Emergency preservation and resuscitation methods

Abstract

Provided are methods for inducing preservation in a patient and resuscitating that patient. At least three hours of preservation, with successful resuscitation, are realized using the methods described herein. The methods involve flushing a patient with an oxygenated, cold-flush solution, such as normal saline, having an energy source. The patient may be cooled to deep or profound hypothermia to induce preservation. The patient may be resuscitated by warming to from about 33° C. to about 36° C., and then may be slowly warmed over a 24 to 72 hour period to normothermia. Kits for inducing preservation also are provided.

1 . A method of inducing preservation for at least about three hours in a patient suffering from cardiopulmonary arrest, comprising cooling the patient within about 8 minutes of cardiopulmonary arrest or cessation of cardiopulmonary resuscitation by flushing the patient's vasculature with an oxygenated, aqueous cold-flush solution comprising an energy source, wherein the cold-flush solution is introduced into the patient at from about 1° C. to about 4° C. and the patient is cooled to a tympanic temperature of less than about 10° C. in a time period of less than about 30 minutes. 
   
   
       2 . The method of  claim 1 , wherein the patient is cooled to a tympanic temperature of about 7° C. 
   
   
       3 . The method of  claim 1 , wherein the patient is cooled to a tympanic temperature of less than about 10° C. in a time period of less than about 27 minutes. 
   
   
       4 . The method of  claim 3 , wherein the patient is cooled to a tympanic temperature of less than about 10° C. in a time period of less than about 20 minutes. 
   
   
       5 . The method of  claim 4 , wherein the patient is cooled to a tympanic temperature of about 7° C. in a time period of less than about 20 minutes. 
   
   
       6 . The method of  claim 1 , wherein the patient is warmed within about three hours of initiation of preservation by introducing blood into the patient's vasculature and warming the patient to a state of mild hypothermia at from about 33° C. to about 36° C. 
   
   
       7 . The method of  claim 6 , comprising raising the patient's temperature from mild hypothermia to about 37° C. over a time period of from about 24 to about 72 hours. 
   
   
       8 . The method of  claim 6 , comprising raising the patient's temperature from mild hypothermia to about 37° C. over a time period of from about 48 to about 72 hours. 
   
   
       9 . The method of  claim 1 , wherein the cold-flush solution is introduced into the patient through the patient's aorta. 
   
   
       10 . The method of  claim 1 , wherein the cardiopulmonary arrest follows exsanguination. 
   
   
       11 . The method of  claim 1 , wherein the cardiopulmonary arrest follows from about 2 hours to about 6 hours of hemorrhagic shock. 
   
   
       12 . The method of  claim 1 , wherein the cardiopulmonary arrest is substantially normovolemic. 
   
   
       13 . The method of  claim 1 , wherein the cardiopulmonary arrest follows a poisoning event. 
   
   
       14 . The method of  claim 1 , wherein the cold-flush solution further comprises one or more nitroxide antioxidants. 
   
   
       15 . The method of  claim 14 , wherein the one or more nitroxide antioxidants are selected from the group consisting of TEMPO and TEMPOL. 
   
   
       16 . The method of  claim 1 , wherein the cold-flush solution further comprises TEMPOL. 
   
   
       17 . The method of  claim 1 , wherein the cold-flush solution is introduced into the aorta of the patient. 
   
   
       18 . The method of  claim 1 , wherein the cold-flush solution is normal saline. 
   
   
       19 . The method of  claim 1 , wherein the cold-flush solution comprises an oxygen carrier. 
   
   
       20 . The method of  claim 1 , wherein the oxygen carrier is one or both of polynitroxylated albumin and polynitroxylated hemoglobin. 
   
   
       21 . The method of  claim 1 , wherein the energy source is glucose. 
   
   
       22 . The method of  claim 21 , wherein the energy source is from about 0.1% w/v to about 5% dextrose. 
   
   
       23 . The method of  claim 21 , wherein the energy source is about 2.5% dextrose. 
   
   
       24 . The method of  claim 1 , wherein the cold-flush solution is a saline solution. 
   
   
       25 . The method of  claim 24 , wherein the saline solution is from about 0.85% w/v to about 1.5% w/v saline. 
   
   
       26 . The method of  claim 24 , wherein the cold-flush solution is isotonic. 
   
   
       27 . The method of  claim 24 , wherein the cold-flush solution is mildly hypertonic. 
   
   
       28 . The method of  claim 1 , wherein the cold-flush solution is isotonic. 
   
   
       29 . The method of  claim 1 , wherein the cold-flush solution is mildly hypertonic. 
   
   
       30 . The method of  claim 1 , wherein the cold-flush solution comprises a neuroprotective agent. 
   
   
       31 . The method of  claim 30 , wherein the neuroprotective agent is one or more agents selected from the group consisting of an anesthetic, an anticonvulsant, an anti-apoptotic agent and an anti-inflammatory agent. 
   
   
       32 . The method of  claim 30 , wherein the neuroprotective agent is one or more agents selected from the group consisting of a barbiturate, thiopental, pentobarbital, ketamine, an opioid, phenyloin, valproate, a caspase inhibitor, a kinase inhibitor, a mitogen-activated protein kinase inhibitor, a protease inhibitor, a calpain antagonist, a cyclosporin, FK 506, methyl prednisolone, a cyclooxygenase-2 antagonist, an antagonists of a pro-inflammatory cytokine(s), TNF-alpha, IL-1 and IL-10. 
   
   
       33 . The method of  claim 1 , wherein the cold-flush solution comprises one or both of ATP and an inorganic phosphate. 
   
   
       34 . A method of resuscitating a patient from preservation, the patient having been subjected to induction of preservation by flushing the patient's brain or vasculature with a cold-flush solution to induce hypothermia, comprising:
 (a) introducing blood into the patient's vasculature and warming the patient to a state of mild hypothermia at from about 33° C. to about 36° C.; and   (b) warming the patient to about 37° C. over from about 24 hours to about 48 hours.   
   
   
       35 . The method of  claim 34 , wherein the patient is warmed to mild hypothermia by cardiopulmonary bypass. 
   
   
       36 . The method of  claim 34 , wherein the patient is warmed from mild hypothermia to about 37° C. over from about 48 to about 72 hours. 
   
   
       37 . A method of preserving organs of a cadaver, comprising, cooling the cadaver by flushing the cadaver's blood vessels with an oxygenated cold-flush solution comprising an energy source, wherein the cooling solution is about 1° C. to about 4° C. and the cadaver is cooled to a tympanic temperature of less than about 10° C. in a time period of less than about 30 minutes. 
   
   
       38 . The method of  claim 37 , wherein the energy source is glucose. 
   
   
       39 . The method of  claim 38 , wherein the energy source is from about 0.1% w/v to about 5% dextrose. 
   
   
       40 . The method of  claim 37 , wherein the energy source is about 2.5% dextrose. 
   
   
       41 . The method of  claim 37 , wherein the cold-flush solution is a saline solution. 
   
   
       42 . The method of  claim 41 , wherein the saline solution is from about 0.85% w/v to about 1.5% w/v saline. 
   
   
       43 . The method of  claim 41 , wherein the cold-flush solution is isotonic. 
   
   
       44 . The method of  claim 41 , wherein the cold-flush solution is mildly hypertonic. 
   
   
       45 . The method of  claim 37 , wherein the cold-flush solution is isotonic. 
   
   
       46 . The method of  claim 37 , wherein the cold-flush solution is mildly hypertonic. 
   
   
       47 . The method of  claim 37 , wherein the cold-flush solution comprises a neuroprotective agent. 
   
   
       48 . The method of  claim 47 , wherein the neuroprotective agent is one or more agents selected from the group consisting of an anesthetic, an anticonvulsant, an anti-apoptotic agent and an anti-inflammatory agent. 
   
   
       49 . The method of  claim 47 , wherein the neuroprotective agent is one or more agents selected from the group consisting of a barbiturate, thiopental, pentobarbital, ketamine, an opioid, phenyloin, valproate, a caspase inhibitor, a kinase inhibitor, a mitogen-activated protein kinase inhibitor, a protease inhibitor, a calpain antagonist, a cyclosporin, FK 506, methyl prednisolone, a cyclooxygenase-2 antagonist, an antagonists of a pro-inflammatory cytokine(s), TNF-alpha, IL-1 and IL-10. 
   
   
       50 . The method of  claim 37 , further comprising re-introducing blood into the cadaver, warming the cadaver and harvesting an organ of the cadaver. 
   
   
       51 . The method of  claim 37 , further comprising harvesting an organ of the cadaver. 
   
   
       52 . The method of  claim 37 , wherein the cold-flush solution comprises one or both of ATP and an inorganic phosphate. 
   
   
       53 . A kit for use in inducing preservation in a patient, comprising:
 (a) an access cannulation set;   (b) a cold-flush solution reservoir containing an aqueous cold-flush solution comprising an energy source; and   (c) a pump configured to deliver the cold-flush solution through the access cannulation set and into a patient,   wherein the aqueous cold-flush solution is oxygenated or the kit comprises an oxygenator configured to oxygenate the cold-flush solution prior to delivery of the cold-flush solution to a patient.   
   
   
       54 . The kit of  claim 53 , wherein the reservoir is insulated and the aqueous cold-flush solution is between 0° C. and about 4° C. 
   
   
       55 . The kit of  claim 53 , wherein the reservoir is insulated and the aqueous cold-flush solution is from about 1° C. to about 2° C. 
   
   
       56 . The kit of  claim 53 , further comprising an indicia describing a procedure for use of the kit in inducing preservation. 
   
   
       57 . The kit of  claim 53 , further comprising a tympanic thermometer. 
   
   
       58 . The kit of  claim 53 , further comprising one or more of a decompression cannula, a pump, a heat exchanger, a computerized control and an oxygenator. 
   
   
       59 . The kit of  claim 58 , comprising a heat-exchanger, a cold-flush solution reservoir, a computerized control and a pump, wherein the pump, heat-exchanger, cold-flush solution reservoir, and computerized control are integrated. 
   
   
       60 . The kit of  claim 58 , further comprising one or more of a cold-flush solution temperature sensor, a pump flow rate sensor, a tympanic temperature sensor and a cold-flush solution oxygen sensor. 
   
   
       61 . The kit of  claim 53 , wherein the energy source is glucose. 
   
   
       62 . The kit of  claim 61 , wherein the energy source is from about 0.1% w/v to about 5% dextrose. 
   
   
       63 . The kit of  claim 61 , wherein the energy source is about 2.5% dextrose. 
   
   
       64 . The kit of  claim 53 , wherein the cold-flush solution is oxygenated normal saline comprising the energy source. 
   
   
       65 . The kit of  claim 53 , wherein the cold-flush solution is a saline solution. 
   
   
       66 . The kit of  claim 65 , wherein the saline solution is from about 0.85% w/v to about 1.5% w/v saline. 
   
   
       67 . The kit of  claim 65 , wherein the cold-flush solution is isotonic. 
   
   
       68 . The kit of  claim 65 , wherein the cold-flush solution is mildly hypertonic. 
   
   
       69 . The kit of  claim 53 , wherein the cold-flush solution is isotonic. 
   
   
       70 . The kit of  claim 53 , wherein the cold-flush solution is mildly hypertonic. 
   
   
       71 . The kit of  claim 53 , wherein the cold-flush solution comprises a neuroprotective agent. 
   
   
       72 . The kit of  claim 71 , wherein the neuroprotective agent is one or more agents selected from the group consisting of an anesthetic, an anticonvulsant, an anti-apoptotic agent and an anti-inflammatory agent. 
   
   
       73 . The kit of  claim 71 , wherein the neuroprotective agent is one or more agents selected from the group consisting of a barbiturate, thiopental, pentobarbital, ketamine, an opioid, phenyloin, valproate, a caspase inhibitor, a kinase inhibitor, a mitogen-activated protein kinase inhibitor, a protease inhibitor, a calpain antagonist, a cyclosporin, FK 506, methyl prednisolone, a cyclooxygenase-2 antagonist, an antagonists of a pro-inflammatory cytokine(s), TNF-alpha, IL-1 and IL-10. 
   
   
       74 . The kit of  claim 53 , wherein the cold-flush solution comprises one or both of ATP and an inorganic phosphate. 
   
   
       75 . A cold-flush solution comprising an oxygenated, aqueous solution comprising an energy source. 
   
   
       76 . The cold-flush solution of  claim 75 , wherein the solution is between 0° and about 2° C. 
   
   
       77 . The cold-flush solution of  claim 75 , saturated with oxygen. 
   
   
       78 . The cold-flush solution of  claim 75 , contained within one of an arterial cannula and an aortic cannula. 
   
   
       79 . The cold-flush solution of  claim 75 , wherein the energy source is glucose. 
   
   
       80 . The cold-flush solution of  claim 79 , wherein the energy source is from about 0.1% w/v to about 5% dextrose. 
   
   
       81 . The cold-flush solution of  claim 79 , wherein the energy source is about 2.5% dextrose. 
   
   
       82 . The cold-flush solution of  claim 75 , wherein the cold-flush solution is oxygenated normal saline comprising the energy source. 
   
   
       83 . The cold-flush solution of  claim 75 , further comprising one or more of an antioxidant, an oxygen carrier, a drug, a perfluorocarbon, a glucose analog and an energy substrate. 
   
   
       84 . The cold-flush solution of  claim 75 , further comprising an antioxidant selected from TEMPO and TEMPOL. 
   
   
       85 . The cold-flush solution of  claim 75 , wherein the cold-flush solution is a saline solution. 
   
   
       86 . The cold-flush solution of  claim 85 , wherein the saline solution is from about 0.85% w/v to about 1.5% w/v saline. 
   
   
       87 . The cold-flush solution of  claim 85 , wherein the cold-flush solution is isotonic. 
   
   
       88 . The cold-flush solution of  claim 85 , wherein the cold-flush solution is mildly hypertonic. 
   
   
       89 . The cold-flush solution of  claim 75 , wherein the cold-flush solution is isotonic. 
   
   
       90 . The cold-flush solution of  claim 75 , wherein the cold-flush solution is mildly hypertonic. 
   
   
       91 . The cold-flush solution of  claim 75 , wherein the cold-flush solution comprises a neuroprotective agent. 
   
   
       92 . The cold-flush solution of  claim 91 , wherein the neuroprotective agent is one or more agents selected from the group consisting of an anesthetic, an anticonvulsant, an anti-apoptotic agent and an anti-inflammatory agent. 
   
   
       93 . The cold-flush solution of  claim 91 , wherein the neuroprotective agent is one or more agents selected from the group consisting of a barbiturate, thiopental, pentobarbital, ketamine, an opioid, phenyloin, valproate, a caspase inhibitor, a kinase inhibitor, a mitogen-activated protein kinase inhibitor, a protease inhibitor, a calpain antagonist, a cyclosporin, FK 506, methyl prednisolone, a cyclooxygenase-2 antagonist, an antagonists of a pro-inflammatory cytokine(s), TNF-alpha, IL-1 and IL-10. 
   
   
       94 . The cold-flush solution of  claim 75 , comprising one or both of ATP and an inorganic phosphate. 
   
   
       95 . An arterial or aortic cannula comprising an oxygenated, aqueous solution comprising an energy source, wherein the solution is between 0° and about 2° C.