Use of endovascular hypothermia in organ and/or tissue transplantations

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.).

Description

introduced into the input port 240 will circulates through the inflow lumen 254, into the central lumen 222, out 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 226a, 226b and outer lumens 230a, 230b 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 of an outlet port 242.

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 224a, 224b, 228a, 228b 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 300 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.

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.

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. 11A 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 228a to the outer edge of 228b) 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 laminarflow 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:

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.

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.

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'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'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's the organs or tissues.

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'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.

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's vasculature and used to cool blood flowing though the vasculature such that all or a portion of the donor'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 & controllers that might be useable in this step of the method are described in PCT International Application No. PCT/US99/18939 and U.S. Pat. Nos. 5,486,208 (Ginsburg), 6,149,676 (Ginsburg), 6,149,673 (Ginsburg), 5,957,963 (Dobak III), 6,096,608 (Dobak III, et al.), 6,110,168 (Ginsburg), 6,126,684(Gobin, et al.) and 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's entire body such that the donor'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's heart such that venous blood that is cooled by the heat exchange apparatus will subsequently be pumped throughout the donor's body by the donor'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 over-shoot 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.

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.

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.

Claims

1. A method for preventing hypoxic damage to a potentially transplantable organ or tissue prior to explantation of the organ or tissue from the body of a mammalian donor; said method comprising the steps of:

a. placing an intravascular heat exchange apparatus within a blood vessel of the donor such that the donor's blood continues to circulate through that blood vessel and heat is exchanged between the circulating blood and the intravascular heat exchange apparatus; and,

b. using the intravascular heat exchange apparatus to cool the donor's flowing blood, thereby lowering the donor's core body temperature to a temperature that is below normothermia.

2. A method according to claim 1 wherein Step a comprises inserting a heat exchange catheter having a heat exchange region into the vasculature of a donor and positioning the catheter such that blood flowing to at least the potentially transplantable organ or tissue passes within heat exchange proximity to the heat exchange region and wherein Step b comprises exchangeing heat with the blood that passes in heat exchange proximity to the heat exchange region for a period of time sufficient to cool at least the potentially transplantable organ or tissue to a temperature below normothermia.

3. A method according to claim 1 wherein performance of the method is begun before any declaration of donor brain death has been made.

4. A method according to claim 1 wherein performance of the method is begun after a declaration of donor brain death has been made.

5. A method according to claim 1 wherein the temperature is between approximately 30° C. and approximately 36° C.

6. A method according to claim 1 wherein the intravascular heat exchange device is an elongate flexible catheter having a heat exchange region formed on a portion of the catheter that becomes inserted into the donor's vasculature.

7. A method according to claim 6 wherein the heat exchange region of the catheter occupies less than the full length of the catheter portion that becomes inserted in the donor's vasculature.

8. A method according to claim 1 wherein the heat exchange apparatus is placed in the donor's venous vasculature.

9. A method according to claim 8 wherein the heat exchange apparatus is placed in the donor's vena cava.

10. A method according to claim 9 wherein the heat exchange apparatus is placed in the donor's inferior vena cava.

11. A method according to claim 9 wherein the heat so exchange apparatus is placed in the donor's superior vena cava.

12. A method according to claim 1 wherein the donor's entire body is cooled to a temperature below normothermia.

13. A method according to claim 1 wherein the core body temperature is cooled to a desired temperature below normothermia and the remainder of the donor's body is either hypothermic, normothermic or hyperthermic.

14. A method according to claim 13 wherein at least one raised area is formed on the heat exchange apparatus to increase its heat exchange surface area.

15. A method according to claim 14 wherein said raised area comprises a structure selected from the group consisting of a fin, a projection, a bulge, a hollow raised area and a solid raised area.

16. A method according to claim 1 wherein performance of the method is continued until explantation of the potentially transplantable organ or tissue.

17. A method according to claim 1 wherein the organ or tissue is selected from the group consisting of:

heart;

lung;

liver;

kidney;

nervous tissue;

tendon;

bone;

a limb;

a finger;

a toe;

skin;

cornea;

bone marrow; and,

intestine.

18. A method according to claim 1 further comprising the steps of:

monitoring the temperature of at least a portion of the donor's body and adjusting the heat exchange between the heat exchanger and the donor's blood to maintain the monitored temperature within a desired range.

19. A method according to claim 1 wherein the heat exchange device comprises a heat exchanger through which heat exchange fluid is circulated.

20. A method according to claim 19 wherein said heat exchanger comprises a heat exchange balloon.

21. A method according to claim 20 wherein the balloon is a single-lobed balloon.

22. A method according to claim 20 wherein the balloon is a multi-lobed balloon.

23. A method according to claim 1 wherein the heat exchange apparatus comprises a heat exchanger that is metallic.

24. A method according to claim 1 wherein the heat exchange apparatus comprises a balloon catheter, the balloon catheter comprising a catheter shaft and a balloon located on the catheter shaft, the balloon functioning as a heat exchanger, said balloon having an interior space and an exterior surface, the exterior surface of the balloon being in heat exchange proximity to blood that flows past it, the shaft having an inflow lumen and an outflow lumen wherein the inflow lumen is in fluid communication with the interior space of said balloon and the outflow lumen is in fluid communication with the interior space of said balloon, and wherein heat exchange fluid is circulated into the balloon through the inflow lumen and out of the balloon through the outflow lumen.

25. A method according to claim 1 comprising the additional step of sensing the temperature of the donor, and adjusting the step of exchanging heat with the blood in response to the sensed temperature.

26. A method according to claim 25 wherein the temperature sensed is the temperature of the donor's blood at a location that is not within heat exchange proximity to the intravascular heat exchange apparatus.

27. A method according to claim 25 wherein the temperature sensed is the donor's body temperature as measured at the donor's tympanic membrane.

28. A method according to claim 25 wherein the temperature sensed is the donor's rectal temperature.

29. A method according to claim 25 wherein the temperature sensed is representative of the whole body temperature of the donor.

30. A method according to claim 25 comprising the additional steps of selecting a target temperature below normothermia and maintaining the temperature of at least the potentially transplantable tissue or organ at the target temperature after said target temperature has been reached.

31. A method according to claim 30 comprising the additional steps of adding heat when the sensed temperature is below the target temperature, and removing heat from the blood when the sensed temperature is above the target temperature.

32. A method as in claim 2 further comprising the steps of inserting a second heat exchange catheter in heat exchange proximity to the blood flowing away from the potentially transplantable organ or tissue to maintain at least a portion of the patient's body other than the potentially transplantable organ or tissue at a temperature different than the potentially transplantable organ or tissue.

33. A method as in claim 32 wherein the potentially transplantable organ or tissue is maintained at a temperature below 30° C. and the heart is maintained at a temperature at least as high as 30° C.

34. A method according to claim 32 wherein the potentially transplantable organ or tissue is selected from the group consisting of:

kidney;

lung;

liver;

nervous tissue;

tendon;

bone;

a limb;

a finger;

a toe;

skin;

cornea;

bone marrow; and,

intestine.

35. A method according to claim 1 wherein Step A comprises inserting a heat exchange catheter having a heat exchange region into the vasculature of a donor and positioning the catheter such that it exchanges heat with blood flowing to the heart to maintain the temperature of the heart above the temperature that which cardiac arrest or significant cardiac dysfunction occurs, and further including a second catheter positioned in the vasculature and exchanging heat with the blood after it has exited the heart and is flowing to the potentially transplantable organ or tissue to cool at least the potentially transplantable organ or tissue to a temperature below the temperature at which the heart is maintained.

36. A method for deterring rejection of a transplanted organ or tissue in a body of a mammalian transplant recipient, said method comprising the steps of:

a. placing an intravascular heat exchange apparatus within a blood vessel of the recipient such that the recipient's blood continues to circulate through that blood vessel and heat is exchanged between the circulating blood and the intravascular heat exchange apparatus; and,

b. using the intravascular heat exchange apparatus to cool the recipient's flowing blood, thereby lowering the recipient's core body temperature to a temperature that is below normothermia.

37. A method according to claim 36 wherein Step a comprises inserting a heat exchange catheter having a heat exchange region into the vasculature of the recipient and positioning the catheter such that blood flowing to at least the transplanted organ or tissue passes within heat exchange proximity to the heat exchange region and wherein Step b comprises exchanging heat with the blood that passes in heat exchange proximity to the heat exchange region for a period of time sufficient to cool at least the transplanted organ or tissue to a temperature below normothermia.

38. A method as in claim 37 further comprising the steps of inserting a second heat exchange catheter in heat exchange proximity to the blood flowing away from the transplanted organ or tissue to maintain at least a portion of the recipient's body other than the translanted organ or tissue at a temperature different than the organ or tissue.

39. A method according to claim 36 wherein the temperature is between approximately 30° C. and approximately 36° C.

40. A method according to claim 36 wherein the intravascular heat exchange apparatus is an elongate flexible catheter having a heat exchange region formed on a portion of the catheter that becomes inserted into the recipient's vasculature.

41. A method according to claim 40 wherein the heat exchange region of the catheter occupies less than the full length of the catheter portion that becomes inserted in the recipient's vasculature.

42. A method according to claim 36 wherein the heat exchange apparatus is placed in the recipient's venous vasculature.

43. A method according to claim 42 wherein the heat exchange apparatus is placed in the recipient's vena cava.

44. A method according to claim 43 wherein the heat exchange apparatus is placed in the recipient's inferior vena cava.

45. A method according to claim 44 wherein the heat exchange apparatus is placed in the recipient's superior vena cava.

46. A method according to claim 36 wherein the recipient's entire body is cooled to a temperature below normothermia.

47. A method according to claim 36 wherein the core body temperature is cooled to a desired temperature below normothermia and the remainder of the recipient's body is either hypothermic, normothermic or hyperthermic.

48. A method according to claim 36 wherein at least one raised area is formed on the heat exchange apparatus to increase its heat exchange surface area.

49. A method according to claim 36 wherein the organ or tissue is selected from the group consisting of:

heart;

lung;

liver;

kidney;

nervous tissue;

tendon;

bone;

a limb;

a finger;

a toe;

skin;

cornea;

bone marrow; and,

intestine.

50. A method according to claim 36 further comprising the steps of:

monitoring the temperature of at least a portion of the recipient's body and adjusting the heat exchange between the heat exchanger and the recipient's blood to maintain the monitored temperature within a desired range.

51. A method according to claim 36 wherein the heat exchange device comprises a heat exchanger through which heat exchange fluid is circulated.

52. A method according to claim 36 wherein said heat exchanger comprises a heat exchange balloon.

53. A method according to claim 36 wherein the heat exchange apparatus comprises a balloon catheter, the balloon catheter comprising a catheter shaft and a balloon located on the catheter shaft, the balloon functioning as a heat exchanger, said balloon having an interior space and an exterior surface, the exterior surface of the balloon being in heat exchange proximity to blood that flows past it, the shaft having an inflow lumen and an outflow lumen wherein the inflow lumen is in fluid communication with the interior space of said balloon and the outflow lumen is in fluid communication with the interior space of said balloon, and wherein heat exchange fluid is circulated into the balloon through the inflow lumen and out of the balloon through the outflow lumen.

54. A method according to claim 36 comprising the additional step of sensing the temperature of the recipient, and adjusting the step of exchanging heat with the blood in response to the sensed temperature.

55. A method according to claim 54 wherein the temperature sensed is the temperature of the recipient's blood at a location that is not within heat exchange proximity to the intravascular heat exchange apparatus.

56. A method according to claim 54 wherein the temperature sensed is the recipient's body temperature as measured at the recipient's tympanic membrane.

57. A method according to claim 54 wherein the temperature sensed is the recipient's rectal temperature.

58. A method according to claim 54 wherein the temperature sensed is representative of the whole body temperature of the recipient.

59. A method according to claim 54 comprising the additional steps of selecting a target temperature below normothermia and maintaining the temperature of at least the tissue or organ at the target temperature after said target temperature has been reached.

60. A method according to claim 59 comprising the additional steps of adding heat when the sensed temperature is below the target temperature, and removing heat from the blood when the sensed temperature is above the target temperature.

61. A method according to claim 36 wherein Step a comprises inserting a heat exchange catheter having a heat exchange region into the vasculature of a recipient and positioning the catheter such that it exchanges heat with blood flowing to the organ or tissue to maintain the temperature of the organ or tissue at about the temperature at which significant anti-platelet activity is effected.