animals who&#39;s organs may be suitable for xenotransplantation (i.e., transplantation of an organ or tissue from one species of animal into another species of animal) in humans. However, it remains uncertain as to whether xenotransplantation research will ultimately give rise to universally useable organs of all needed types and even if the current research is successful, the potential clinical implementation of xenotransplantation techniques remains many years away. Another approach has been to obtain some types of organs from human cadaveric donors who have been declared dead by traditional cardiac death criteria as opposed to brain death criteria. However, a number of important transplantable organs (e.g., hearts) can not typically be harvested from cadaveric donors more than just a few minutes after the cardiac death has occurred because the viability of the organ is lost.  
         [0004]     On Jan. 6, 2001 The United Network for Organ Sharing (UNOS) national patient waiting list for organ transplant included the following:  
                                                                     Patients Waiting           Type of Transplant   for Transplant                                        kidney transplant   47,689           liver transplant   16,815           pancreas transplant   1,033           pancreas islet cell transplant   178           kidney-pancreas transplant   2,457           intestine transplant   147           heart transplant   4,152           heart-lung transplant   206           lung transplant   3,676           *Total Patients Total   *73,989                      
 
         [0005]     However, because of the shortage of suitable donor organs, the number of organ transplants that will actually be performed during the year 2001 is likely to be substantially lower than the number of patients on the waiting list. During the year 2000, the number of transplants actually performed in the United States were as follows:  
                                                                 Type of Transplant   Number                                        kidney alone transplants   13,290           (5,227 were living donors)           liver transplants   4,934           pancreas alone transplants   436           kidney-pancreas transplants   914           intestine transplants   79           heart transplants   2,197           heart-lung transplants   48           lung transplants   956           Total   22,854                      
 
         [0006]     Apart from the fact that the pool of potential organ donors is relatively small compared to the demand for transplantable organs, the shortage of organs is further exacerbated by the fact that sometimes, even after a potential donors family has agreed to organ donation, that donor&#39;s organs are lost because the donors cardiac activity can not be maintained for sufficient time to allow the necessary testing to establish and certify brain-death and to arrange for the arrival of the team of surgeons who are trained to remove the desired organ(s) from the donor&#39;s body. In view of these facts, there remains a need in the art for the development of new techniques to facilitate the harvesting of viable organs for transplantation so that more organs may be made available.  
       SUMMARY OF THE INVENTION  
       [0007]     The present invention provides methods for decreasing the potential for hypoxic damage to transplantable organs in brain dead “beating heart” organ donors. The present invention also provides methods for preventing or treating episodes of acute transplant rejection in patients who have received organ or tissue transplants.  
         [0008]     In accordance with one embodiment of the present invention, a heat exchange apparatus is inserted into the vasculature of a potential organ donor who is believed to be brain dead, but who has not yet been declared brain dead. The heat exchange apparatus is then used to cool the blood flowing through the potential donor&#39;s vasculature, thus cooling all of a portion of the donor&#39;s body to a desired temperature below normothermia (e.g., from about 37° C. to about 35° C. or less, often as low as 30°), thereby decreasing the oxygen demand of the tissues or organs to be transplanted and thus decreasing the likelihood that such tissues or organs will suffer hypoxic damage as a result of a hypoxic event while the patient is undergoing the necessary evaluation of his/her suitability as an organ donor, during the performance of testing necessary to confirm brain death (i.e., the “brain death work-up”) and until such time as brain death has been certified and any organs deemed suitable for transplantation have been harvested from the donor&#39;s body. The types of hypoxic events that may occur during this period of time include periods of cardiac arrest where the donor&#39;s heart ceases to beat for a period of time, periods of extreme hypotension or periods where the mechanical ventilation is inadvertently or purposely interrupted.  
         [0009]     Further in accordance with the present invention, a heat exchange apparatus is may be inserted into the vasculature of a potential organ donor who has already been declared brain dead but from whose body the organs or tissues desired for transplantation have not yet been harvested. The heat exchange apparatus is then used to cool the blood flowing through the potential donor&#39;s vasculature, thus cooling all of a portion of the donor&#39;s body to a desired temperature below normothermia (e.g., from about 37° C. to about 35° C. or less), thereby decreasing the oxygen demand of the tissues or organs to be transplanted and thus decreasing the likelihood that such tissues or organs will suffer hypoxic damage as a result of a hypoxic event while the patient is undergoing the necessary evaluation of his/her suitability as an organ donor and until such time as brain death has been certified and any organs deemed suitable for transplantation have been harvested from the donor&#39;s body. The types of hypoxic events that may occur during this period of time include periods of cardiac arrest where the donor&#39;s heart ceases to beat for a period of time, periods of extreme hypotension or periods where the mechanical ventilation is inadvertently or purposely interrupted.  
         [0010]     Still further in accordance with the present invention, the heat exchange apparatus may be a pliable or flexible structure that is formed or mounted and configured to expand when filled with thermal exchange fluid. One or more lumens may extend through the catheter to permit infusion or circulation of thermal exchange fluid through the heat exchange apparatus in situ. The catheter may be initially inserted into the vasculature of the donor or recipient patient using well known percutaneous catheter insertion techniques and the catheter may then be advanced through the vasculature to a position where the heat exchange apparatus is situated at a desired location. The heat exchange apparatus may comprise a balloon or inflatable structure that is attached to one or more lumens of the catheter such that cooled thermal exchange fluid may be infused into or circulated through the heat exchange apparatus in situ. Blood flowing in heat exchanging proximity to the heat exchange apparatus will thereby become cooled. The subsequent circulation of the cooled blood will then cool all or a selected portion of the donor&#39;s or patient&#39;s body to the desired temperature below normothermia. The core body temperature or the temperature of a particular body part or organ of the donor or patient may be monitored and the temperature of the heat exchange apparatus may be modified periodically or continuously in response to the monitored temperature to prevent significant overshoot beyond the desired temperature and to thereafter maintain the temperature of the body or portion thereof at the desired temperature or within a range of desired temperatures, such as about 33° C. to about 30° C. An automated controller may be connected to temperature sensor(s) used to monitor the core body temperature or the temperature of the desired organ or portion of the donor&#39;s or patient&#39;s body. Also, such controller may be operatively connected to an apparatus that changes the temperature of the thermal exchange fluid being circulated through the heat exchange apparatus and/or the rate at which such thermal exchange fluid is circulated through the heat exchange apparatus. Based on the signal(s) received from the temperature sensor(s), the controller will then modify the temperature and/or rate of the thermal exchange fluid to optimize the cooling and maintenance of the temperature of the donor&#39;s or patient&#39;s body or portion thereof.  
         [0011]     Further aspects and advantages of the present invention will become apparent to those of skill in the art upon reading and understanding the detailed descriptions of certain embodiments of the invention set forth herebelow and in the accompanying drawings. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0012]      FIG. 1  is a perspective drawing of an embodiment of the catheter of the invention.  
         [0013]      FIG. 1A  is a perspective drawing of an alternative tie-down at the proximal end of the catheter shown in  FIG. 1 .  
         [0014]      FIG. 2  is a cross-sectional drawing of the shaft of the catheter taken along the line  2 - 2  in  FIG. 1 .  
         [0015]      FIG. 3  is a cross-sectional drawing of the heat exchange region of the catheter taken along the line  3 - 3  in  FIG. 1 .  
         [0016]      FIG. 3A  is a cross-sectional view through line  3 A- 3 A of  FIG. 1 .  
         [0017]      FIG. 4  is a perspective drawing of a segment of the heat exchange region of the catheter within the circle  4 - 4  in  FIG. 1 .  
         [0018]      FIG. 5  is a cross-sectional drawing of the heat exchange region of the catheter taken along the line  5 - 5  in  FIG. 1 .  
         [0019]      FIG. 6  is a perspective drawing of a segment of the heat exchange region of the catheter within the circle  6 - 6  in  FIG. 1 .  
         [0020]      FIG. 7  is a perspective drawing of the multi-lobed balloon of one embodiment of the invention.  
         [0021]      FIG. 8  is a perspective drawing of the distal portion of the shaft of one embodiment of the invention.  
         [0022]      FIG. 9  is a perspective drawing of the heat exchange region formed by the shaft and multi-lobed balloon of  FIGS. 7 and 8 .  
         [0023]      FIG. 10  is an expanded view of the attachment of the central lumen of the balloon to the shaft of the catheter of  FIG. 9  showing the region within the circle  10 - 10  in  FIG. 9 .  
         [0024]      FIG. 10 A  is an expanded view of the plug between the shaft and the central lumen of the balloon of the catheter of  FIG. 9  showing the region within the circle  10 A- 10 A in  FIG. 9 .  
         [0025]      FIG. 11  is a perspective view of a portion of a multi-lobed, curvilinear heat exchange balloon that forms a portion of one embodiment of the invention.  
         [0026]      FIG. 11 A  is a cross sectional view of the heat exchange region taken along the line  11 A-!!A in  FIG. 11 .  
         [0027]      FIG. 12  is a sectional view of the proximal portion of the heat exchange region of one embodiment of the invention.  
         [0028]      FIG. 12A  is a cross-sectional view of a portion of the heat exchange region taken along the line  12 A- 12 A of  FIG. 12 .  
         [0029]      FIG. 12B  is a cross-sectional view of a portion of the heat exchange region taken along the line  12 B- 12 B of  FIG. 12 .  
         [0030]      FIG. 12C  is a cross-sectional view of a portion of the heat exchange region taken along the line  12 C- 12 C of  FIG. 12 .  
         [0031]      FIG. 13  is a sectional view of the distal portion of the heat exchange region of one embodiment of the invention.  
         [0032]      FIG. 13A  is a cross-sectional view of a portion of the heat exchange region taken through line  13 A- 13 A of  FIG. 13 .  
         [0033]      FIG. 13B  is a cross-sectional view of a portion of the heat exchange region taken through line  13 B- 13 B  FIG. 13 .  
         [0034]      FIG. 14  is a general flow diagram of a method of the present invention wherein endovascular hypothermia is used in a beating heart organ dead donor to minimize the likelihood of hypoxic damage to the donor&#39;s organs between the time the donor is pronounced brain dead and the time the organs are actually harvested from the donor&#39;s body.  
         [0035]      FIG. 15  is a general flow diagram of a method of the present invention wherein endovascular hypothermia is used in a beating heart but brain dead organ donor to minimize the likelihood of hypoxic damage to the donor&#39;s organs from the time brain death is suspected to have occurred, during the time the brain death work-up is performed and until the organs are actually harvested from the donor&#39;s body.  
         [0036]      FIG. 16  is a general flow diagram of the present invention wherein endovascular hypothermia is used in a beating heart but brain dead organ donor to cool potentially transplantable organs or tissue while simultaneously maintaining other tissue at a higher temperature. 
     
    
     DETAILED DESCRIPTION OF EMBODIMENTS  
       [0037]     The following detailed description is provided for the purpose of describing only certain embodiments or examples of the invention and is not intended to describe all possible embodiments and examples of the invention.  
       A. A Preferred Intravascular Heat Exchange Catheter System Useable to Perform the Methods of this Invention  
       [0038]     Referring to  FIGS. 1 through 10 A, in one embodiment, the catheter is comprised of a shaft  50  with a heat exchange region  100  thereon. The shaft has two roughly parallel lumens running through the proximal shaft, an inflow lumen  52  and an outflow lumen  54 . The shaft generally also comprises a working lumen  56  running therethrough for the insertion of a guide wire, or the application of drugs, radiographic dye, or the like to the distal end of the catheter. The heat exchange region comprises a four-lumen balloon, with three outer lumens  58 ,  60 ,  62  disposed around an inner lumen  64  in a helical pattern. In the particular embodiment shown, the balloon preferably makes one full rotation about the inner lumen  64  for each 2 to 4 inches of length. All four lumens  58 ,  60 ,  62  and  64  are thin walled balloons and each outer lumen  58 ,  60 ,  62  shares a common thin wall segment  66 ,  68 ,  70  with the inner lumen. The balloon is approximately twenty-five centimeters long, and when inflated has an outer circumference  72  of approximately 0.328 in. When deflated, the profile is generally about 9 French (3 French is 1 mm in diameter). When the balloon portion is installed on the shaft, both the proximal end  74  of the balloon and the distal end  76  of the balloon are sealed around the shaft in fluid tight seals, as described more fully herebelow. Heat exchange fluid may be directed in through the inflow lumen, return through the outer lobes of the balloon in heat exchange proximity with blood flowing over the outside of the balloon, and then out through the outflow lumens, as will be described in greater detail below.  
         [0039]     The catheter is attached at its proximal end to a hub  78 . At the hub, the guide wire lumen  56  communicates with a guide wire port  80 , the inflow lumen  52  is in fluid communication with an inflow port  82 , and the outflow lumen  54  is in communication with an outflow port  84 . Attached at the hub and surrounding the proximal shaft is a length of strain relief tubing  86  which may be, for example, a length of heat shrink tubing. The strain relief tubing may be provided with suture tie-downs  88 ,  90 . Alternatively, a butterfly tie-down  92  may be provided. (See  FIG. 1A ).  
         [0040]     Between the strain relief tubing  86  and the proximal end of the balloon  74 , the shaft  50  is extruded with an outer diameter of about 0.118 inches. The internal configuration is as shown in cross-section in  FIG. 2 . Immediately proximal of the balloon attachment  74 , the shaft is necked down  94 . The outer diameter of the shaft is reduced to about 0.100 to 0.110 inches, but the internal configuration with the three lumens is maintained. Compare, for example, the shaft cross-section of  FIG. 2  with the cross-section of the shaft shown in  FIG. 3 . This length of reduced diameter shaft remains at approximately constant diameter of about 0.100 to 0.110 inches between the necked down location at  94  and a distal location  96  where the outflow lumen is sealed and the guide wire extension tube  98  is attached as will be described.  
         [0041]     At the necked down location  94 , a proximal balloon marker band  102  is attached around the shaft. The marker band is a radiopaque material such as a platinum or gold band or radiopaque paint, and is useful for locating the proximal end of the balloon by means of fluoroscopy while the catheter is within the body of the patient.  
         [0042]     At the location marked by the marker band, all four lobes of the balloon are reduced down and fastened around the inner member  67  in a fluid-tight seal. This may be accomplished by folding the outer lobes of the balloon  58 ,  60 ,  62  down around the inner lumen  64 , placing a sleeve, for example a short length of tubing, snugly over the folded-down outer lumens of the balloon and inserting adhesive, for example by wicking the adhesive, around the entire inner circumference of the sleeve. The inner lumen is then fastened to the shaft using a second short length of tubing. The second short length for example 1 mm, of intermediate tubing  104  is heat welded to the inside of the inner lumen. The intermediate tube has an outer diameter approximately the same as the inner diameter of the inner lumen. The intermediate tube is then slid over the shaft at about the location of the neck-down region near the proximal marker  102 , and adhesive  106  is wicked into the space between the inside of the intermediate tubing and the outer surface of the shaft  50 . A similar process may be used to attach the distal end of the balloon, as will be described, except that the distal end of the balloon is attached down around the guide wire extension tube  98  rather than the shaft.  
         [0043]     Just distal of the proximal balloon seal, under the balloon within the inner lumen, an elongated window  108  is cut through the wall of the outflow lumen in the shaft. Along the proximal portion of the balloon above this window, five slits, e.g.  110 , are cut into the common wall between each of the outer lumens  58 ,  60 ,  62  and the inner lumen  64 . Because the outer lumens are twined about the inner lumen in a helical fashion, each of the outer tubes passes over the outflow lumen of the inner shaft member at a slightly different location along the length of the inner shaft and, therefore, an elongated window  108  is cut into the outflow lumen of the shaft so that each outer lumen has at least one slit e.g.  110  that is located over the window in the shaft. Additionally, there is sufficient clearance between the outer surface of the shaft and the wall of the inner lumen to allow relatively unrestricted flow of heat exchange fluid through all  5  slits in each outer lumen, around the shaft, and through the elongate window  108  into the outflow lumen  54  in the shaft  50 .  
         [0044]     Distal of the elongated window in the outflow lumen, the inner lumen  64  of the four-lumen balloon is sealed around the shaft in a fluid tight plug. Referring to  FIG. 10   a , the plug is formed by, for example shrinking a relatively thick length of PET tubing to form a length of plug tubing  112  where the inner diameter of the length of plug tubing is approximately the same as the outer diameter of the shaft at the location where the plug is to be formed. The plug tubing is slid over the shaft and fits snugly against the shaft. The shaft is generally formed of a material that is not heat shrinkable. As may be seen in  FIGS. 10A  and  FIG. 3 , some clearance exists between the outer wall of the shaft and the inner wall of the inner lumen  64 . The walls of the inner lumen are composed of thin heat shrinkable material, for example PET. A probe with a resistance heater on the distal end of the probe is inserted into the guide wire lumen of the shaft and located with the heater under the plug tubing. The probe is heated, causing the heat shrink wall of the inner lumen to shrink down against the plug tubing, and the plug tubing to shrink slightly down against the shaft. The resultant mechanical fit is sufficiently fluid tight to prevent the outflow lumen and the space between the shaft and the wall of the inner lumen from being in fluid communication directly with the inner member or the inflow lumen distal of the plug except through the outer lumens as will be detailed below.  
         [0045]     Just distal of the plug, the outflow lumen is closed by means of a heat seal  99 , and the inflow lumen is skived to form an opening  101  to the inner member. This may be accomplished by necking down the shaft at  96 , attaching a guide wire extension tube  98  to the guide wire lumen, and simultaneously opening the inflow lumen  101  to the interior of the inner lumen and heat sealing the outflow lumen shut  101 . The guide wire extension tube continues through the inner lumen, beyond the distal seal of the balloon (described below) to the distal end of the catheter  114  and thereby creates communication between the guide wire port  80  and the vessel distal of the catheter for using a guide wire to place the catheter or for infusing drugs, radiographic dye, or the like beyond the distal end of the catheter.  
         [0046]     The distal end of the balloon  76  is sealed around the guide wire extension tube in essentially the same manner as the proximal end  74  is sealed down around the shaft. Just proximal of the distal seal, five slits  116  are cut into the common wall between each of the three outer lumens  58 ,  60   62  of the balloon and the inner lumen  64  so that each of the outer lumens is in fluid communication with the inner lumen.  
         [0047]     Just distal of the balloon, near the distal seal, a distal marker band  118  is placed around the guide wire extension tube. A flexible length of tube  120  may be joined onto the distal end of the guide wire tube to provide a soft tip to the catheter as a whole.  
         [0048]     In use, the catheter is inserted into the body of a patient so that the balloon is within a blood vessel, for example in the inferior vena cava (IVC). Heat exchange fluid is circulated into the inflow port  82 , travels down the inflow lumen  52  and into the inner lumen  64  distal of the plug tube  112 . The heat exchange fluid fills the inner lumen and travels down the inner lumen, thence through slits  116  between the inner lumen  64  and the three outer lumens  58 ,  60 ,  62 .  
         [0049]     The heat exchange fluid then travels back through the three outer lumens of the balloon to the proximal end of the balloon. Since outer lumens are wound in a helical pattern around the inner lumen, at some point along the length of the balloon near the proximal end and proximal of the plug, each outer lumen is located over the portion of the shaft having the window to the outflow lumen  108 . There is also sufficient clearance between the wall of the inner lumen and the shaft, as illustrated in  FIG. 3 , that even the slits that are not directly over the window  108  allow fluid to flow into the space between the wall of the inner lumen and the outer wall of the shaft  50  and then through the window  108  and into the outflow lumen. The heat exchange fluid then flows down the outflow lumen and out the outflow port  84 . At a fluid pressure of  41  pounds per square inch, flow of as much as 500 milliliters per minute may be achieved with this design.  
         [0050]     Counter-current circulation between the blood and the heat exchange fluid is highly desirable for efficient heat exchange between the blood and the heat exchange fluid. Thus if the balloon is positioned in a vessel where the blood flow is in the direction from proximal toward the distal end of the catheter, for example if it were placed from the femoral vein into the Inferior Vena Cava (IVC) cava, it is desirable to have the heat exchange fluid in the outer balloon lumens flowing in the direction from the distal end toward the proximal end of the catheter. This is the arrangement described above. It is to be readily appreciated, however, that if the balloon were placed so that the blood was flowing along the catheter in the direction from distal to proximal, for example if the catheter was placed into the IVC from a jugular insertion, it would be desirable to have the heat exchange fluid circulate in the outer balloon lumens from the proximal end to the distal end. Although in the construction shown this is not optimal and would result is somewhat less effective circulation; this could be accomplished by reversing which port is used for inflow direction and which for outflow.  
         [0051]     Where heat exchange fluid is circulated through the balloon that is colder than the blood in the vessel into which the balloon is located, heat will be exchanged between the blood and the heat exchange fluid through the outer walls of the outer lumens, so that heat is absorbed from the blood. If the temperature difference between the blood and the heat exchange fluid (sometimes called “ΔT”), for example if the blood of the patient is about 37° C. and the temperature of the heat exchange fluid is about 0° C., and if the walls of the outer lumens conduct sufficient heat, for example if they are of very thin (0.002 inches or less) plastic material such as polyethylene terephthalate (PET), enough heat may be exchanged (for example about 200 watts) to lower the blood temperature sufficiently to effect hypothermic anti-platelet activity, and to cool the temperature downstream of the catheter, for example of the heart, sufficiently for therapeutic inhibition of platelet activation, aggregation and/or adhesion. If the cooling catheter is left in place long enough for example for over half an hour, the entire body temperature of the patient may be cooled sufficiently for hypothermic anti-platelet activity. In this way, for example, blood to the brain and even the brain tissue itself may be cooled sufficiently for therapeutic hypothermic anti-platelet effect.  
         [0052]     The helical structure of the outer lumens has the advantage over straight lumens of providing greater length of heat exchange fluid path for each length of the heat exchange region. This creates additional heat exchange surface between the blood and the heat exchange fluid for a given length of balloon. It may also provide for enhanced flow patterns for heat exchange between flowing liquids. The fact that the heat exchange region is in the form of an inflatable balloon also allows for a minimal insertion profile, for example 9 French or less, while the heat exchange region may be inflated once inside the vessel for maximum diameter of the heat exchange region in operation.  
         [0053]     Automated control of the process is optional. Examples of apparatus and techniques that may be used for automated control of the process are described in U.S. Pat. Nos. 6,149,673 and 6,149,676 and co-pending United States Patent Application SN  09 / 138 , 830 , the entireties of which are expressly incorporated herein by reference.  
         [0054]     Referring now to  FIGS. 11 through 13  B, in another example of a preferred embodiment, the heat exchange region is in the form of a series of five lumens arranged side-by-side in a configuration that may be loosely described as a twisted ribbon. The heat transfer fluid circulates to and from the heat exchange region  202  via channels formed in the shaft  206  in much the same manner as previously described for shaft  50 . Indeed, although not depicted, the shaft has a similar internal configuration as the shaft previously described with an inflow lumen, an outflow lumen, and a working lumen. Although also not depicted, a hub is attached at the proximal end of the shaft which is maintained outside the body; the hub has a guide wire port communicating with the working lumen, an inflow port communicating with the inflow lumen, and an outflow port communicating with the outflow lumen. Heat exchange fluid is directed into the catheter through the inflow port and removed from the catheter through the outflow port. A guide wire, or alternatively medicaments, radiographic fluid or the like are introduced through the guide wire port and may thus be directed to the distal end of the catheter.  
         [0055]      FIGS. 11 and 11 A illustrate this embodiment of a heat exchange region  202  comprising a plurality of tubular members that are stacked in a helical plane. More specifically, a central tube  220  defines a central lumen  222  therewithin. A pair of smaller intermediate tubes  224   a ,  224   b  attaches to the exterior of the central tube  220  at diametrically opposed locations. Each of the smaller tubes  224   a ,  224   b  defines a fluid lumen  226   a ,  226   b  therewithin. A pair of outer tubes  228   a ,  228   b  attaches to the exterior of the intermediate tubes  224   a ,  224   b  in alignment with the aligned axes of the central tube  220  and intermediate tubes  224   a ,  224   b . Each of the outer tubes  228   a ,  228   b  defines a fluid lumen  230   a ,  230   b  within. By twisting the intermediate and outer tubes  224   a ,  224   b ,  228   a ,  228   b  around the central tube  220 , the helical ribbon-like configuration of  FIG. 11  is formed.  
         [0056]     Now with reference to  FIGS. 12 and 12 A- 12 C, a proximal manifold of the heat exchange region  202  will be described. The shaft  206  extends a short distance, desirably about 3 cm, within the central tube  220  and is thermally or adhesively sealed to the interior wall of the central tube as seen at  250 . As seen in  FIG. 12A , the shaft  206  includes a planar bulkhead or web  252  that generally evenly divides the interior space of the shaft  206  into an inflow lumen  254  and an outflow lumen  256 . A working or guide wire lumen  260  is defined within a guide wire tube  262  that is located on one side of the shaft  206  in line with the bulkhead  252 . Desirably, the shaft  206  is formed by extrusion. The outflow lumen  256  is sealed by a plug  264  or other seal at the terminal end of the shaft  206 . The inflow lumen  254  remains open to the central lumen  222  of heat exchange region  202 . The guide wire tube  262  continues a short distance and is heat bonded at  270  to a guide wire extension tube  272  generally centered within the central tube  220 .  
         [0057]     A fluid circulation path is illustrated by arrows in  FIG. 12  and generally comprises fluid passing distally through the inflow lumen  254  and then through the entirety of the central lumen  222 . The heat exchange fluid is directed from the central lumen  222  to the intermediate and outer tubes as will be described below, and returns through the lumens  226   a ,  226   b , and  230   a ,  230   b  of the intermediate and outer tubes  224   a ,  224   b , and  228   a ,  228   b , respectively, and enters reservoirs  274  and  275 . Alternatively, two windows may be formed  276  and a counterpart not shown in  FIG. 12  one helical twist farther down the shaft, between each side of the twisted ribbon (i.e., lumens  224   a  and  224   b  on one side, and  228   a  and  228   b  on the other side). In this way, one reservoir from each side of the twisted ribbon is formed in fluid communication with the outflow lumen  256  (configuration not shown). Fluid then enters the outflow lumen  256  through apertures, e.g.,  276 , provided in the central tube  220  and a longitudinal port  278  formed in the wall of the shaft.  
         [0058]     A distal manifold of the heat exchange region  202  is shown and described with respect to  FIGS. 13 and 13 A- 13 B. The outer tubes  228   a ,  228   b  taper down to meet and seal against the central tube  220  which, in turn, tapers down and seals against the guide wire extension tube  272 . Fluid flowing distally through the central lumen  222  passes radially outward through a plurality of apertures  280  provided in the central tube  220 . The apertures  280  open to a distal reservoir  282  in fluid communication with lumens  226   a ,  226   b , and a distal reservoir  281  in fluid communication with lumens  230   a ,  230   b  of the intermediate and outer tubes  224   a ,  224   b , and  228   a ,  228   b.    
         [0059]     With this construction, heat exchange fluid introduced into the input port  240  will circulates through the inflow lumen  254 , into the central lumen  222 , out through the apertures  280 , and into the distal reservoir  282 . From there, the heat exchange fluid will travel proximally through both intermediate lumens  226   a ,  226   b  and outer lumens  230   a ,  230   b  to the proximal reservoirs  274  and  275 . Fluid then passes radially inwardly through the apertures  276  and port  278  into the outflow lumen  256 . Then the fluid circulates back down the shaft  206  and out the outlet port  242 .  
         [0060]     The ribbon configuration of  FIGS. 11-13B  is advantageous for several reasons. First, the relatively flat ribbon does not take up a significant cross-sectional area of a vessel into which it is inserted. The twisted configuration further prevents blockage of flow through the vessel when the heat exchange region  202  is in place. The helical configuration of the tubes  224   a ,  224   b ,  228   a ,  228   b  also aids to center the heat exchange region  202  within a vessel by preventing the heat exchange region from lying flat against the wall of the vessel along any significant length of the vessel. This maximizes heat exchange between the lumens and the blood flowing next to the tubes. Because of these features, the twisted ribbon configuration is ideal for maximum heat exchange and blood flow in a relatively small vessel such as the carotid artery. As seen in  FIG. 11A , an exemplary cross-section has a maximum diameter of about 5 mm, permitting treatment of relatively small vessels. The helical pattern of the balloon in the fluid flow may act to induce a gentle mixing action of the flowing blood to enhance heat exchange between the heat exchange surface and the blood without inducing hemolytic damage that would result from more violent churning action.  
         [0061]     The deflated profile of the heat exchange region is small enough to make an advantageous insertion profile, as small as 7 French for some applications. Even with this low insertion profile, the heat exchange region is efficient enough to adequately exchange heat with blood flowing past the heat exchange region to alter the temperature of the blood sufficient for anti-platelet action and affect the temperature of tissue downstream of the heat exchange region. Because of its smaller profile, it is possible to affect the temperature of blood in smaller vessels and thereby provide treatment to more localized body areas.  
         [0062]     This configuration has a further advantage when the heat exchange region is placed in a tubular conduit such as a blood vessel, especially where the diameter of the vessel is approximately that of the major axis (width) of the cross section of the heat exchange region. The configuration tends to cause the heat exchange region to center itself in the middle of the vessel. This creates two roughly semicircular flow channels within the vessel, with the blood flow channels divided by the relatively flat ribbon configuration of the heat exchange region. It has been found that the means for providing maximum surface for heat exchange while creating minimum restriction to flow is this configuration, a relatively flat heat exchange surface that retains two approximately equal semi-circular cross-sections. This can be seen in reference to  FIG. 1   1 A if the functional diameter of the dashed circle  300  is essentially the same as the luminal diameter of a vessel into which the twisted ribbon is placed. Two roughly semi-circular flow paths  302 ,  304  are defined by the relatively flat ribbon configuration of the heat exchange region, i.e. the width or major axis (from the outer edge of  228   a  to the outer edge of  228   b ) is at least two times longer than the height, or minor axis (in this example, the diameter of the inner tube  222  ) of the overall configuration of the heat exchange region. It has been found that if the heat exchange region occupies no more than about 50% of the overall cross-sectional area of the circular conduit, a highly advantageous arrangement of heat exchange to flow is created. The semi-circular configuration of the cross-section of the flow channels is advantageous in that, relative to a round cross-sectioned heat exchange region (as would result from, for example, a sausage shaped heat exchange region) the flow channels created minimize the surface to fluid interface in a way that minimizes the creation of laminar flow and maximizes mixing. Maximum blood flow is important for two reasons. The first is that flow downstream to the tissue is important, especially if there is obstruction in the blood flow to the tissue. The second reason is that heat exchange is highly dependent on the rate of blood flow past the heat exchange region, with the maximum heat exchange occurring with maximum blood flow, so maximum blood flow is important to maximizing heat transfer.  
       B. Examples of Methods for Preventing Hypoxic Damage to Organs and Tissues in a Beating Heart Organ Donor  
       [0063]      FIGS. 14, 15  and  16  are flow diagrams that illustrate examples of methods wherein endovascular hypothermia is used in beating heart organ donors, prior to the harvesting of organs and/or tissues for transplantation, in order to decrease the potential for hypoxic damage to the transplantable organs and tissues in the event of an hypoxic episode. The types of hypoxic episodes that may occur in beating heart organ donors include; cardiac arrest, ventricular arrhythmia, periods of hypotension, disruption of ventilation due to inadvertent disconnection of ventilator tubing, hypoxia secondary to pulmonary embolus, etc.  
         [0064]     In the example of  FIG. 14 , the endovascular hypothermia is initiated in an organ donor after the organ donor has been formally declared or pronounced brain dead. In the example of  FIG. 15 , the endovascular hypothermia is initiated in an organ donor who is suspected to be brain dead but who has not yet been declared or pronounced brain dead, and such hypothermia is maintained while the potential donor is subjected to the tests and evaluations necessary to make a clinical determination of brain death.  
         [0065]     Additionally, even after the declaration or pronouncement of brain death has been made, there may be substantial further delays before the organs or tissues can be harvested from the donor&#39;s body. This is especially true in cases where a time-critical organ such as the heart has been matched to a recipient who is located far away from the donor and it is necessary to wait until a surgical team has been flown in from the recipient&#39;s location to perform the organ harvest and to then transport the critical organ to the location where the transplant surgery is to be conducted. Accordingly, in such cases, the provision of endovascular hypothermia even after the brain death declaration or pronouncement has been made may be beneficial in avoiding hypoxic damage to donor&#39;s the organs or tissues.  
         [0066]     Moreover, a substantial period of time may be required before the brain death declaration or pronouncement may be made, as it is often necessary for heath care workers to locate and obtain written consent from the donor&#39;s family and to perform extensive tests and evaluations to confirm that the donor is in fact brain dead. The exact criteria by which brain death may be declared or pronounced may differ from state to state, country to country, or even institution to institution. In many jurisdictions, a declaration or pronouncement of brain death can only be made after numerous tests and evaluations have been completed (collectively referred to herein as the “brain death work-up”). These required tests and evaluations may include a clinical assessment to establish the lack of neurological responses and reflexes, hypoxia test(s) to confirm that the spontaneous respiratory drive is absent, and multiple electroencephalograms (EEGs) taken at time points separated by a prescribed waiting period (e.g., 24 hours). In at least some institutions, the declaration or pronouncement of brain death must be made by no fewer than two (2) physicians. Thus, the time period required to obtain the requisite consent and complete the entire brain death work up may span 48 hours or even longer. The provision of endovascular hypothermia during the brain death work up period in accordance with the method of  FIG. 15  may be extremely beneficial in such cases to, for example, protect potential donor organs and tissue.  
         [0067]     Specifically referring to the method of  FIG. 14 , in a case where the potential organ donor has already been declared or pronounced brain dead in accordance with the applicable criteria, an endovascular heat exchange apparatus is inserted into the patient&#39;s vasculature and used to cool blood flowing though the vasculature such that all or a portion of the donor&#39;s body is cooled to a temperature below 37° C. (i.e., below normothermia). In many cases, the desired temperature will be in the range of about 34° C. through about 28° C. and preferably about 30° C. Generally the lower the temperature, the more protective it is of the donor organs or tissue, but below a temperature of about 25° C. the heart function may be adversely affected. In order to accomplish endovascular hypothermia, the heart must generally be pumping effectively, so a body temperature of about 30° C. will effectively protect the organ or tissue for preservation and at the same time, will not adversely affect cardiac function. The endovascular heat exchange device may comprise a catheter of the type shown in  FIGS. 1-13C  and described hereabove. The endovascular heat exchange device may further be used in conjunction with a controller and/or related equipment useable to monitor and control the temperature of the catheter and/or the patient. Examples of heat exchange catheters and related devices &amp; controllers that might be useable in this step of the method are described in PCT International Application No. PCT/US 99/18939 and U.S. Pat. No. 5,486,208 (Ginsburg), U.S. Pat. No. 6,149,676 (Ginsburg), U.S. Pat. No. 6,149,673 (Ginsburg), U.S. Pat. No. 5,957,963 (Dobak III), U.S. Pat. No. 6,096,608 (Dobak III, et al.), U.S. Pat. No. 6,110,168 (Ginsburg), U.S. Pat. No. 6,126,684 (Gobin, et al.) and U.S. Pat. No. 6,264,679 (Keller, et al.), the entire disclosures of which expressly incorporated herein by reference. In particular, one presently preferred intravascular heat exchange catheter system for use in the present invention is described in U.S. application Ser. No. 09/777,612 the entirety of which is expressly incorporated herein by reference and portions of which are set forth in the paragraphs herebelow. In cases where it is desired to cool the donor&#39;s entire body such that the donor&#39;s core body temperature is in the desired range, the endovascular temperature exchange device may be positioned in the inferior vena cava near the right atrium of the donor&#39;s heart such that venous blood that is cooled by the heat exchange apparatus will subsequently be pumped throughout the donor&#39;s body by the donor&#39;s the heart, cooling the entire body in the process. In other cases where it is desired to selectively cool only a specific body portion (e.g., a limb, organ or group of organs) to a temperature within the desired target range, the heat exchange apparatus may be positioned within a blood vessel through which blood flows into the specific body portion (e.g., a limb, organ or group of organs) and that heat exchange apparatus may then be used to cool blood flowing into the specific organ or specific portion of the body, thereby also cooling the parenchyma of that specific organ or specific portion of the body to the desired target temperature. A temperature monitoring probe or thermocouple may be placed within the specific body portion (e.g., a limb, organ or group of organs) to facilitate the controlled cooling of that specific body portion (e.g., a limb, organ or group of organs) to the desired target temperature without significant overshoot and to thereafter maintain the specific body portion (e.g., a limb, organ or group of organs) at the target temperature for the desired period of time. Some incidental cooling of other portions of the body may or may not occur concurrently with the selective cooling of the specific body portion (e.g., a limb, organ or group of organs) to the desired target temperature and subsequent maintenance of that target temperature.  
         [0068]     In cases where it is desired to minimize or prevent cooling of portions of the body other than the selected body portion (e.g., a limb, organ or group of organs), a second heat exchange apparatus may be placed in one or more other blood vessels from which blood flows out of or away from the selected body portion (e.g., a limb, organ or group of organs) and the second heat exchange apparatus may be used to rewarm blood that flows out of or away from the selected body portion (e.g., a limb, organ or group of organs or blood flowing from the heart), thereby preventing the remainder of the body or at least the heart from becoming as hypothermic as the tissue or organ desired for transplantation. In this manner it is possible to cool the organ or tissue for transplantation well below the 25° C. temperature at which the heart begins to experience fibrillation or other adverse events, and yet keep the heart above that temperature to maintain effective cardiac function. For example, a first, cooling catheter might be placed in the renal artery to cool a kidney and a second warming catheter be placed in the renal vein or the IVC to warm blood returning from the kidneys to the heart. In fact, several additional catheters might be used, for example a cooling catheter might be placed in the artery for each kidney, and a warming catheter in each of the veins coming from the kidneys, and a warming catheter in IVC all to keep the heart warm enough to function effectively as a pump, and yet cool the target organ or tissue. This method of persevering organs or tissue is illustrated in the flow chart of  FIG. 16 .  
         [0069]     Although several illustrative examples of means for practicing the invention are described above, these examples are by no means exhaustive of all possible means for practicing the invention. The scope of the invention should therefore be determined with reference to the appended claims, along with the full range of equivalents to which those clams are entitled.

Technology Classification (CPC): 0