X-Message-Number: 7594 Date: Wed, 29 Jan 1997 17:35:53 -0500 (EST) From: Charles Platt <> Subject: Cryopreservation report (part 1b) Mike Darwin has asked me to post his report of the cryopreservation of CryoCare's first patient, James Gallagher. Part One of this report was first published in CryoCare Report number 6. Part Two appeared in issue number 9. Many photographs and charts appeared in the printed version and cannot be reproduced here. Subscriptions to CryoCare Report are available for $9 (four issues) per year. Because this text is long, I am dividing it into subsections. Thus Part 1 will be posted as Part 1a, Part 1b, and Part 1c. Part Two will be posted as Part 2a and Part 2b. --Charles Platt CryoCare ------------------------------------------------------------- Part 1b Decision to Terminate Life Support At the beginning of December the patient became increasingly oxygen dependent and began experiencing a return of visual disturbances which were prodromal to his prior homonymous hemianopia. He also experienced a return of urinary incontinence. The patient expressed justifiable concern that the original brain metastases, or another, was again beginning to cause problems, or that structures adjacent to the tumor were experiencing the un-typical delayed death as a result of the high dose radiation to which they were exposed. Further, the nausea which had been present since shortly after the illness was diagnosed was now more or less constant with occasional vomiting. Attempts at pharmacologic control of the nausea using hydroxyzine, chlorpromazine, compazine, ginger, and tetrahydrocannabinol (THC) were unsuccessful. During the first days of December the patient repeatedly contacted BPI and expressed a desire to withdraw from palliative oxygen and to abruptly stop steroids and "get it over with." He explained that his quality of life was no longer acceptable, and that he wished to take action to end his life in a legal manner before the quality deteriorated further, and especially before he became unable to exercise choice in the matter. Unfortunately, while the patient had responded well to prompt anti-viral therapy for influenza, two of the team members were ill with the flu and with the non-bacterial bronchitis which accompanied it. Complicating matters further was the illness (again with the flu) of one of the team members' two small children. The patient was told that while we would respond if he was set upon immediate implementation of this course of action, optimum response would best be had by delaying a week or so longer in order to give team members time to recover and to permit final set-up of equipment in the home and last minute preparations to be made. When staff were largely recovered, a window of time was agreed for discontinuation of life support. The patient's private primary care physician (not involved with BPI) was closely involved in this decision, and advised BPI that he felt withdrawal of oxygen would result in rapid decompensation and cardiovascular collapse. He said he felt the patient was making an informed and "rational" choice (i.e., he saw no indication of compromising psychiatric illness, organic brain disorder, or undue influence). The physician commented that he was comfortable with the patient's decision since the patient had repeatedly told him he would have withdrawn from life support far earlier had it not been for his cryopreservation arrangements. The physician expressed a willingness to be present when the patient discontinued life support and to pronounce legal death. Further, the physician ordered that a Hickman catheter be implanted in the patient to facilitate administration of pain medication (his peripheral veins were "exhausted" from repeated sticks and catheter placement). BPI requested that the catheter be a large-bore Hickman to facilitate rapid, low resistance of transport medications, and the physician agreed to this request. During the weekend of 9-10 December the patient's home was fully prepared for standby and transport. The Mobile Advanced Life Support System (MALSS) was set up in the living room and the extracorporeal circuit strung. An operating room light was put in place, back tables were set up and instrument trays and ancillary supplies were laid out and readied. Specialized monitoring equipment for blood pressure, cerebral function, pulse oximetry, and acute lab collection (blood gases) was also put in place. The CDI point-of-care in-line blood gas system was also set up next the MALSS and the monitoring cells cut into the arterial and venous lines of the extracorporeal circuit to allow for continuous acquisition of blood gas data during initial bypass-assisted cooling, and during blood washout and replacement with 21CMBP-002 flush-store solution. The patient's physician was then consulted about the possibility of administering pre-cryopreservation medications to reduce the insult from the agonal hypoperfusion/hypoxia and post-pronouncement ischemia which would necessarily occur prior to mechanical restoration of circulation and breathing during transport by BPI. The physician reviewed the medications suggested and agreed to prescribe all those available in the U.S. and Mexico. The patient had made arrangements through an AIDS buyers' club to obtain other medications which he believed would be efficacious in helping to ameliorate ischemic injury. These were largely drugs which 21st Century Medicine animal research had shown to be cerebro-protective if given before the ischemic insult. The following schedule of pre-cryopreservation medication was begun by the patient on 10 December, 1995: Medications for 10 December: aspirin, 1.25 grain, p.o., daily ascorbic acid, 1 g t.i.d. N-t-butyl-a-phenylnitrone, 500 mg, p.o. with evening meal sodium selenite, 1000 mcg selenium p.o. co-enzyme Q10, 100 mg p.o. t.i.d. dexamethasone, 4 mg p.o. t.i.d. doxycycline, 100 mg p.o. d-alpha tocopherol, 1,000 IU, t.i.d. phenytoin (Parke Davis), 100 mg, t.i.d. morphine sulfate by IV pump p.r.n. for pain. 50 mg thalidomide, p.o. before retiring 10 mg melatonin, p.o. before retiring Medications for 11 December: aspirin, 1.25 grain, p.o., daily ascorbic acid, 1 g t.i.d. piracetam 800 mg p.o. at 10:00 N-t-butyl-a-phenylnitrone, 1g mg, p.o. with evening meal sodium selenite, 1000 mcg selenium p.o. co-enzyme Q10, 100 mg p.o. t.i.d. dexamethasone, 4 mg t.i.d. doxycycline, 100 mg, t.i.d. d-alpha tocopherol, 1,000 IU , t.i.d. phenytoin (Parke Davis), 100 mg, t.i.d. morphine sulfate by IV pump p.r.n. for pain. 50 mg thalidomide, p.o. before retiring 10 mg melatonin, p.o. before retiring Patient agreed to take no solid food after 11 December at 2400 since it was his decision to withdraw life support the following afternoon. Medications for 12 December: aspirin, 1.25 grain, p.o., daily ascorbic acid, 1 g t.i.d. N-t-butyl-a-phenylnitrone, 1 g, p.o. with evening meal sodium selenite, 1000 mcg p.o. co-enzyme Q10, 100 mg p.o. t.i.d. dexamethasone, 4 mg t.i.d. doxycycline, 100 mg , t.i.d. d-alpha tocopherol, 1,000 IU , t.i.d. phenytoin (Parke Davis), 100 mg, at 100 and 1600 morphine sulfate by IV pump p.r.n. for pain. misoprostol, 100 micrograms at 1600 melatonin, 50 mg, p.o. at 1900 prilosec, 20 mg, p.o. at 1900 800 mg ibuprofen at 1900 phenytoin, 500 mg, p.o. at 1900 Maalox, 60 cc p.o. immediately before discontinuing oxygen. The patient obtained on his own, and self-administered without assistance at about 2100 through his implanted Hickman catheter, 250 cc of Dextran 40 in normal saline (Baxter, Irvine, CA) containing 1 mg of Nimodipine (A.G. Bayer, Germany), 40,000 IU of sodium heparin and 5 grams of a proprietary agent developed by 21st Century Medicine. This latter agent will be hereinafter referred to as 21CM-006; it was developed to protect against ischemic injury, up-regulate the efficacy of anaerobic metabolism, and ameliorate V/Q mismatch (where blood flows through unventilated area of lung and thus does not get oxygenated) and prevent loss off normal vasomotion (where blood delivered to the tissues is not distributed to the capillaries properly resulting in "shunting" and failure of delivery of oxygen and nutrients to the tissues in shock) concurrent with discontinuing high flow oxygen support (8-10 LPM by mask with reservoir bag: FIO2 was ca. 80-90%). A final conversation was had with the patient at about 1900 at which time he was repeatedly advised that he could change his mind without any problem to BPI and that he should feel no pressure to pursue this course of action. His response was: "You don't understand. This is easy. The hard thing would be taking one more day of life like this." The patient appeared in good spirits and laughed and joked with family and team members. He explained that he had accepted he was either to die or recover from cryopreservation, and that either way he was fully prepared and psychologically ready. He had played a card game with family and friends that afternoon, and explained that while he was a little apprehensive, he intended to take some alprazolam (Xanax) and get ready for the journey ahead. Several BPI team members spoke with the patient privately and said their good-byes. Cardiopulmonary Arrest At the request of the patient and his family (for reasons of intimacy; saying farewells etc., and basic privacy) the entire BPI team withdrew to the BPI transport vehicle parked outside the patient's apartment. The patient's attending and primary care physician remained with the patient and the patient's family to supervise withdrawal of life support, assure adequate palliation of air hunger and discomfort, and promptly pronounce legal death. BPI personnel were to be summoned immediately after pronouncement by cell phone (four BPI personnel had cell phones!). At approximately 22:50, the patient discontinued oxygen. He had taken approximately 3 mg of alprazolam about an hour before discontinuing oxygen, and he had access to self- administered morphine (pump limited boluses) to ease air hunger. It was reported that the patient rapidly lost consciousness on withdrawal of oxygen and experienced cardiopulmonary arrest at 2311 on 12 December, 1995. Transport Phase 1: CPR, Medication, External, Initial Cooling Intubation was accomplished at 23:13 by Dr. Harris, and "Active Compression-Decompression-High-Impulse CPR" (ACDC- HICPR), using a custom built Michigan Instruments "Thumper" mechanical chest compressor, was initiated at 23:14. A standard Ambu ACDC silastic suction cup was used on the Thumper to achieve the ACDC component of the ACDC-HICPR. Placement of a tympanic temperature probe was achieved concurrent with intubation (during securing of the endotracheal tube). The initial tympanic temperature reading was 36.8 degrees C. [missing figure] Tympanic (eardrum) temperatures were used in this patient because it is well established that tympanic temperature reflects true brain temperature since the blood supply for the eardrum and midrain and cerebral cortex are the same. Typmanic temperature is thus a much more reliable measure of the temperature of the iorgan we are *most* interested in preserving (the brain) than are esophageal or rectal temperatures. Further, work with dogs at 21st has established a far closer correlation between tympanic temperature and actual measured brain temperature (via invasive probes) than esophageal or rectal temperatures Family and friends had begun icing the patient at the time of pronouncement (legs, abdomen and lower thorax; leaving the head unencumbered so that airway management could be instituted before icing) and the head, thorax and axilla were iced concurrent with the start of cardiopulmonary support. Simultaneous with the start of external cooling, a Darwin rectal thermocouple probe was placed in the descending leg of the double barreled colostomy and the 60 cc balloon inflated to anchor it in place. A Darwin colonic lavage tube with a 60 cc silastic balloon and fenestrated tip was also inserted in the stoma of the ascending end of the colostomy, and the balloon on the lavage tube was also inflated to anchor it into the ascending colon. [missing figures] Immediately thereafter a stab wound was made (using sterile technique) through the medial aspect of the right external oblique muscle 3 cm to the right of the navel, at the level of the iliac crest. The stab wound was rapidly extended in depth by blunt dissection with Metzenbaum scissors (Mets) until the peritoneum was reached, and a 1 cm incision was made in the peritoneum with Mets and a Darwin peritoneal lavage tube was inserted and its 60 cc silastic balloon rapidly inflated to seal and anchor it in place. Once all lavage tubes were in place the patient's ascending, transverse colon, and terminal ileum were irrigated with 2 liters of iced Normosol-R, pH 7.4, and the peritoneal cavity was irrigated with 4 more liters of this solution (Abbott Pharmaceuticals, Chicago, IL). Reservoirs connected to the colonic and peritoneal lavage tubes were placed on the floor and the lavage fluid was allowed to drain into the respective bags by gravity. The first pulse oximetry and end-tidal CO2 readings were obtained at 23:16 and were 95% and 5% respectively. Wave form acquisition on the pulse oximeter was excellent and the pulse rate of 80 per minute correlated exactly with the action of the Thumper. At 23:19 the patient's tympanic and descending colon temperatures had declined to 29.8 degrees C. By 23:20 the descending colon temperature had rebounded to 34 degrees C. At 23:21 the peritoneum was lavaged with 2 additional liters of iced Normosol. At 23:22 the tympanic temperature was 28.7 degrees C and the descending colon temperature was 28.6 degrees C. Oxygen saturation at that time was 93%, and End tidal CO2 (EtCO2) was 4%. Administration of Transport Medications began at 23:12 and was as follows: Epinephrine 12.6 mg, 23:12, IV push (given to support blood pressure during CPR). The drug 21CM-005 3.15 g, IV push, 23:16, (This drug is a proprietary compound given to inhibit lactic acidosis and increase the efficacy of anaerobic metabolism). 3.15 g of 21CM-005 contains approximately 40 mEq of potassium, an amount sufficient to preclude restoration of spontaneous cardiac activity. Soporate (21CM-004) 6.30 g IV push, 23:12 (Soporate is a proprietary compound given to inhibit excito-toxicity in a class of brain receptors found to be critical in mediating cerebral re-perfusion injury in dogs following 12+ minutes of global cerebral ischemia using a cardiac arrest model. The drug also acts as a general anesthetic preventing patient's from regaining consciousness during cardiopulmonary support.) 21CM-005 6.30 g IV push, 23:12 (see above for explanation of the pharmacology of this agent). Oxynil (21CM-003) 630 mg IV push, 23:13 (Oxynil is a proprietary agent which has been shown to ameliorate brain ischemia in dogs by its free radical trapping ability. It is useful primarily as an adjunct and potentiator of other antioxidant medications). 21CM-002 100 ml; 50 ml IV push, 50 ml over ca. 10 minutes. Push dose given at 23:15, infusion completed at 23:28. (21CM-002 is a cremophor emulsion (micellized) mixture of two proprietary antioxidants which rapidly cross the blood brain barrier. One of these antioxidants crosses mitochondrial membranes rapidly and prevents failure of high energy metabolism in neuron and glial cells following re- perfusion after global ischemic injury in dogs of 12+ minutes duration). Deferoxamine 2g was added to the mannitol infusion (126 g mannitol as 20% solution in water). Mannitol infusion was begun at 23:32 and concluded at 23:40. Exiquell (21CM-005) 315 mg IV push. (Exiquell is a proprietary agent used to inhibit the quaint-quisqualate receptor system which is a significant source of excito- toxicity following global cerebral ischemia in the dog.) THAM (tromethamine) 15.75 g in 250 cc (50 cc IV push), with the balance by IV infusion, 23:18 Mannitol (see Deferoxamine above). Pavulon (pancuronium bromide) 2 mg, 23:16, to inhibit shivering and prevent return of spontaneous respiration. Methylprednisolone 1 g IV infusion over a minimum of 5 minutes, begun 23:16, ended, 23:20. Cipro IV (ciprofloxacin; antibiotic causing no cold agglutination) 400 mg IV infusion given slowly between 23:16 and 23:30. Dextran 40 (Gentran) in 10% saline, 500 cc. Administration of all transport medications to this patient was completed at 23:40. The first blood sample for gases, chemistries and electrolytes could not be collected until after the conclusion of medication administration. A central venous sample was collected via the patient's Hickman line at 23:50 on 13 December and yielded the following results: ------------------------------------------------------------- End of Part 1b Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=7594