Date: 19 Mar 96 00:18:15 EST From: Mike Darwin <> Subject: BPI TECH BRIEF #18 Cryopreservation of CryoCare Patient #C-2150 by Mike Darwin Introduction On December 12th, 1995 James Gallagher, a 55-year-old software developer from Sunset Beach, California, became CryoCare's first member to enter cryopreservation. He also became the first patient ever to benefit from new technologies developed to reduce three forms of injury: * pre-mortem shock * warm ischemia (the time interval between pronouncement of death and restoration of adequate blood circulation) * cold ischemia experienced during initial blood washout and cooling, and also during iced-transport from the location where legal death occurred to the facility where cryoprotective perfusion is carried out. The following is not quite a full technical report, but neither is it simply a lay-level of summary of key events without reference to the technical details and the impact those details had upon this patient's care and potentially, future patents' care. It is the aim of this report to include enough quantitative detail that direct comparisons can be drawn with previous cases. It can be argued that this is just *one* patient, that solid inferences or statistical significance cannot be established with n=1. Generally, this would be true. However, this patient's course is being compared with many other animals and humans subjected to similar protocols. Using relevant animal models over the last three years, BioPreservation, Inc. (BPI), the transport and perfusion/cool-down service provider for this patient, in conjunction with 21st Century Medicine (21st) has been evaluating aspects of the protocol used on this patient. Further, BPI and several of BPI's core technical staff have had extensive experience applying pre-mortem medication, transport, and cryoprotective perfusion protocols with patients from other cryonics organizations in the past, and also have access to relevant case data from other cryonics patients whose illness, agonal course, and time to post- arrest intervention are directly comparable with this patient's. At a minimum, we believe that the close correlation of this patient's response to that observed in the canine experiments using the same protocol, and especially when contrasted with results achieved in comparable human cryopreservation patients treated with previously used protocols (including a patient treated by BPI; ACS Patient #9577), is significant. Of particular importance is this patient's core temperature cooling data, since cooling is constrained by physical laws which are well understood, and where the predictability and simplicity of the system used to carry out cooling allows for little variation from case to case (where patient mass, body fat content and distribution, and surface area, are comparable, of course). The significance of other measured parameters in this case, such as tissue-specific enzyme release (markers of ischemic injury for specific organs and for the patient as a whole) and metabolic parameters, is presently more open to debate. However, even here we believe that the results achieved with this patient are so different from that observed in patients with comparable diagnoses and agonal courses (and in such close agreement with animal data) that careful consideration should be given to the results. Social and Medical Background The patient first contacted CryoCare (CC) on 15 July, 1995 to inquire about cryopreservation services. He was familiar with cryonics due to prior association with a contract worker whom he employed in the early 1980's who was heavily involved in cryonics. He had also read cryonics organizations' literature and met with various cryonics organization members and personnel (where cryonics was a topic of discussion) again since the early 1980s. The patient had been in-touch with several cryonics organizations before contacting CC, after being informed he was terminally ill. Formal communication with CC administration began by e- mail on 17 July and Mike Darwin, President of BPI was brought in for a cryonics consult with the patient on 20 July. At that time the patient informed BPI that he had been recently diagnosed with terminal cancer and was interested in putting cryopreservation arrangements in place. BPI questioned the patient extensively about his medical history and treatment and discovered the following relevant information: * The patient did not have health insurance and was paying for medical care piecemeal as crises or problems occurred. * The patient had not had a definitive diagnosis of cancer. After more than five months of sacral pain, the patient had been CT'ed by his family physician, and the diagnosis was presumptively based on a single CT scan of the chest and abdomen which revealed numerous solid lesions which appeared to be tumor, present in the left kidney and obliterating the left adrenal gland, and also present in the caudal lobe of the liver, and possibly the descending colon. * The patient was seeing an alternative medicine provider (a biochemist, not a physician) who told him he probably had primary cancer of the kidney (primary renal carcinoma) and prescribed a nutrient supplementation regime coupled with the administration of large doses of urea and creatinine (waste products of metabolism normally excreted by the body in the urine) purportedly to stop the spread of the cancer and convert the cancer cells back to more "normal morphology." Nutritional supplements of a wide variety but notably including co-enzyme Q10, vitamin A, beta carotene, selenium, vitamins E and C, and cesium chloride (13 g/day cesium chloride ostensibly to stimulate the immune system to attack and destroy the cancer) were also being administered. At this time Mike Darwin refused to accept the patient as a BPI client until a definitive diagnosis of terminal illness was established. The patient was told that some moderately to highly treatable cancers such as non-Hodgkin's lymphoma may appear indistinguishable on CT from other, untreatable cancers. It was also noted that on the initial radiology report (which was read to Darwin) that the radiologist reading the CT remarked on what he felt might be a mass in the posterior part of the descending colon, but was unable to tell with certainty due to the presence of feces in the bowel. The radiologist listed primary adenocarcinoma of the colon (the most common type of bowel cancer) as the number one possibility to rule out. Since the patient did not have health insurance, a variety of options was discussed to determine the nature and the treatability of the apparent malignant disease. The patient was referred to BPI's medical consultant Steven B. Harris, M.D. and the number of options was rapidly pared down. If it *was* primary renal carcinoma, the only way to definitively establish that would be to obtain a sample of the tumor using CT-guided needle biopsy or to do an "open biopsy" or lapropscopic biopsy wherein surgery is performed to open or access a body cavity with a trocar and fiberoptic scope, to inspect and directly obtain a sample of the questionable tissue. Due to the statistically comparatively low likelihood of primary renal carcinoma in a 55 year-old man (versus the likelihood of primary adenocarcinoma of the bowel), the remarks of the radiologist about the possible presence of a bowel mass on the CT scan, and the absence of health insurance, it was decided that the most cost-effective and medically most conservative way to proceed would be to have the patient undergo fiberoptic colonoscopy (direct visualization with a flexible fiberoptic viewing device) of the colon and look to see if there was any tumor present. (Common things are common; metaphorically the CT was the equivalent of loud hoof beats in the distance, and when one hears hoof beats in the Western United States one generally thinks of horses, not zebras. In this case horses = primary adenocarcinoma of the bowel). A few days later the colonoscopy was performed and our suspicions were confirmed; there was a large mass nearly obstructing the descending colon which appeared on visual inspection to be a malignancy. Dr. Harris and Mike Darwin both advised the patient that bowel obstruction by the rapidly growing tumor was imminent and that he should consider a palliative colostomy. The patient was resistant to doing this for several reasons. First, he had considerable confidence that enemas with urea, and his alternative cancer treatment regime would at least shrink the tumor (he was receiving considerable encouragement from his alternative care provider in this regard), so that surgery could be avoided. Secondly, the anticipated cost of a colostomy and associated care would jeopardize the funding the patient had set aside from his savings for cryopreservation. This created a new and difficult ethical problem for both BPI and CC. Clearly CC needed to maintain its funding minimums at a level sufficient to provide reasonable safety margins for continued cryogenic care of the patient. And, clearly, BPI is not in the charity business and has staff to pay and marginal costs to address. On the other hand, it is hardly tenable to confront a patient with the choice between foregoing cryopreservation or facing a gruesome and agonizing death from an obstructed bowel (months earlier than would be the case if colostomy or colectomy were performed) Since this patient was low on funds already (nearly $50,000 of savings having been spent on piecemeal alternative "medical" care) he had already agreed to the use of new procedures and to the biopsying of his brain in exchange for reducing the basic cost of BPI's procedures. Confronted with this new situation, BPI reduced its charge to below the break-even level and the patient volunteered to cooperate with what then constituted extraordinary antemortem monitoring. This was the first time BPI, CC, or, to our knowledge, any cryonics organization has been faced with a situation where a patient (and his cryonics organizations) was confronted with a choice between reasonable standard of care (avoiding a serious, life shortening, and definitely quality- of-life reducing complication of the illness), and being cryopreserved. This was deeply disturbing for all involved, and merits intense discussion in the immediate future, not just by CC and BPI, but by the cryonics community as a whole. While it is inappropriate to belabor this point here, this case points up that increasingly cryonics organizations will be dealing with both members and non-members who have no health insurance (not even HMO coverage), no access to government healthcare such Medicaid, Medicare or VA care, and/or who have limited access to health care with HMO, PSO, PPO or other care which forces them to make major quality of life or length of life decisions based on use of their non- healthcare allocated funds such as savings, property equity, and even accumulated cash value or resale value of life insurance policies--including those specifically earmarked for cryonics. Further, in some cases the state, acting through the courts, may appropriate these assets at the request of guardians or relatives. The issues raised by the inevitability of a massive restructuring of health care cost and availability in the United States which is occurring now, should be considered now. This case should serve as a sentinel in this respect. A few days after his colonoscopy, the patient began to experience symptoms of bowel obstruction (increased anorexia, nausea, shot-gun pellet stool, vomiting and abdominal distention), and so a double-barreled colostomy was performed on 29 July. This procedure was uneventful and the patient returned home where he was cared for by his sister, his brother-in-law and his nephew. The patient continued with his alternative medicine regime, although, due to increasing nausea, he abandoned use of the cesium chloride. At this point BPI became disengaged from close involvement with the case over issues related to funding details. This was an issue between the patient and CC, and until the patient became a fully signed-up CC cryopreservation member, it was inappropriate for BPI to be as closely involved. As financial negotiations proceeded favorably, BPI again became involved and made a home visit on 15 October with medical advisor Dr. Harris and BPI staff members Carlotta Pengelley, LVN, Joan O'Farrell, Sandra Russell, and Mike Darwin also present. The purpose of this visit was to evaluate the home for logistics of access (it was a second- story apartment with outside stair-access only) and equipment set-up, meet the family and prepare them for the reality of transport, assure the patient's medical and pain control needs were being met, encourage the patient to enroll in home hospice, and to carefully medically examine the patient in order to determine "staging" or likely time-course to legal death for cryonics reasons. Dr. Harris examined the patient thoroughly during this visit and baseline blood chemistries were drawn, including samples collected, spun-down and frozen to dry ice temperature on-site for subsequent baseline antioxidant and lactate levels (the former to be done by Pantox Labs of San Diego, CA) as well as for a routine chemistry panel an a screening for infectious diseases. During this visit Dr. Harris noted that the patient had right leg weakness (barely noticeable) a right visual field cut (right homonymous hemianopia), nausea and anorexia (lack of appetite) and that he weighed 73.1 kg down from a previous healthy weight of 86-88 kg. Careful history taking also disclosed recent (2 weeks duration) inability to read, which the patient attributed to lack of ability to concentrate, and urinary incontinence. The patient was noted to have cancer wasting syndrome and complained of severe back pain of eight months duration. Further, Dr. Harris felt it very likely the now nearly immobilizing back pain (the patient was constrained to lie face down on a specially modified cot most of the time) was due to involvement of the sacrum with metastatic disease. Dr. Harris' presumptive diagnoses at the conclusion of the home visit were probable large metastases (4-6 cm) of the primary colon cancer to the left occipital lobe of the brain which was likely responsible for the right-sided visual field cut, weakness, and incontinence. Probable metastatic involvement of the sacrum was assumed, with resulting uncontrolled bone pain. Further presumptive diagnoses were tumor necrosis factor (TNF) and related cytokine cancer wasting syndrome, and poor nutritional status (calorie count estimated at 1500 kcal/day or less). The family was urged to take the patient to an imaging center and have an MRI or CT of the head done to rule out malignant involvement of the brain (the patient's family was informed of the high probability of the metastasis, but the patient at this time was not). A CT scan with and without contrast was performed on 17 October and a 6cm mass was indeed found in the left occipital lobe of the brain. Dr. Harris, in conjunction with the patient's newly acquired primary care physician persuaded the patient that it was imperative that he undergo palliative radiotherapy to his head and to his sacrum (lower back). The patient was resistant to undergoing this treatment because of his disdain for "radiation treatment of cancer" and because of his concerns about possible damage to his brain from the radiation which might compromise his chances for good cryopreservation. Dr. Harris was instrumental in convincing the patient to get palliative radiation treatment. He explained that failure to do so would result in hemiplegia (paralysis on one side) possible loss of speech, complete incontinence of bladder and stool, and likely death from elevated intracranial pressure which might very likely expose his higher brain to extended periods of periods of minimal or absent blood flow (ischemia) for hours prior to cardio- respiratory arrest and pronouncement of legal death. The consequences of unchecked growth of an aggressive malignant tumor in the brain, versus the by comparison trivial effect of palliative radiotherapy (increased sleepiness and fatigue, hair loss and modest compromise of short-term memory) were emphasized. (In cases of metastatic brain disease the entire brain is usually radiated both to hold down the costs associated with shielding and selective irradiation of the tumor, and, more importantly, to "head off" the proliferation of other metastases; where you see one seed sprouting there are likely other to be others germinating. Whole brain irradiation decreases the likelihood of secondary tumors developing in a patient who is terminal with aggressive malignant disease). The patient had previously been scheduled to have a chronic intrathecal line placed into his lumbar spine for delivery of chronic intrathecal morphine by pump for chronic pain control, and on 16 October, this was done. Within 48 hours, however, the patient was unable to walk, and was admitted to the hospital. There, neurological exam showed profound bilateral leg weakness and normal spinal fluid. X- rays also showed a metastatic lytic lesion to the right sacrum, with possible nerve compression to the right leg. The neurologist examining the patient for the first time thought that the new weakness was due to cauda-equina compression syndrome from tumor; and rejected the idea, put forth by Dr. Harris, that the very rapid onset of weakness coupled with the relationship to the intrathecal line placement, made that procedure suspect. Dr. Harris, however, was able to convince the patient's primary physician of this possibility, and the intrathecal morphine was discontinued. Within a day the patient recovered use of his legs, but a definitive diagnosis of the problem was never made. He continued for the rest of his course, however, on morphine delivered via peripheral line. During hospitalization for the leg problem, the patient was seen by a radiotherapist, and radiotreatment to his brain and sacrum was initiated. In particular, he underwent 10 fractionated doses of palliative radiotherapy to his head, with 4,000 rads (cGy) to the whole brain and a 10,000 rad boost to the tumor. The patient was also enrolled in a good Home Hospice program which did much to help the family by providing basic care advice and improved pain management. Financial negotiations between the patient, the patient's representative family member and CC continued (with some last-minute input from BPI) and the patient became a fully funded CC cryopreservation member on 7 November, 1995. On 5 November the patient spoke with Dr. Harris by phone and reported himself as being very depressed and wishing to withdraw from the program of anti-TNF and immune stimulating drugs the patient had been started on after the withdrawal of the alternative medicine practitioner. Dr. Harris noted that the patient sounded sort of breath (dyspneic) on the phone and asked the patient if he was, which the patient denied. That evening the patient was transported to the emergency department (ED) of a nearby hospital acutely short of breath and panicky with air hunger. The paramedics who carried out the transport noted that the patient had diminished breath sounds on the right side nearly to the base of the right lung, and began oxygen at 2 liters per minute (LPM) during transport. When the patient was examined in the ED the ED physician said he could find no diminished breath sounds, stopped the oxygen, waited "a few minutes," noted the patient's oxygen saturation by pulse oximetry was 96%, and told him to go home. At that point Dr. Harris spoke with the ED physician and requested that arterial blood gases be drawn and a chest X-ray be taken. This was a medically sound request for several reasons: first, it would help establish the basis of the patient's shortness of breath and determine if palliative oxygen therapy should be considered to reduce or eliminate "air hunger." Or, failing relief of air hunger with oxygen supplementation, increase the degree of sedation to make the patient more comfortable. Second, from a cryonics standpoint it was important to know if the patient was experiencing a complication or exacerbation of the primary disease (such as pneumonia; a big risk here since the brain tumor required immunosuppressively high doses of dexamethasone to control intracranial pressure) which would justify deployment of the standby team. The ED physician politely but firmly brushed off Dr. Harris' request (even though the patient was willing to pay for the requested tests in cash) and sent the patient home. During the trip home the patient again became acutely dyspneic and spent the night miserable and panicky with air hunger. The next morning the patient's HMO waiting period was up (he had HMO coverage available regardless of pre-existing illness, but only after a waiting period) and the patient was again transported by ambulance, this time to the office of the internist employed by the HMO. The physician lifted the blanket, looked at the patient, informed the patient that "pneumonia was the cancer patient's friend," further informed the patient that he had end-stage cancer, and sent the patient home, *again without oxygen*. At this point Dr. Harris intervened and arranged for palliative oxygen therapy in conjunction with the patient's private physician. The following weeks saw an up and down course for the patient. The radiotherapy restored his vision and ability to work initially, and he experienced much less bone pain. (Prior to this time the patient had worked as a consulting programmer on a part-time basis as his illness had permitted.) However, he continued to lose weight and eventually began to experience intermittent but progressive dyspnea, constant nausea with occasional vomiting, and exogenous depression associated with clearly deteriorating quality of life. Finally, he became unable to work once again. The patient was now receiving more or less continuous IV morphine administered peripherally through a strap-on battery-operated pump. The day after Thanksgiving, 24 November, a second home visit by BPI staff (without Dr. Harris) was carried out for the purpose of collecting baseline cerebral functioning monitoring (CFM) data and evaluating the patient's condition first hand. The patient was noted to appear slightly more wasted, to be largely oxygen dependent, but to have well managed pain and to be ambulatory for hygiene, and limited socialization. Baseline EKG and CFM data were collected and the patient's feelings and thoughts about cryopreservation, and his informed consent were videotaped. An unfortunate and unexpected sequelae to this visit was that one of the BPI team members was infected with influenza A and unaware of it at the time of the visit. Within 48 hours of the visit the patient was febrile (39 degrees C), severely dyspneic, and suffering profound malaise and myalgia. The patient called BPI to report he was ill and the hospice nurse was called in to evaluate breath sounds and consult with BPI's medical advisor (Harris). The hospice nurse reported no change in breath sounds, no cough and no evidence of pneumonia, but rather a febrile illness with myalgia consistent with the flu. It was explained to the patient that he probably had early influenza (onset of symptoms was that AM) and that this could probably be treated with combination anti viral drugs and an antibiotic to protect against secondary infection. Alternatively, the patient was told he could elect to refuse treatment which would carry with it the likelihood of death from pneumonia or some other inter-current infection. These choices were reviewed with the patient because of the patient's prior, repeatedly stated desire to refuse further life-extending care, including refusal to see a pulmonologist and oncologist to evaluate the cause of the dyspnea and perhaps treat it, if it was secondary to tumor-related compression of a large bronchus. (Such treatment can be simply carried out with additional localized radiotherapy, or even laser ablation of tumor growing into a bronchus.) The patient decided to accept treatment for the influenza infection and was started on p.o. (oral) ribavirin 400 mg q. 8 hours, and 100 mg b.i.d. rimantidine, an antiviral specific for influenza A. Antibiotic prophylaxis for secondary infection was instituted with doxycycline 100 mg b.i.d. There was prompt improvement in symptoms and signs of the illness with the patient becoming afebrile in less than 24 hours from the start of treatment with antivirals and antibiotic. During the closing days of November the patient experienced the typical interleaving of relatively "good" days with progressively worse and more frequent "bad " days. The patient's p.o. medications at this time were: aspirin 1.25 grain, p.o., daily co-enzyme Q10, 100 mg p.o. t.i.d. dexamethasone, 4 mg t.i.d. doxycycline, 100 mg, b.i.d. d-alpha tocopherol, 1,000 I.U., t.i.d. ascorbic acid, 1 g t.i.d. phenytoin (Parke Davis), 300 mg q.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 END OF PART OF BPI TECH BRIEF #18