James Gallagher in 1988
Note: This extensive and informative report is from CryoCare Report Number 6, January 1996, and CryoCare Report Number 9, October 1996. This is the first online version that is complete with all figures and graphs which were made available courtesy of Mike Darwin and Charles Platt. This patient was the first to be cryopreserved by CryoCare, which is no longer in business. The patient (now designated as A-1871) was transferred to Alcor on January 24, 2001.
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:
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.
James Gallagher in 1994
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:
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 as 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
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.
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.
Final preparations for the patient's transport are underway. Carlotta Pangelley, L.V.N. (right) draws up transport medications, Mike Darwin (left) begins preparations to prime the extracorporeal circuit of the Mobile Advanced Life Support System (MALSS) as Sandra Russell looks on. The metal object anchored by guy wires at front, center is a field operating light.
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.
Tympanic temperature monitoring assembly of the type developed by BioPreservation.
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.
Rectal thermocouuple probe of the type developed by BioPreservation.
Colonic lavage tube, developed by BioPreservation, accelerates the rate of cooling by allowing a cold solution to be administered directly to the patient's colon and/or abdominal cavity.
Mike Fletcher, C.R.T. (left) holds up peritoneal lavage bag containing chilled, buffered Normosol-R as transport begins. The patient is in the ice bath of the MALSS and is undergoing ACD-CPR as well as external cooling.
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:
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:
Tympanic Temperature: 25.7 degrees C, Descending Colon Temperature 19.0 degrees C
|pH||7.34||7.35 (mean) |
|pCO2||52.4 mmHg||45-55 |
|pO2||37.0 mmHg||40-50 |
|O2 Sat||89%||70-75 |
|BUN||15.0 mg/dl||7-25 |
|Creatinine||1.1 mg/dl||0.7-1.4 |
|Sodium||120 mEq/l||135-146 |
|Potassium||5.5 mEq/l||3.5-5.3 |
|Chloride||82 mEq/l||95-108 |
|Magnesium||1.7 mEq/l||1.2-2.0 |
|Calcium||7.2 mg/dl||8.5-10.3 |
|Phosphorus||7.8 mg/dl||2.4-4.5 |
|Protein, Total||5.8 g/dl||6.0-8.5 |
|Glucose||251 mg/dl||70-125 |
|Bilirubin,Total||0.8 mg/dl||0.0-1.3 |
|Alk Phosphatase||76 U/L||20-125 |
|LDH, Total||227 U/L||0-250 |
|GGT||58 U/L||0-65 |
|AST||101 U/L||0-42 |
|ALT||69 U/L||0-48 |
|Uric Acid||0.5 mg/dl||4.0-8.5 |
|Iron, Total||138 mcg/dl||25-170 |
|Iron Binding Capacity||748 mcg/dl||200-450 |
|% Saturation||18||12-57 |
The next central venous blood sample collected during CPR at 0020 on 13 December, yielded the following results:
Tympanic Temperature: 23.0 degrees C, Descending Colon Temperature13.8 degrees C
|pH||7.115||7.35 (mean) |
|pCO2||27.8 mmHg||45-55 |
|pO2||35.1 mmHg||40-50 |
|O2 Sat||88%||70-75 |
|BUN||17.0 mg/dl||7-25 |
|Creatinine||1.1 mg/dl||0.7-1.4 |
|Sodium||132 mEq/l||135-146 |
|Potassium||4.3 mEq/l||3.5-5.3 |
|Chloride||91 mEq/l||95-108 |
|Magnesium||1.8 mEq/l||1.2-2.0 |
|Calcium||7.8 mg/dl||8.5-10.3 |
|Phosphorus||9.9 mg/dl||2.4-4.5 |
|Protein, Total||3.4 g/dl||6.0-8.5 |
|Glucose||300 mg/dl||70-125 |
|Bilirubin, Total||1.1 mg/dl||0.0-1.3 |
|Alkaline Phosphatase||92 U/L||20-125 |
|LDH, Total||376U/L||0-250 |
|GGT||69 U/L||0-65 |
|AST||182 U/L||0-42 |
|ALT||126 U/L||0-48 |
|Uric Acid||0.5 mg/dl||4.0-8.5 |
|Iron, Total||177 mcg/dl||25-170 |
|Iron Binding Capacity||779 mcg/dl||200-450 |
|% Saturation||18||12-57 |
At 0050 another central venous sample was collected from the Hickman catheter and revealed the following results:
Tympanic Temperature: 21. degrees C, Descending Colon Temperature 9.9 degrees C
|pH||7.087||7.35 (mean) |
|pCO2||25.2 mmHg||45-55 |
|pO2||39.2 mmHg||40-50 |
|O2 Sat||91%||70-75 |
|BUN||17.0 mg/dl||7-25 |
|Creatinine||1.0 mg/dl||0.7-1.4 |
|Sodium||134 mEq/l||135-146 |
|Potassium||4.9 mEq/l||3.5-5.3 |
|Chloride||91 mEq/l||95-108 |
|Magnesium||1.9 mEq/l||1.2-2.0 |
|Calcium||7.9 mg/dl||8.5-10.3 |
|Phosphorus||10.6 mg/dl||2.4-4.5 |
|Protein, Total||3.5 g/dl||6.0-8.5 |
|Glucose||308 mg/dl||70-125 |
|Bilirubin, Total||1.1 mg/dl||0.0-1.3 |
|Alkaline Phosphatase||91 U/L||20-125 |
|LDH, Total||366 U/L||0-250 |
|GGT||69 U/L||0-65 |
|AST||204 U/L||0-42 |
|ALT||140 U/L||0-48 |
|Uric Acid||0.5 mg/dl||4.0-8.5 |
|Iron, Total||179 mcg/dl||25-170 |
|Iron Binding Capacity||778 mcg/dl||200-450 |
|% Saturation||23||12-57 |
The final central venous sample taken during CPR was at 01:20 on 13 December and yielded the following results:
Tympanic Temperature: 19.3. C, Descending Colon Temperature 7.5 degrees C
|pH||7.047||7.35 (mean) |
|pCO2||23.7 mmHg||45-55 |
|O2 Sat||98.1%||70-75 |
|BUN||17.0 mg/dl||7-25 |
|Creatinine||1.0 mg/dl||0.7-1.4 |
|Sodium||133 mEq/l||135-146 |
|Chloride||92 mEq/l||95-108 |
|Magnesium||1.9 mEq/l||1.2-2.0 |
|Calcium||7.9 mg/dl||8.5-10.3 |
|Phosphorus||11.3 mg/dl||2.4-4.5 |
|Protein, Total||3.5 g/dl||6.0-8.5 |
|Glucose||364 mg/dl||70-125 |
|Bilirubin, Total||1.2 mg/dl||0.0-1.3 |
|Alkaline Phosphatase||92 U/L||20-125 |
|LDH, Total||380 U/L||0-250 |
|GGT||69 U/L||0-65 |
|AST||214 U/L||0-42 |
|ALT||148 U/L||0-48 |
|Uric Acid||0.5 mg/dl||4.0-8.5 |
|Iron, Total||178 mcg/dl||25-170 |
|Iron Binding Capacity||777 mcg/dl||200-450 |
|% Saturation||23||12-57 |
From the laboratory and temperature data above, several important conclusions can be drawn, particularly when taken in the context of the protocol used in this case, in comparison with results obtained in two previous cases which compare with this one closely (Alcor patient A-1260, and ACS patient 9577).
Direct comparisons of many of the parameters in these two cases is not possible owning to absence of data in the previous cases. For instance, in patient A-1260 no temperature data was acquired until 32 minutes after cardiac arrest. Thus, a direct comparison between cooling rates during (say) the critical first 10 minutes post arrest is not possible here. However, comparisons can still be made where data does exist at corresponding intervals.
These three patients are of particular interest to compare because they match each other closely in sex, weight, fat distribution, and body surface areas, and they are of reasonably close ages. All patients were cooled at a minimum using a portable ice bath and ice-water circulating pump/distribution assembly (two with identical equipment). All patients had cooling and CPR begun within 2-4 minutes of cardiopulmonary arrest, and all were promptly medicated using the specified protocol. It is also important to note that all patients died of illnesses, two of AIDS and one of disseminated cancer, which left them cachectic and which involved compromise to multiple organ systems. One notable difference was the prolonged agonal course of ACS-9577 compared to the other two patients, and the poor response to cardiopulmonary support this patient exhibited, probably as a result of the antemortem ischemic injury and pulmonary compromise.
Data from one other patient, A-1049, a 32.8 kg severely wasted patient who arrested from dehydration secondary to end-stage adenocarcinoma of the lung, is also relevant. This patient is included since her mass and fat content/distribution and response to cardiopulmonary support were the most favorable of any patient cryopreserved by comparable methods available to this author. This patient thus serves as "best-case" for the efficacy of previously used methods of cooling, medication and CPR.
Comparison of Cooling Rates of Four Cryopreservation Cases
|Cardiopulmonary Response Score||****||**||[zero]||***|
|Surface Area (square meters)||1.85||1.87||1.725||1.21|
|Cooling rate (°C/min) First 10 minutes||1.05||N/A||0.175||0.32|
|Cooling rate (°C/min) First 30 minutes||0.56||0.24||0.21||0.38|
A critical determining factor in how well a patient will cool during transport in addition to surface area, mass and fat quantity and distribution (fat is a good insulator) is the adequacy of blood circulation. Warm blood being delivered to the surface of the body and to structures with good surface to volume ratios that facilitate good exchange (such as fingers, toes, arms, and legs) will clearly be superior in patients with good cardiac output. The patient's antemortem condition will be a major factor in determining how well s/he will respond to CPR. However, also of great importance is the use of highly efficient means of CPR and the use of drugs which prevent shunting of blood away from tissues that need it, and which prevent shunting of blood through parts of the lung which are fluid filled or not able to exchabfe oxygen. No doubt part, but by no means all of the superior cooling results observed in this patient were as a result of better perfusion during CPR.
As can be seen from the table above, patient C-2150, the subject of this report, cooled at a rate of approximately 1 degree C/min during the first ten minutes post arrest, and at a rate of 0.56 degrees C/min for the entire 30 minute period after arrest. This is a rate twice that of a patient with roughly half his mass and with far less subcutaneous fat during the first 10 minutes post arrest, and twice that at 30 minutes post arrest. It is also interesting to note that the 30-minute post arrest cooling rates of all three other patients are well below 0.5 degrees C/min., and are in close agreement (0.24 and 0.21) for the two patients whose mass, fat distribution and surface area most closely approximate those of this patient.
We believe that this patient experienced such superior rates of cooling—indeed, rates achieveable in a patient of his surface area only with extracorporeal (blood/body core) cooling—because of the following factors:
The use of these modalaties and the cooling rates achievable with them was established in dog lab. Further, other cooling approaches such as the use of ice-slush lavages in stomach, inaddition to the colon and peritoneum, and the addition of liquid ventilation (using perfluburon chilled to 0-2 degrees C) or subzero jet gas ventilation, are currently under investigation (and patent) and may provide for cooling rates approach 1.5 to 2.0 degrees C per minute if added to the modalities used in this patient.
Administration of all transport medications to this patient was completed at 2340.
Surgery to raise the right femoral artery and vein was begun at 23:30 following standard prep of the right groin with Betadine scrub/solution, and creation of a sterile field with sterile muslin towels and disposable drapes. Two femoral arteries of 3-5 mm in diameter were rapidly located and a pressure line was placed in one at 23:55 (initial pressure measured was MAP 47 mmHg).
However, despite extensive further dissection of the right groin no femoral vein could be located. Dissection along the tissue plane of the femoral arteries failed to reveal the femoral vein (although the sciatic nerve was identified) and the femoral arteries appeared to bifurcate within the abdomen. (Subsequent autopsy disclosed that the patient had no femoral vein and a right iliac artery that bifurcated into two femoral vessels at the terminus of the abdominal aorta). Several small veins (3-5 mm in diameter) were located and one of these opened to determine feasibility of cannula placement for venous return. While this was deemed not possible, it was noted that the venous blood was free-flowing and arterial red in color, indicating adequate oxygen delivery to the patient (the patient's tympanic temperature at that time was approximately 23 degrees C, colonic temperature 14.5 degrees C).
By 00:15 a decision had been made to abandon the right groin wound and proceed with surgery to raise the left femoral artery and vein. Prep of the left groin was made at 00:21 and the femoral artery and femoral vein were rapidly identified. The femoral vein was cannulated with a Biomedicus Carmeda-coated, 21 Fr. x 50 cm venous cannula (#34284).
However, a further complication occurred in that the femoral artery was invaded with malignancy; apparently between the tunica media vasorum and the intima of the vessel. The vessel also was moderately atherosclerotic (soft yellow atheroma). This complicated arterial cannulation and required extensive further dissection of the groin to avoid a dissecting aneurysm of the entire arterial tree secondary to cannula placement.
Thumper support was discontinued at 01:07 at a tympanic temperature of 20.2 degrees C and a colonic temperature of 8.4 degrees C. MAP had dropped to 35 mmHg at this time, and it was felt that further Thumper support was not productive.
Both cannulae were in place by 01:18 and closed circuit femoral-femoral bypass was begun at about 01:18, using a prime consisting of 750 cc Dextran 50 in Normal saline, 1500 cc of Normosol-R pH 7.4, 500 cc 20% mannitol in water, and 50 cc (1 mEq/cc) of sodium bicarbonate solution. At 01:21 a "popping sound" was heard, and the polycarbonate housing of the Sarns 9444 Turbo oxygenator was noted to have developed a leak at the joint between the two halves of the housing. This occurred at a pressure of 260 mmHg, well below the 760 mmHg pressure this unit is rated for.
Surgery to connect the patient to the extracorporeal circuit of the MALSS is complete and the patient is on bypass. Sandra Russell and Mike Darwin (right) have broken scrub. Mike Fletcher, CRT, lifts a bag containing the first ten liters of 5% glycerol flush solution to begin filling the MALSS reservoir in preparation for total body washout.
The problem (popping sound) was noted at exactly 01:20 and the pump was shut down and lines were clamped at 01:21. The circuit was carefully inspected for air from the oxygenator through the filter and up to the patient, and none was noted. The oxygenator was changed out of the circuit and replaced with a fresh one and the bypass line was used to prime the new oxygenator and debubble the circuit. Bypass was resumed uneventfully at 01:33, 12 minutes later. Closed circuit bypass was continued at a MAP of 45 mmHg and flow rate of 2-3 liters per minute (LPM).
When the patient's tympanic temperature reached approximately 16 degrees C (colonic , 6.2 degrees C) the patient was progressively hemodiluted with 10 liters of Viaspan using 2 liters of open circuit flush at a MAP of 45- 50 mmHg. At the conclusion of the Viaspan flushes, the patient was flushed with 10 liters of 5% (v/v) glycerol in 21CM-BPI-002 base perfusate. Glycerol-containing flush was introduced slowly in two liter aliquots. Flushing with 5% glycerol began at 01:42 and was followed by flushing with 10 liters of 10% w/v glycerol perfused in the same fashion. Flushing with 2 liter aliquots of 10% w/v glycerol was completed at 02:35. Flushing proceeded more slowly than normal due to partial cold and chemical-induced rupture of both plastic bags containing the flush solution, with leakage which required a great deal of effort to contain.
At 02:02 the tympanic probe was replaced with a frontal sinus probe to facilitate movement of the patient at the conclusion of bypass. It is interesting to note that frontal sinus and tympanic temperatures agreed to within 0.2 degrees C. Frontal sinus temperature at the conclusion of flushing/glycerolization was 5.5 degrees C, colonic, 1.6 degrees C.
Following the conclusion of total body washout and phase I glycerolization, the patient was disconnected from the extracorporeal circuit with care taken to avoid introduction of air into either the arterial or venous cannula (the cannulae were cross-connected with a short length of 3/8" x 3/32" bypass tubing which was filled with perfusate and carefully purged of air before the occluding clamps on the cannulae were removed).
The patient was then removed from the PIB of the MALSS and placed in a more easily transportable PIB for transfer to the BPI/21CM facility for cryoprotective perfusion. Originally it had been planned that the patient would be moved with extracorporeal support on the MALSS continuing. However, the patient occupied a second story apartment with a stairway that became extremely slick and hazardous during what was the first (and unexpected) rain of the Los Angeles basin's winter season. For the safety of the patient and the personnel, a decision was made not to attempt to transport the 600 pound-plus MALSS, with the patient in it, down the stairs in heavy rain.
The patient was transported by BPI ambulance from Huntington Beach to Rancho Cucamonga, CA starting at approximately 0350. Driving conditions were very poor with heavy rain and an earlier than usual morning rush hour traffic beginning by the time the freeway was reached at 0400. The patient arrived at the facility at 0545 on 13 December.
The impact of intracorporeal cooling in the form of colonic and peritoneal lavages with 0 degrees C buffered Normosol can be seen graphically in figure 1. As was previously noted, a cooling rate of slightly over 1.0 degrees C per minute was achieved for the first 10 minutes post arrest.
Figure 1: James L. Gallagher Cooling to Near Freezing
Close examination of this patient's cooling curve discloses what we believe to be additional valuable information. For the first 50 minutes of CPR, rectal and tympanic temperatures smoothly track each other. However, at approximately the 50-minute post arrest mark there is a sudden reduction in the rate of tympanic temperature descent. This flattening of the tympanic temperature cooling curve continues until the start of extracorporeal support at which time there is a sharp decrease in tympanic temperature and resumption of "tracking" of the rectal temperature.
We believe this sudden slowing in the rate of tympanic temperature descent, which persisted until the start of femoral-femoral bypass, indicates a failure of cerebral perfusion. The author has repeatedly observed the same phenomenon in the dog lab with confirmation of failed cerebral perfusion obtained by intravenous dye administration followed by necropsy. In conventional closed-chest CPR. Using a canine model and the standard ACLS drug protocol we typically see failure of cerebral perfusion following 10 to 15 minutes of mechanical CPR. If the delay before starting of CPR is greater than 5 minutes after the onset of cardiac arrest it is uncommon to achieve any significant degree of cerebral cortical reperfusion during CPR.
In view of the canine data from our laboratory, the persistence of cerebral perfusion as indicated by continued decrease in tympanic temperature for the first 50 minutes of CPR in this patient is encouraging. However, it should also be noted that the presumed loss of cerebral perfusion occurred at approximately 24 degrees C (without further significant reduction in tympanic temperature) approximately 110 minutes prior to the beginning of bypass, and associated resumption of both cerebral perfusion and cerebral cooling.
Clearly, it is critical to be able to take advantage of the relatively brief period of CPR-generated brain perfusion to achieve the maximum amount of cooling possible. In this case, another 2 to 3 degrees C of cooling could have been achieved with the addition of partial liquid ventilation by filling the patient's lungs to vital capacity with an appropriate heat exchange medium which is also capable of gas exchange [Darwin M, "A Bypass on the Way to Bypass," CryoCare Report Number 7, April 1996, pp 11-16].
It is also apparent that further colonic and peritoneal lavages with 0 degree C fluid would have been useful during the first 50 minutes of CPR.
Finally, faster application of extracorporeal support is critically important and every effort should be made to initiate bypass within a maximum of 45 to 50 minutes of cardiac arrest and sooner wherever possible.
As figures 2 and 3 show, venous pO2 and pCO2 improved steadily during CPR. Lactate levels rose steadily (figure 4) but remained impressively low during 142 minutes of CPR, peaking at 13 mmol/L immediately prior to the start of bypass.
Figure 2: James L. Gallagher Venous pO2During CPR
Figure 3: James L. Gallagher pCO2 During CPR
Figure 4: James L. Gallagher Lactate Pre and Post Arrest (corrected for dilution w/cyroprotectant)
Serum glucose levels rose steadily during CPR (figure 5) indicating adequate hepatic perfusion (there was no exogenously administered glucose) but failure of glucose regulation, with serum glucose being above 350 mg/dl at the start of bypass.
Figure 5: James L Gallagher Venous Glucose Concentration During CPR
Venous pH was not aggressively raised to 7.4 in this patient, but rather was to be held in the range of 7.0 to 7.2 during CPR. Control of pH was not as tight as was desired and the patient remained acidotic with a pH ranging from 6.95 to 6.84, which is undesirably low (figure 6). The decision to keep pH in the range of 7.0 to 7.2 is based upon experimental evidence from our laboratory and elsewhere [Lemasters J J et. al., "Reperfusion injury to heart and liver cells: Protection by acidosis during ischemia and a 'pH paradox' after reperfusion." In Surviving Hypoxia, ed. P W Hochachka et. al., Boca Raton: CRC Press, 1993] that rapid correction of pH to normal levels can be deleterious to the brain and that low pH is somewhat protective during cerebral ischemia.
Figure 6: James L. Gallagher Venous pH During CPR
In the future, it would be desirable to be able to measure pH dynamically in the patient during CPR and we are actively investigating means for doing this.
Other indicators of the efficacy of CPR in meeting this patient's metabolic demands are the patient's serum sodium, potassium, and chloride levels which are presented in figure 7. Note that the patient's serum potassium remains stable at under 5 mmol/L throughout 120 minutes of CPR. Similarly, serum sodium is constant at between 130 and 135 mmol/L.
Figure 7: James L. Gallagher Sodium, Potassium & Chloride During CPR
Graphic data for arterial pressure during bypass and total body washout (TBW) are presented in figure 8 and again reflect the good physiologic state of the patient.
Figure 8: James L. Gallagher Mean Arterial Pressure During Washout
Following transport of the patient to BPI's facilities in Southern California for cryoprotective perfusion and freezing (arrival time 0545 on 13 December, 1995) the patient was moved from the portable ice bath and onto the operating table. Assessment of the patient at that time disclosed evidence of good cutaneous blood washout and no evidence of rigor mortis, and the patient was repacked in ice.
The patient was assessed for the presence of pulmonary edema radiologically and by measuring peak and mean inspiratory airway pressure. The chest film disclosed lungs clear to the bases bilaterally and peak airway pressure was 36 cm H2O when inflated with 10 cc/kg of air. This was consistent with absence of pulmonary injury which has previously invariably occurred as a result of antemortem shock, CPR and TBW during Transport.
Determination of lung water status (i.e., the absence of pulmonary edema) was critical in this case because of our desire to carry out cryoprotective perfusion using femoral-femoral vascular access, as opposed to performing a median sternotomy and achieving vascular access via the aortic root and right atrium. Work done at BPI over the past two years has established the safety and efficacy of this approach to cryoprotective perfusion utilizing newly developed flat-wire, high-flow, low-resistance, femorally placed venous cannulae which allow for caval drainage at the level of the right atrium. However, for this approach to be used safely it is essential that the patient not develop high intra-thoracic pressure from lung edema which could impede venous return.
In the past, all patients undergoing cryopreservation in the authors' experience have developed marked edema of the lungs during transport which has invariably progressed to massive edema of the lung parenchyma with alveolar transudation and filling during cryoprotective perfusion. Often this edema is so severe that closure of the chest wound over the distended lungs is problematic. Such massive fluid accumulation and accompanying increase in intrathoracic pressure would be unacceptable and lead to compartment syndrome and consequently failed caudal perfusion in a patient with a closed chest.
Assessment of lung compliance during cryoprotective perfusion was carried out by measuring peak inspiratory pressure using the same tidal volume at several intervals during cryoprotective perfusion. (Peak inspiratory pressure increases during cryoprotective perfusion as a result of reduced lung compliance due to cryoprotective-associated stiffening of the pulmonary parenchyma and this must be taken into account during evaluation). Radiologic evaluation can also be used to determine lung edema status dynamically.
Final preparation of the patient for cryoprotective perfusion consisted of the application of occluding tourniquets to all four limbs (metal hose clamps were used) and re-establishment of the extracorporeal circuit by connection of the femoral arterial and venous cannulae to the cryoprotective perfusion circuit (see figure 20). Care was taken to avoid introduction of any air into the tubing/cannulae during re-establishment of the extracorporeal circuit.
Figure 20: Cryoprotective perfusion circuit
In parallel with reestablishing the bypass circuit, the patient underwent aseptic preparation and draping for craniotomy. Scalp incisions were then made 2 cm from the midline over each parietal lobe, and a DePuy pneumatic perforator was used to make two burr-holes ca. 10 mm in diameter in the cranial bone. The dura was opened in each burr hole using a dura hook and iris scissors and was dissected away to the edge of the burr hole using the iris scissors. The brain was noted to be slightly dehydrated and retracted from the margin of the burr holes bilaterally by 2 mm. A silastic and teflon clad, copper-constantan thermocouple probe (22 gauge) was placed on the cortical surface at the level of the temporal lobes by advancing the thermocouples through the burr holes over the cortical surface. Initial temperature readings were 1.8 C for the right temporal and 2.0 C for the left temporal lobes.
Cryoprotective perfusion was begun at BPI at 0834 at a flow rate of 1.1 LPM, a MAP of 45 mmHg, an FiO2 of 9.2, sweep gas flow rate of 4 LPM an esophageal temperature of 3.2 C, a right brain surface temperature 1.8 C and left brain surface temperature of 2.0C. Patient temperatures during cryoprotective perfusion are presented graphically in figure 9.
Figure 9: James L. Gallagher Cryoprotective Perfusion Temperature
Click here for larger image
A Sarns 16310 oxygenator-heat exchanger was used for oxygenation and temperature control. Sweep gas FiO2 was decreased to 2.4 at 0842. Cryoprotective perfusion was initiated with 10% (v/v) glycerol in MHP-2 base perfusate. This perfusate was recirculated for 10 minutes before beginning the glycerolization ramp.
Increase of glycerol concentration over 10% (v/v) was begun at 0840 by the addition of 200 cc/min of 60% (v/v) glycerol to the recirculating system (patient loop) and the removal of 170 cc /min of perfusate from the venous return line to discard. Initial arterial and venous glycerol concentrations were 0.2 M and 0.7 M respectively at 0846. Arterial and venous glycerol concentration during the course of cryoprotective perfusion are presented graphically in figure 10.
Figure 10: James L. Gallagher Glycerolization
Arterial and venous perfusate samples were drawn at 15 minute intervals during cryoprotective perfusion. The initial two venous chemistry samples were of questionable value due to technician error during collection (the arterial side of the 3 gang stopcock was not completely shut off during venous sample collection). The first venous sample (chemistry) results are thus not reported. The first arterial and venous (gases) perfusate samples were collected at 0839 and disclosed the following:
|Measured Values |||Normal Range|
|Protein, Total||0.3 g/dl||6.0-8.5|
|Bilirubin, Total||0.0 mg/dl||0.0-1.3|
|Alkaline Phosphatase||0.0 U/L||20-125|
|LDH, Total||113 U/L||0-250|
|Measured Values |||Normal Range|
The next labs were drawn as follows:
Arterial (gases) 0855:
|Measured Values |||Normal Range|
Arterial (chemistries) 0904:
|Measured Values |||Normal Range|
|Alkaline Phosphatase||0.0 U/L||20-125|
|LDH, Total||63 U/L||0-250|
Venous (gases) 0905:
|Measured Values |||Normal Range|
Venous (chemistries) 0904:
|Measured Values |||Normal Range|
|Alkaline Phosphatase||5.0 U/L||20-125|
|LDH, Total||64 U/L||0-250|
Data for arterial and venous perfusate gases and relevant chemistries are presented graphically as figures 11 through 17. Graphic data for mean arterial perfusion pressure is presented in figure 18.
Figure 11: James L. Gallagher Arterial & Venous pO2 During Cryoprotective Perfusion
Figure 12: James L. Gallagher Arterial & Venous pCO2 During Cryoprotective Perfusion
Figure 13: James L. Gallagher Cryoprotective Perfusion Arterial and Venous Calcium
Figure 14: James L. Gallagher Arterial and Venous pH During Cryoprotective Perfusion
Figure 15: James L. Gallagher Arterial and Venous CPK During Cryoprotective Perfusion
Figure 16: James L. Gallagher Glucose Levels During Cryoprotective Perfusion
Figure 17: James L. Gallagher Washout & Cryoprotective Perfusion Arterial & Venous AST
Figure 18: James L. Gallagher Mean Arterial Pressure Cryoprotective Perfusion
Cryoprotective perfusion proceeded uneventfully. CVP remained below 10 mmHg until 1000 at which time it was 11 mmHg at a MAP of 68, flow rate of 1.1 LPM and a glycerol concentration of 5.0M arterial, and 4.2M venous.
The cerebral cortical surface was repeatedly examined during cryoprotective perfusion using both flexible and rigid fiberoptic endoscopes. A Storz Hopkins 26156B, 30 degree angle rigid endoscope was used for maximum resolution of the cortical surface and could be extended through the burr holes to view the cortical surface over a 5-6 cm area underlying the burr hole once cerebral dehydration had become pronounced (greater than 20%). The flexible scope is a 4 mm diameter 20 cm long custom "cerebroscope" manufactured by Trimedyne Corp. of Santa Ana, CA. A Storz endoscope camera and Xenon light were used as the cold light source and imager.
Resolution with the Storz rigid endoscope is at the level of small arterioles and venules, and particles in the range of 20 to 30 microns can be easily seen inside vessels. As a consequence of altered tissue refractive index due to glycerolization the cortical surface becomes translucent and it is possible to look into the cerebral cortical surface to a depth of approximately 3-5 millimeters by adjusting the focal plane.
In this patient blood washout was judged to be excellent. The cortical microvasculature was examined at multiple locations in both brain hemispheres and only occasionally were any aggregates of RBCs observed; the frequency of RBC aggregates was comparable to that observed in nonischemic dogs undergoing cryoprotective perfusion following induction of hypothermia and TBW under controlled (and optimum) conditions.
Optical resolution limitations do not allow for such detailed evaluation of the intravascular space using the flexible fiberoptic cerebroscope, however the device does allow gross evaluation of the cortical surface for nonperfused areas as large pial vessels which are blood filled are easily resolved with this instrument. Flexible fiberoptic endoscopy of the surface of both cerebral hemispheres disclosed no visible areas of failed perfusion as evidenced by the absence of blood filled pial vessels. Because the results of the endoscopic exam indicated uniform cerebral perfusion, and because clinical observations did not indicate any problems with cryoprotective perfusion (i.e., no edema, acceptable MAP and flow rate) intravascular dye was not administered to evaluate brain perfusion status in this patient.
Near the end of cryoprotective perfusion an external temperature probe was anchored with surgical staples to the left temple. The esophageal probe was repositioned (guided by fluroscopy) in the left frontal sinus with the tip resting on the bone abutting the forebrain. The brain was noted to be moderately dehydrated at the conclusion of cryoprotective perfusion with an estimated 30% reduction in volume.
Terminal glycerol concentrations were 6.7M arterial and 5.45M venous at 1045. Perfusion was discontinued at 1050.
Surgery for cephalic isolation was begun at 1055. The skin, cervical musculature, and spinal cord all exhibited complete blood washout and typical signs of thorough and uniform glycerolization (dehydration, waxy texture, ambering of the skin and deepening of skeletal muscle color).
Closure of the burr holes was delayed until the completion of cephalic isolation. The cranial vault was then bilaterally suctioned of perfusate (burr hole drainage) and the isolated head was turned calvarium down to facilitate additional drainage of perfusate from the burr holes while the stump was covered in gauze 4"x4" squares and stockinette put in place. The head was then positioned calvarium up at which time the burr holes were filled with bone wax (with the thermocouple probes still in place) and the skin incisions over the burr-holes were closed with staples. All probes were further secured with surgical staples to the skin of the patient's head.
Cooling to -79 Degrees Celsius
The stockinette was then unrolled to cover the entire head with the temperature probes exiting from the crown of the head through the stockinette. The stockinette was secured to the thermocouple probe bundle and excess stockinette trimmed. The patient (cephalon) was then placed in two 1 mil polyethylene bags. The patient was then submerged in a 15 liter Silcool bath which had been precooled to -39.8 degrees C.
The first temperature readings after submersion in the Silcool were right brain 5.3 C, left brain 6.4C, frontal sinus, 3.7 C and skin surface -12 C.
The patient's cooling curve to dry ice temperature is shown in figure 19.
Figure 19: James L. Gallagher Cooling to Dry Ice
A thorough postmortem examination was performed on the noncryopreserved remains of this patient. Examination of the abdominal and thoracic viscera disclosed no infarcted areas and apparently uniform distribution of cryoprotectant with the exception of the left ventricular endocardium. On cross section of the left ventricle it was noted that the endocardium had not perfused and that epicardial glycerolization extended only 5-7 mm into the ventricular wall. The transition from perfused to unperfused tissue was strikingly sharp. We believe this selective failure of left ventricular endocardial perfusion is a result of distention of the left ventricle under the static pressure load of the retrograde aortic perfusion.
Distention of the left ventricle and presumed compromise of endocardial blood flow are normally avoided in sustained circulatory arrest cardiopulmonary bypass by the expedient of venting the left ventricle through the cardiotomy reservoir. Use of the closed chest approach to cryoprotective perfusion prohibits this technique from being applied. While this is likely of no significance in patients who have elected for neuro-cryopreservation it may be a relative contraindication to the use of this technique in whole-body cryopatients. Certainly this finding (confirmed in canine cryoprotective perfusion using a variety of CPAs) indicates that in whole body patients undergoing open chest cardiopulmonary bypass the left ventricle should be routinely vented to assure adequate perfusion of the endocardium.
Samples of spinal cord, liver, kidney (renal cortex) and cardiac muscle (left ventricle) were collected for subsequent evaluation. One set of samples was cooled with the patient, and is currently undergoing freeze-substitution at -80 degrees C so that transmission electron microscopy can be performed to determine the ultrastructural integrity of the tissue and the quantity and location of ice in the cryopreserved state.
Samples of spinal cord, left ventricle, and renal cortex were weighed to 0.01 g and then homogenized in known weights of distilled water for determination of glycerol concentration by osmometery. Glycerol concentration was highest in the kidney and lowest in the left ventricle. Results are given in the Table below.
Glycerol Concentration in Selected Tissues
|Concentration in Moles|
|*Note that this sample included some visibly nonglycerolized endocardium.|
Postmortem examination disclosed widespread metastatic adenocarcinoma of the bowel. Metastases were noted in the liver, both kidneys, lungs, pancreas, mesentery, abdominal and thoracic lymph nodes, and the mediastinum. The liver was heavily invaded with tumor both macroscopically and microscopically. Remarkably a number of the patient's arteries were invaded with linear rod or wire-like metastases (confirmed histologically) including the right femoral and iliac arteries.
Also atypical was the presence of multiple cystlike, spherical metastases in the kidney, and widespread invasion of the skin with multiple metastases ranging in size from 1 cm to 6 cm and also typically presenting as spherical, cyst-like masses.
The patient had suffered unrelenting nausea with occasional vomiting and was unable to take normal quantities of food during the final months of his illness. Despite aggressive treatment with a wide range of potent antiemetics (including marijuana) this remained an intractable problem throughout the patient's illness. CT of the abdomen was unremarkable save for the presence of hepatic and renal masses, and the cause of the patient's nausea remained undiagnosed during life.
Autopsy disclosed extensive carcinomatous invasion of the stomach presenting the classic "leather bottle" appearance with extension of the tumor from the cardiac portion of the stomach into the mediastinum. The vagus nerve was encased in tumor to a level above the bronchial hilus. This is noteworthy in that the patient developed a moderate bradycardia (HR of 50-60) during the last months of his illness which was in sharp contrast to his previous high resting heart rate of 80-90 when he had enjoyed good health. We presume that vagal involvement with malignant disease was responsible for this bradycardia as the few cardiac metastases that were observed were epicardial and right ventricular and did not appear to impact the cardiac conduction system.
Another remarkable finding at autopsy in this patient was the presence of bead-like coal-black nodules in the mediastinum with many of the hilar lymph nodes exhibiting a similar appearance. These lesions were strikingly pigmented and yielded an oily black smear when cut on gauze. Subsequent histopathological evaluation of these masses and of the lung disclosed these lesions to be anthracosis. This finding is remarkable in that the patient had no history of exposure to coal dust or hydrocarbon pyrolysis products and the patient had not smoked cigarettes (or cohabited with smokers) in over a decade. The finding of anthracosis is consistent with the histological finding of bilateral moderately advanced emphysema in all lung samples submitted for pathological evaluation. The etiology of the anthracosis and chronic obstructive pulmonary disease remains unknown.
We believe the care this patient received during the premortem, agonal, and transport phases of his cryopreservation represents the best achieved anywhere to date. Mitigation of antemortem and postmortem shock-mediated ischemia-reperfusion injury by premedication seems to have played a critical role in protecting this patient's lungs and brain from ischemic injury. The use of advanced methods of CPR allowed for restoration and prolonged maintenance of acceptable mean arterial pressure and optimum levels of blood gases and CO2.
However, we believe further improvements to transport can be made, particularly improved rates of cooling using intracorporeal (intraperitoneal and intrapulmonary) methods until extracorporeal circulation and cooling can be achieved.
It is now arguably possible to recover and stabilize selected cryopatients who have been pronounced legally and medically dead without the complication of cerebral ischemic injury (i.e., to stabilize such patients at near 0 degrees C with brains which are viable by contemporary medical criteria). However, we note with continuing frustration that inflicting massive gross, histological, and ultrastructural disruption as a result of cryoinjury is still unavoidable. We suggest, in the strongest possible terms, that future research efforts (and the expenditure of nearly all discretionary money available to cryonics organizations) be focused on improving the subzero aspects of human cryopreservation (cryoprotection and cooling to long-term storage temperature).