Organ care solution for ex-vivo machine perfusion of donor lungs

Abstract

An ex-vivo lung solution for machine perfusion of donor lungs on OCS. The solution may be mixed with whole blood or packed red blood cells to form the OCS lung perfusion solution.

1 . An ex-vivo perfusion solution for machine perfusion of donor lungs comprising:
 an energy-rich perfusion nutrient,   a colloid,   a hormone,   a steroid,   a buffer,   magnesium sulfate anhydrate, and   at least one of a phosphodiesterase inhibitor and a nitrate.   
     
     
         2 . The solution of  claim 1 , wherein the phosphodiesterase inhibitor is a phosphodiesterase 3 inhibitor. 
     
     
         3 . The solution of  claim 1 , wherein the phosphodiesterase inhibitor is milrinone. 
     
     
         4 . The solution of  claim 1 , wherein the nitrate is nitroglycerin. 
     
     
         5 . The solution of  claim 1 , wherein the solution includes the phosphodiesterase inhibitor and the nitrate, and the phosphodiesterase inhibitor is milrinone and the nitrate is nitroglycerin. 
     
     
         6 . The solution of  claim 5 , wherein each liter of solution comprises milrinone in amount of about 4000 mcg and nitroglycerine in an amount of about 10 mg to 50 mg. 
     
     
         7 . The solution of  claim 1 , additionally comprising whole blood. 
     
     
         8 . The solution of  claim 1 , additionally comprising red blood cells. 
     
     
         9 . The solution of  claim 5 , additionally comprising whole blood. 
     
     
         10 . The solution of  claim 5 , additionally comprising red blood cells. 
     
     
         11 . The solution of  claim 5 , wherein the nutrient includes glucose monohydrate, sodium chloride, potassium chloride, and M.V.I. Adult® multi-vitamin or equivalent; the colloid includes dextran 40; the hormone includes insulin; the steroid includes methylprednisolone; and the buffer includes disodium phosphate anhydrate, monopotassium phosphate and sodium bicarbonate. 
     
     
         12 . The solution of  claim 6 , wherein each liter of the solution comprises
 dextran 40 in the amount of about 50 g;   sodium chloride in an amount of about 8 g;   potassium chloride in an amount of about 0.4 g;   magnesium sulfate anhydrate in an amount of about 0.098 g;   disodium phosphate anhydrate in an amount of about 0.046 g;   monopotassium phosphate in an amount of about 0.063 g;   glucose monohydrate in an amount of about 2 g;   insulin in an amount of about 20 IU;   the multi-vitamin in an amount of about 1 unit vial;   sodium bicarbonate in an amount of about 15 mEq;   methylprednisolone in an amount of about 1 g.   
     
     
         13 . The solution of  claim 5 , wherein the hormone comprises insulin. 
     
     
         14 . The solution of  claim 5 , wherein the hormone comprises about 20 IU insulin in each liter of solution. 
     
     
         15 . The solution of  claim 5 , wherein nutrient comprises a multi-vitamin and glucose monohydrate. 
     
     
         16 . The solution of  claim 15  wherein the multi-vitamin includes fat-soluble and water-soluble vitamins. 
     
     
         17 . The solution of  claim 5 , wherein nutrient comprises about 2 g glucose monohydrate in each liter of solution. 
     
     
         18 . The solution of  claim 5  wherein the buffer comprises sodium bicarbonate. 
     
     
         19 . The solution of  claim 5  wherein the buffer initially comprises about 15 mEq sodium bicarbonate in each liter of solution. 
     
     
         20 . The solution of  claim 5  wherein the steroid comprises a glucocorticoid steroid. 
     
     
         21 . The solution of  claim 20  wherein the glucocorticoid steroid comprises methylprednisolone. 
     
     
         22 . The solution of  claim 5  wherein the steroid comprises 1 g methylprednisolone in each liter of solution. 
     
     
         23 . A method of perfusing a donor lung at or near physiologic conditions comprising:
 flowing perfusion liquid through the lung, the perfusion liquid being at a physiologic temperature, the perfusion liquid comprising   a nutrient, a colloid, a hormone, a steroid, a buffer, magnesium sulfate anhydrate, an antimicrobial agent and at least one of a phosphodiesterase inhibitor and a nitrate.   
     
     
         24 . The method of  claim 23 , wherein
 the nutrient includes glucose monohydrate, sodium chloride, potassium chloride, and a multi-vitamin; the colloid includes dextran 40; the hormone includes insulin; the steroid includes methylprednisolone; the buffer includes disodium phosphate anhydrate, monopotassium phosphate and sodium bicarbonate; phosphodiesterase inhibitor includes milrinone, and the nitrate includes nitroglycerin.   
     
     
         25 . The method of  claim 24 , wherein each liter of liquid comprises
 milrinone in an amount of about 4000 mcg;   nitroglycerin in an amount of about 10 mg to 50 mg;   dextran 40 in the amount of about 50 g;   sodium chloride in an amount of about 8 g;   potassium chloride in an amount of about 0.4 g;   magnesium sulfate anhydrate in an amount of about 0.098 g;   disodium phosphate anhydrate in an amount of about 0.046 g;   monopotassium phosphate in an amount of about 0.063 g;   glucose monohydrate in an amount of about 2 g;   insulin in an amount of about 20 IU;   the multi-vitamin in an amount of about 1 unit vial;   sodium bicarbonate in an amount of about 15 mEq;   methylprednisolone in an amount of about 1 g.   
     
     
         26 . The method of  claim 25  further comprising mixing the perfusion liquid with whole blood. 
     
     
         27 . The method of  claim 25  further comprising mixing the perfusion liquid with red blood cells. 
     
     
         28 . The method of  claim 25  further comprising mixing the perfusion liquid with leukocyte-depleted whole blood. 
     
     
         29 . A method of producing a solution for perfusing a lung at near physiologic conditions comprising the steps of:
 adding pre-weighed amounts of dextran 40, sodium chloride, potassium chloride (KCL), magnesium sulfate anhydrate, disodium phosphate anydrate, monopotassium phosphate, glucose monohydrate, milrinone, nitroglycerin, antimicrobial agents and water to a container to form a solution;   mixing and heating the solution until fully dissolved;   monitoring the pH of the solution during mixing and adjusting the pH with 1M hydrochloric acid;   allowing the solution to cool;   filtering the solution;   dispensing the solution into a primary container;   sterilizing the filled primary container with heat using a sterilization cycle that has been validated to achieve a Sterility Assurance Level of 10 −6 .   
     
     
         30 . A method of producing a perfusion solution comprising
 combining pre-weighed amounts of a nutrient, a colloid, a hormone, a steroid, a buffer, magnesium sulfate anhydrate, and at least one of a phosphodiesterase inhibitor and a nitrate to form a solution for perfusing a lung at near physiologic conditions.   
     
     
         31 . The method of  claim 30  wherein
 the solution includes the phosphodiesterase inhibitor and the nitrate, and 
 the nutrient includes glucose monohydrate, sodium chloride, potassium chloride, and a multi-vitamin, wherein the multi-vitamin is selected from the group consisting of M.V.I. Adult® or equivalent; the colloid includes dextran 40; the hormone includes insulin; the steroid includes methylprednisolone; buffer includes disodium phosphate anhydrate, monopotassium phosphate and sodium bicarbonate; the phosphodiesterase inhibitor includes milrinone, and the nitrate includes nitroglycerin. 
 
     
     
         32 . The method of  claim 31 , wherein each liter of solution includes
 milrinone in an amount of about 4000 mcg;   nitroglycerin in an amount of about 10 mg to 50 mg;   dextran 40 in the amount of about 50 g;   sodium chloride in an amount of about 8 g;   potassium chloride in an amount of about 0.4 g;   magnesium sulfate anhydrate in an amount of about 0.098 g;   disodium phosphate anhydrate in an amount of about 0.046 g;   monopotassium phosphate in an amount of about 0.063 g;   glucose monohydrate in an amount of about 2 g;   insulin in an amount of about 20 IU;   the multi-vitamin in an amount of about 1 unit vial;   sodium bicarbonate in an amount of about 15 mEq;   methylprednisolone in an amount of about 1 g;   
       the method further comprising
 mixing and heating the solution until fully dissolved; 
 monitoring the pH of the solution during mixing and adjusting the pH with 1M hydrochloric acid; 
 allowing the solution to cool; 
 filtering the solution; 
 dispensing the solution into a primary container; 
 sterilizing the filled primary container with heat using a sterilization cycle that has been validated to achieve a Sterility Assurance Level of 10 −6 . 
 
     
     
         33 . The method of  claim 32  further comprising mixing the perfusion liquid with whole blood. 
     
     
         34 . The method of  claim 32  further comprising mixing the perfusion liquid with red blood cells. 
     
     
         35 . The method of  claim 32  further comprising mixing the perfusion liquid with leukocyte-depleted whole blood. 
     
     
         36 . A system for perfusing a donor lung in a lung perfusion circuit at or near physiologic conditions comprising:
 a single use disposable lung care module including
 an interface adapted for attachment to the single use module, and 
 a lung chamber assembly having a first interface for allowing a flow of a perfusion solution into the lung and a second interface for allowing ventilation of the lung with a ventilation gas; and 
   a drain system for draining a flow of perfusion solution from the lung chamber assembly; and   the perfusion solution including
 dextran 40; sodium chloride; potassium chloride; magnesium sulfate anhydrate; disodium phosphate anhydrate; monopotassium phosphate; glucose monohydrate; milrinone; nitroglycerin; insulin; a multi-vitamin; sodium bicarbonate; and methylprednisolone. 
   
     
     
         37 . A method of flushing a lung prior to preservation on an OCS comprising:
 flushing a donor lung prior to excising the lung from the donor's body with a solution comprising a nutrient, a colloid, a buffer, magnesium sulfate anhydrate, and a nitrate;   excising the donor lung from the donor's body;   placing the lung on an organ care system.   
     
     
         38 . The method of  claim 37  wherein
 the nutrient includes glucose monohydrate, sodium chloride and potassium chloride; the colloid includes dextran 40; the buffer includes disodium phosphate anhydrate and monopotassium phosphate; and the nitrate includes nitroglycerin. 
 
     
     
         39 . The method of  claim 38 , wherein each liter of solution comprises
 nitroglycerin in an amount of about 10 mg to 50 mg;   dextran 40 in the amount of about 50 g;   sodium chloride in an amount of about 8 g;   potassium chloride in an amount of about 0.4 g;   magnesium sulfate anhydrate in an amount of about 0.098 g;   disodium phosphate anhydrate in an amount of about 0.046 g;   monopotassium phosphate in an amount of about 0.063 g;   glucose monohydrate in an amount of about 2 g.   
     
     
         40 . The solution of  claim 1  further comprising an antimicrobial agent. 
     
     
         41 . The solution of  claim 40 , wherein the antimicrobial agent comprises at least one of cefazolin, ciprofloxacin, and voriconazole. 
     
     
         42 . The solution of  claim 40  wherein each liter of solution comprises cefazolin in an amount of about 1 g, ciprofloxacin in an amount of about 0.2 g, and voriconazole in an amount of about 0.2 g. 
     
     
         43 . An ex-vivo perfusion solution for machine perfusion of donor lungs comprising:
 an energy-rich perfusion nutrient,   a colloid,   a hormone,   a steroid,   a buffer,   magnesium sulfate anhydrate,   at least one of a phosphodiesterase inhibitor and a nitrate, and   an antimicrobial agent.   
     
     
         44 . The solution of  claim 6 , wherein each liter of the solution further comprises
 dextran 40 in the amount of about 50 g;   sodium chloride in an amount of about 8 g;   potassium chloride in an amount of about 0.4 g;   magnesium sulfate anhydrate in an amount of about 0.098 g;   disodium phosphate anhydrate in an amount of about 0.046 g;   monopotassium phosphate in an amount of about 0.063 g;   glucose monohydrate in an amount of about 2 g;   insulin in an amount of about 20 IU;   the multi-vitamin in an amount of about 1 unit vial;   sodium bicarbonate in an amount of about 15 mEq;   methylprednisolone in an amount of about 1 g;   cefazolin in an amount of about 1 g;   ciprofloxacin in an amount of about 0.2 g;   voriconazole in an amount of about 0.2 g.