Systems and methods for ex vivo organ care

• US 20080017194A1
• Filed: 04/19/2007
• Published: 01/24/2008
• Est. Priority Date: 04/19/2006
• Status: Active Grant

• Current Assignee: TransMedics, Inc. (TransMedics Group, Inc.)
• Original Assignee: TransMedics, Inc. (TransMedics Group, Inc.)
• Inventors: Saleh, Hesham, Fattah, Ihab, Trachtenberg, Jon, Kyi, Stanley, Havener, Robert, Hassanein, Waleed, Khayal, Tamer
• Granted Patent: US 8,535,934 B2
• Time in Patent Office: Days
• US Class Current: 128/200.24
• CPC Class Codes: A01N 1/02 Preservation of living parts
• CPC Class Codes: A01N 1/0226 Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
• CPC Class Codes: A01N 1/0247 for perfusion, i.e. for circulating fluid through organs, blood vessels or other living parts
• CPC Class Codes: A61M 11/00 Sprayers or atomisers specially adapted for therapeutic purposes in general B05B; aerosol containers B65D83/14
• CPC Class Codes: A61M 11/042 electrical
• CPC Class Codes: A61M 16/0078 Breathing bags
• CPC Class Codes: A61M 16/024 including calculation means, e.g. using a processor
• CPC Class Codes: A61M 16/10 Preparation of respiratory gases or vapours
• CPC Class Codes: A61M 2016/0027 pressure meter
• CPC Class Codes: A61M 2016/0033 electrical
• CPC Class Codes: A61M 2016/1025 the O2 concentration
• CPC Class Codes: A61M 2016/103 the CO2 concentration
• CPC Class Codes: A61M 2202/0208 Oxygen
• CPC Class Codes: A61M 2202/0225 Carbon oxides, e.g. Carbon dioxide
• CPC Class Codes: A61M 2202/025 Helium
• CPC Class Codes: A61M 2202/0468 non-physiological
• CPC Class Codes: A61M 2205/3368 Temperature
• CPC Class Codes: A61M 2230/005 Parameter used as control input for the apparatus
• CPC Class Codes: A61M 2230/202 partial carbon oxide pressure, e.g. partial dioxide pressure (P-CO2)
• CPC Class Codes: A61M 2230/205 partial oxygen pressure (P-O2)
• CPC Class Codes: A61M 2230/432 : partial CO2 pressure (P-CO2)
• CPC Class Codes: G01N 33/4925 : measuring blood gas content, e.g. O2, CO2 , HCO3

Abstract

The invention, in various embodiments, provides systems, methods and solutions using an organ ex vivo.

Claims

1. A method for perfusing a lung ex vivo, comprising:

connecting the lung within a fluid perfusion circuit,

flowing a perfusion fluid into the lung through a pulmonary artery interface and away from the lung through a pulmonary vein interface,

providing a respiratory gas to the lung for use in metabolism by the lung, the respiratory gas having a pre-determined composition of oxygen, and

ventilating the lung through a tracheal interface,

wherein the perfusion fluid flowing into the lung includes a first gas component at a substantially constant first composition, and the perfusion fluid flowing away from the lung includes the first gas component at a substantially constant second composition.

2. The method of claim 1, wherein ventilating occurs by flowing the respiratory gas through the tracheal interface.

3. The method of claim 2, comprising removing carbon dioxide produced by the lung through the tracheal interface.

4. The method of claim 2, wherein the first composition of the first gas component is substantially equivalent to the second composition of the first gas component.

5. The method of claim 2, wherein oxygen is maintained in the perfusion fluid flowing into the lung at a partial pressure substantially equivalent to the partial pressure of oxygen in the perfusion fluid flowing out of the lung.

6. The method of claim 2, wherein carbon dioxide is maintained in the perfusion fluid flowing into the lung at a partial pressure that is substantially equivalent to the partial pressure of carbon dioxide in the perfusion fluid flowing out of the lung.

7. The method of claim 2, wherein the respiratory gas flowing through the tracheal interface includes a composition of oxygen, carbon dioxide, and an inert respiratory gas.

8. The method of claim 7, wherein the inert respiratory gas is one of nitrogen and helium.

9. The method of claim 7, wherein the respiratory gas flowing through the tracheal interface includes at least about 10% to about 20% oxygen and at least about 2% to about 8% carbon dioxide.

10. The method of claim 9, wherein the respiratory gas is about 14% oxygen and about 5% carbon dioxide.

11. The method of claim 1 comprising oxygenating the perfusion fluid to a desired level prior to initiating perfusion of the lung.

12. The method of claim 1, comprising delivering the respiratory gas from a first gas source to the perfusion fluid through a gas exchange device connected within the perfusion circuit.

13. The method of claim 12, comprising removing carbon dioxide produced by the lung through the gas exchange device.

14. The method of claim 12, wherein ventilating the lung comprises delivering an isolated gas volume through the tracheal interface.

15. The method of claim 14, wherein the isolated volume gas source is provided by a flexible bag.

16. The method of claim 14, wherein the isolated volume gas source is provided by a hose.

17. The method of claim 14, wherein the isolated volume gas source includes gas components that reach a substantially constant composition within the isolated volume by exchanging with gas components in the perfusion fluid.

18. The method of claim 12, wherein the first composition of the first gas component differs from the second composition of the first gas component by an amount substantially equivalent to a quantity of the first gas component metabolized by the lung.

19. The method of claim 12, wherein the first gas source includes a composition of oxygen, carbon dioxide, and an inert respiratory gas.

20. The method of claim 19, wherein the inert respiratory gas is one of nitrogen and helium.

21. The method of claim 19, wherein the first gas source includes a composition of about 11% to about 14% oxygen and about 3% to about 7% carbon dioxide.

22. The method of claim 20, wherein the first gas source includes a composition of about 12% oxygen and about 5% carbon dioxide.

23. The method of claim 12, comprising oxygenating the perfusion fluid with a second gas source through the gas exchange device.

24. The method of claim 12, wherein oxygen is maintained during perfusion at an equilibrium partial pressure that is greater in the perfusion fluid flowing into the lung than in the perfusion fluid flowing out of the lung.

25. The method of claim 12, wherein carbon dioxide is maintained during perfusion at an equilibrium partial pressure that is lower in the perfusion fluid flowing into the lung than in the perfusion fluid flowing out of the lung.

26. The method of claim 1, wherein the first composition of the first gas component is a partial pressure that is greater than a partial pressure of the first gas component in a predetermined first level, and less than a composition of the first gas component in a predetermined second level.

27. The method of claim 26, wherein the predetermined first level is the partial pressure of the first gas component in physiologic venous blood, and the predetermined second level is the partial pressure of the first gas component in physiologic arterial blood.

28. The method of claim 26, wherein the first gas component is oxygen.

29. The method of claim 27, wherein oxygen in the perfusion fluid flowing into the lung is maintained during perfusion at a partial pressure of about 75 mmHg to about 100 mmHg.

30. The method of claim 27, wherein oxygen in the perfusion fluid flowing into the lung is maintained during perfusion at a partial pressure of about 80 mmHg to about 90 mmHg.

31. The method of claim 30, wherein oxygen in the perfusion fluid flowing into the lung is maintained during perfusion at a partial pressure of about 83 mmHg to about 85 mmHg.

32. The method of claim 1, wherein the first composition of the first gas component is a partial pressure that is less than a partial pressure of the first gas component in a predetermined first level, and greater than a composition of the first gas component in a predetermined second level.

33. The method of claim 32, wherein the predetermined first level is the partial pressure of the first gas component in physiologic venous blood, and the predetermined second level is the partial pressure of the first gas component in physiologic arterial blood.

34. The method of claim 33, wherein the first gas component is carbon dioxide.

35. The method of claim 33, wherein carbon dioxide in the perfusion fluid flowing into the lung is maintained during perfusion at a partial pressure of about 40 mmHg to about 50 mmHg.

36. The method of claim 33, wherein carbon dioxide in the perfusion fluid flowing into the lung is maintained during perfusion at a partial pressure of about 42 mmHg to about 48 mmHg.

37. The method of claim 1 comprising maintaining the perfusion fluid provided to the lung at a near physiologic temperature.

38. The method of claim 1 comprising measuring a level of an arterial-venous (AV) oxygen gradient between the perfusion fluid flowing into the lung and flowing out of the lung.

39. The method of claim 1 comprising measuring at least one of a level of oxygen saturation of blood hemoglobin and a partial pressure of oxygen in the perfusion fluid flowing into the lung.

40. The method of claim 1 comprising measuring at least one of a level of oxygen saturation of blood hemoglobin and a partial pressure of oxygen in the perfusion fluid flowing out of the lung.

41. The method of claim 1, wherein the perfusion fluid includes whole blood.

42. The method of claim 1, comprising delivering one or more therapeutics to the lung during perfusion.

43. The method of claim 42, wherein the one or more therapeutics are selected from antimicrobials, vasodilators, and anti-inflammatory drugs.

44. The method of claim 42, wherein the one or more therapeutics are selected from isuprel, flolan, prostacycline, dextran, prostaglandins, isoproterenol, bronchodilators, surfactants, pentoxifylline and nitric oxide donors.

45. The method of claim 42, wherein the one or more therapeutics are delivered through the tracheal interface through one of a nebulizer and a bronchoscope.

46. The method of claim 1, comprising at least partially depleting the perfusion fluid of leukocytes.

47. The method of claim 1, comprising at least partially depleting the perfusion fluid of platelets.

48. The method of claim 1, comprising ventilating the lung by flowing gas through the tracheal interface.

49. A lung care system comprising:

a portable multiple use module including a portable chassis;

a single use disposable module including,

a disposable structure sized and shaped for interlocking the single use disposable module with the multiple use module for electromechanical inter-operation with the multiple use module, and

a lung chamber assembly having a first interface for allowing a flow of the perfusion fluid into the lung, a second interface for allowing ventilation of the lung, and a third interface for allowing a flow of the perfusion fluid away from the lung;

a pump adapted to flow the perfusion fluid into and away from the lungs; and

a respiratory gas source having a predetermined composition of oxygen.

50. The system of claim 49, wherein the first interface includes a pulmonary artery cannula, and the second interface includes a cannula disposed within a tracheal conduit of the lung.

51. The system of claim 49, wherein the third interface includes a left atrial cuff exposed to the lung chamber assembly for allowing the perfusion fluid to flow from the lung to the lung chamber assembly.

52. The system of claim 49, wherein the third interface includes a semi-sealable connection between a left atrial cuff and a cannula that directs the perfusion fluid to a reservoir.

53. The system of claim 52, wherein the semi-sealable connection is formed by a connector device that mates the cannula with the left atrial cuff.

54. The system of claim 53, wherein the connection is releasable.

55. The system of claim 53, wherein the connector device includes a first surface for engaging the left atrial cuff and a second surface for engaging the cannula.

56. The system of claim 55, wherein the first surface of the connector device includes a plurality of perforations for engaging respective ones of portions of the left atrial cuff.

57. The system of claim 52, wherein the cannula extends vertically above the left atrial cuff.

58. The system of claim 57, wherein the cannula has a cross-section with a diameter that is larger than a diameter of the left atrial cuff.

59. The system of claim 58, wherein the cannula loosely fits around the left atrial cuff.

60. The system of claim 52, wherein a tip portion of the cannula is positioned within a pocket formed by the left atrial cuff.

61. The system of claim 49, wherein the third interface includes a left atrial cuff disposed in a cup-shaped interface inside of the lung chamber assembly for allowing the perfusion fluid to flow from the lung and away from the lung chamber assembly via an outlet conduit coupled to the cup-shaped interface.

62. The system of claim 61, wherein the cup-shaped interface includes a plurality of openings at respective heights along a sidewall of the interface.

63. The system of claim 62, wherein the third interface includes a selector valve in fluid communication with the plurality of openings for controllably drawing the perfusion fluid in the cup-shaped interface away from the lung chamber assembly via a selected one of the plurality of openings and the outlet conduit.

64. The system of claim 49 comprising a flexible housing mounted inside of the lung chamber assembly for supporting the lung and maintaining a shape of the lung.

65. The system of claim 64, wherein the housing substantially prevents the lung from contacting at least one wall of the lung chamber assembly.

66. The system of claim 64, wherein the housing includes a flexible membrane that suspends the lung within the lung chamber assembly.

67. The system of claim 66, wherein the flexible membrane is a netting.

68. The system of claim 64, wherein the housing has a shape of a ribcage.

69. The system of claim 64, wherein the housing includes a diaphragm structure.

70. The system of claim 49, comprising a heater for maintaining the perfusion fluid provided to the lung chamber assembly at a near physiologic temperature.

71. The system of claim 70, wherein the temperature is between about 30°

C. and about 37°

C.

72. The system of claim 71, wherein the temperature is between about 34°

C. and about 37°

C.

73. The system of claim 49, comprising a gas exchange device in fluid communication with at least one gas supply and the perfusion fluid, the gas exchange device being adapted to controllably modulate a composition of a first gas component in the perfusion fluid.

74. The system of claim 71, wherein the gas exchange module includes a gas select switch for selecting from a plurality of gas supplies to modulate the composition of a gas component in the perfusion fluid.

75. The system of claim 49, comprising a respiration device for providing a gas supply through the second interface.

76. The system of claim 49, comprising an isolated volume compartment cannulated to a tracheal conduit of the lung and adapted to ventilate the lung during perfusion.

77. A method for evaluating a lung for transplant suitability comprising:

positioning the lung in an ex vivo perfusion circuit,

flowing a perfusion fluid into the lung through a pulmonary artery interface and flowing the perfusion fluid away from the lung through a pulmonary vein interface, the perfusion fluid being at a physiologic temperature,

providing a gas to the lung through a tracheal interface,

measuring a first composition of a gas component in the perfusion fluid, and

performing an evaluation on the lung based on the first composition.

78. The method of claim 77, wherein the perfusion fluid has a physiologic venous composition.

79. The method of claim 77, wherein the flow of the gas through the tracheal interface comprises about 100% oxygen.

80. The method of claim 77, wherein the flow of the gas through the tracheal interface comprises ambient air.

81. The method of claim 77, wherein the evaluation includes measuring a fractional inspired oxygen concentration.

82. The method of claim 77, wherein the evaluation includes measuring an arterial-venous (AV) oxygen gradient between the perfusion fluid flowing into the lung and the perfusion fluid flowing away from the lung.

83. The method of claim 77, wherein the evaluation includes measuring an alveolar arterial (AA) oxygen gradient.

84. The method of claim 77, wherein the evaluation includes measuring a tidal volume.

85. The method of claim 77, wherein the evaluation includes measuring at least one of a level of oxygen saturation of blood hemoglobin and a partial pressure of oxygen in the perfusion fluid flowing into the lung.

86. The method of claim 77, wherein the evaluation includes measuring at least one of a level of oxygen saturation of blood hemoglobin and a partial pressure of oxygen in the perfusion fluid flowing away from the lung.

87. The method of claim 77, wherein the evaluation includes measuring a positive end expiratory pressure.

88. The method of claim 77, comprising

measuring a saturation of oxygen in the perfusion fluid flowing through the pulmonary artery interface at a plurality of times during a period of testing,

measuring a saturation of oxygen in the perfusion fluid flowing through the pulmonary vein interface at the plurality of times during the period of testing,

comparing pulmonary artery and pulmonary vein oxygen saturation measurements at each of the plurality of times to determine comparative differences at the plurality of times, and

identifying a maximum difference among the comparative differences.

89. The method of claim 88, wherein the flow of the gas through the tracheal interface comprises about 100% oxygen.

90. The method of claim 88, wherein the flow of the gas through the tracheal interface is less than 100% oxygen.

91. The method of claim 88, wherein the flow of the gas through the tracheal interface is less than 75% oxygen.

92. The method of claim 91, wherein the flow of the gas through the tracheal interface is less than 50% oxygen.

93. The method of claim 92, wherein the flow of the gas through the tracheal interface is less than 25% oxygen.

94. The method of claim 93, wherein the flow of the gas through the tracheal interface contains no oxygen.

95. The method of claim 77, comprising applying a suction force through the tracheal interface to clear lung alveoli of debris.

96. The method of claim 77, comprising causing the lung to inhale breaths that are of variable volume to clear lung alveoli of debris.

97. The method of claim 96, wherein the breaths include a first breath having a volume that is larger than the volume of at least two next breaths.

98. The method of claim 77, comprising

adjusting a composition of the flow of gas to the lung after measuring the first composition of the gas component,

measuring a second composition of the gas component in the perfusion fluid after adjusting the composition of the flow of gas;

comparing the measurements of the first and second compositions of the gas component; and

performing the evaluation based on the comparison.

99. A composition for use in a solution for perfusing a lung, comprising one or more carbohydrates that include dextran, and a plurality of amino acids that do not include asparagine, glutamine, or cysteine.

100. The composition of claim 99, further comprising a blood product.

101. The composition of claim 99, further comprising whole blood.

102. The composition of claim 101, further comprising whole blood that has been at least partially depleted of leukocytes.

103. The composition of claim 101, further comprising whole blood that has been at least partially depleted of platelets.

104. The composition of claim 99, further comprising a phosphate.

105. The composition of claim 99, further comprising insulin.

106. The composition of claim 99, further comprising at least one vitamin.

107. The composition of claim 99, further comprising a magnesium ion source.

108. The composition of claim 99, further comprising one or more electrolytes.

109. The composition of claim 108, wherein the one or more electrolytes includes potassium, sodium, calcium, chloride, sulfate, or a combination thereof.

110. The composition of claim 99, further comprising an immunosuppressant.

111. The composition of claim 110, further comprising a steroid.

112. The composition of claim 111, further comprising a colloid.

113. The composition of claim 112, wherein the colloid is selected from dextran, albumen, hyperstarch, and gelatin.

114. The composition of claim 113, comprising dextran.

115. The composition of claim 99, further comprising one or more therapeutic.

116. The composition of claim 112, wherein the one or more therapeutic is selected from antimicrobial, antifungal, antiviral, vasodilators, surfactants adapted to resist collapsing of alveoli within the lung, and anti-inflammatory drugs.

117. The composition of claim 112, wherein the one or more therapeutic is a vasodilator.

118. The composition of claim 117, wherein the vasodilator is selected from beta-1-agonist, isoproterenol and prostaglandine.

119. The composition of claim 112, wherein the one or more therapeutic is selected from pentoxifylline, isuprel, flolan, prostacycline and a nitric oxide donor.

120. The composition of claim 119, further comprising a nitric oxide donor selected from L-arginine, nitroglycerine, and nitroprusside.

121. The composition of claim 112, wherein the one or more therapeutic is formulated for delivery through the tracheal interface by one of a nebulizer and a bronchoscope.

122. The composition of claim 121, wherein the one or more therapeutic is selected from prostaglandines and brochodilators.

123. The composition of claim 122, wherein the one or more therapeutic is beta-2 agonist.

124. The composition of claim 99, further comprising a vector loaded with one or more genes.

125. The composition of claim 99, further comprising an aqueous medium.

126. The composition of claim 99, comprising:

127. The composition of claim 126, comprising the following components in the following amounts per about 1000 mL of aqueous medium:

128. The composition of claim 127, further including a priming solution comprising the following components in the following relative amounts:

129. The composition of claim 128, wherein the priming solution further includes about 10 g to about 30 g of dextran.

130. The composition of claim 128, wherein the priming solution further includes aqueous fluid.

131. The composition of claim 130, wherein the components of the priming solution are in relative amounts per about 500 mL of aqueous fluid.

132. The composition of claim 99, wherein the composition, when perfused with whole blood through a lung, prolongs the lung'"'"'s ability to continue performing physiologic oxygen and carbon dioxide gas exchange ex vivo at a physiologic temperature.