by Ben Best
On Tuesday, January 17 the Cryonics Institute received its 72nd patient, perfused her with vitrification mixture and began cooldown to liquid nitrogen temperature. This was a very challenging case, to put it mildly. In the interest of privacy for those concerned only first names are given and the names that are used are not the real names.
The patient is the 84-year-old mother of two sons. Josh was eager to have his mother cryopreserved. Timothy, the other son, was doubtful that cryonics is of value and did not have conviction that these were his mother's wishes, but he agreed to acquiesce. The two brothers both expressed deep caring for each other and I found it touching to experience. Timothy said he acquiesced mostly because he could recognize how much cryonics means to Josh. This decision was made with a great deal of emotional difficulty, but other families have been torn apart by animosity under similar circumstances.
As an additional complication, however, Timothy refused to sign a Next-of-Kin Agreement or a Consent/Release form. Both brothers had equal authority and power-of-attorney over their mother's financial and human remains. Timothy had shown the Cryonic Suspension Agreement to his lawyer and suggested a modification which we accepted. This could mean implied consent. Timothy said repeatedly and with convincing sincerity that he would not interfere with cryonics arrangements and that lawsuits were against his principles and against family tradition. None of us really understood Timothy's point of view -- including Josh -- but it seemed to be a matter of principle to him that his word is good and it is asking too much to ask for a signature. I became convinced that he meant what he said. But both our Michigan funeral director and the remote funeral director refused to participate without a signed document. On the advice of our lawyer I wrote a letter to Timothy acknowledging his verbal statements that he would not oppose cryonics or bring a lawsuit in connection with the cryopreservation of his mother. Showing this letter to him and his non-response to its contents gave another measure of implied consent. On this basis I wrote letters to the funeral directors taking full legal responsibility for the case -- which they both accepted.
Josh had been interested in cryonics for decades. He investigated the cryonics organizations in the late 1990s when he gained access to the Internet. At that time he discussed cryonics with his mother who Josh says favored the idea over the alternatives. When asked in the nursing home the mother expressed a preference to be "frozen" in the presence of both sons. Written consent prior to hospitalization would have been preferable. But should we assume that the default condition is burial or cremation? If the mother had said in the nursing home that she did not want to be "frozen" there would have been no disagreement, but some people may feel that saying that she wanted to be "frozen" under these conditions was not strong enough permission. How can this really be grounds for burial or cremation? Do these decisions require less decisive evidence simply because they are within the cultural norm? The fact that she said she preferred "freezing" to burial and cremation should be given serious weight, as it was in this case.
The mother has leg problems beginning with osteosarcoma. A saphenous vein was removed from her healthy right leg and grafted onto her left leg, compromising circulation on the right leg and insufficiently restoring circulation in her left leg. A lifetime of smoking led to Chronic Obstructive Pulmonary Disease (COPD). In August 2005 Josh took her into the hospital because of concern about her swollen feet. The hospital treated her for pneumonia. She was placed on ventilation with initial FIO2 (Fraction of Inspired air as Oxygen) as high as 90% (normal is 21%). The ventilator went into her mouth. The mother was in intensive care for 17 days. The hospital told the brothers that her mother would probably not survive more than a few weeks and they were given counseling in which removal of life support was suggested. The brothers were opposed to removal of life support at that time. The brothers were told that their mother was getting essentially no circulation in the left leg and that her only chance of survival was amputation. Her chances of surviving the operation in her condition were not good and the brothers did not believe that their mother would have wanted to live if she could not be removed from the ventilator.
The mother was given a tracheotomy (cut in throat for breathing tube) in the ICU because she would have been too uncomfortable with a tube in her mouth to be effectively weaned from the ventilator. She was moved to a rehabilitation center in hopes of removing her from the ventilator. She had been unconscious most of the time while in the ICU, but recovered consciousness in the rehabilitation center. During her forty days in the center she got as low as 24% on occasion, but could never be weaned from the vent. Eventually she stabilized to FIO2 of 24−35%. This condition went on for a few months during which she became increasingly uncommunicative, at least in part because the tracheotomy made it difficult for her to speak.
Her leg had become gangrenous. Although her quality of life continued to deteriorate, the brothers refused to remove life support as long as their mother was communicative. In early December, however, she began sleeping most of the time and was mostly uncommunicative when awake. This may have been "protective withdrawal" associated with increasing misery. In mid-December a nursing home employee accidently put a feeding tube in her lung she had a medical emergency, was taken to a hospital and ventilated for a short time with 100% oxygen. After a week in the hospital she was returned to the nursing home, after which she was never ventilated on less than 40% FIO2. The mother became communicative about her distress at the time of the crisis and remained slightly more communicative for a short time thereafter ("responding appropriately to about one question in three", as Josh described it, and not responding at all to the other two questions).
There was certainty that the gangrenous leg would eventually lead to multi-organ failure due to sepsis. This was perceived by the brothers and medical staff to be a horrible way to die. In 1991 the mother had signed a Living Will declaring that she did not wish to be kept alive by artificial means if she "suffered from (1) unconsciousness from which I am not reasonably expected to recover or (2) irreversible physical brain damage or deterioration to the extent that I cannot interact with those around me." The decision to remove the ventilator was made independently of the choice to cryopreserve -- certainly for Timothy.
Josh made exceptional efforts to improve the quality of deanimation of his mother. He read much of the material on my website, including Emergency Preparedness for a Local Cryonics Group, The First Cryonics Case in Toronto, Canada and Pre-Treatment for Cryonics Patients. Because removal of the ventilator was a scheduled event he was able to use advice from the latter article to pre-treat his mother between December 27 and January 16 with high-doses of anti-oxidants at her 8am feedings to reduce ischemic damage. Almost all of the products were obtained from the Life Extension Foundation. Blueberry extract (which was only given for the final five days), grapeseed extract and spirulina were Josh's ideas. The mixed tocopherol included both alpha and gamma tocopherol forms of Vitamin E. The Magnesium Oxide was given to prevent low magnesium levels, as often occurs in enterically fed patients and which can worsen brain ischemic injury. In addition to these supplements, the mother was receiving 5 mg Warfarin daily, acetaminophen 300 mg with 30 mg codeine every four hours, 10−20 mg oxycodone about every 12 hours (when needed) and "lots" of Albuteral inhalers.
The first two articles describe the activities and preparations of a well-equipped local support group, but Josh attempted to do an amazing amount of these preparations as a one-man support group. Josh was arranging for cooling in an ice bath (in the Ziegler shipping case), CPS (CardioPulmonary Support -- not "CPR" because the objective is not "Resuscitation") with an Ambu CardioPump and bag mask valve, adding Clorox to the ice bath, inserting a rectal plug to prevent fecal discharge in the ice bath, acquisition of transit permits and coroner's office permits, flight time coordination, temperature probe to monitor temperature, etc. I cautioned Josh several times of the dangers of being overly perfectionistic or of attempting so much that he would collapse from the overload of expectations.
Much of Josh's effort -- as well as the advantage of a planned deanimation -- was lost when the nursing home refused to allow any CPS or cooling on their premises. Previously the nursing home had given assurances that this would be allowed. Someone told me that Josh had pestered staff & administrators so many times with special requests that they decided not to accommodate him at all. Although this is hearsay from a source that may or may not be reliable, others have cautioned how important it is to be careful not to ask for too much from those who have no interest or incentive to be of help. Some of the nursing home staff were very alienated by what they interpreted as an attitude that was indifferent or calculating in anticipation of his mother's death. Josh said "the nursing home administrators had that attitude that my mother was as good as dead and that I should be properly wailing and knashing my teeth rather than wasting their precious time trying to save her." He added, "until welcome reinforcements arrived on the last day I was a one-man band rescue squad, an endeavor that required endless calculation and an unflagging enthusiasm for the process that could give her a second chance."
Without being able to do CPS in the nursing home, the presence of the funeral director at the time of declaration of death became imperative. The funeral director balked at the demands being placed upon him. The plan was to do CPS in the Ziegler shipping case filled with ice in the funeral director's van in a hospital parking lot close to the nursing home until the mother had cooled about 10ºC. The funeral director said he did not want to waste the time of his staff waiting at the nursing home, especially because it was not known how long it would take the patient to deanimate after the ventilator was removed. He was not moved by offers of more money. He said his staff was committed to other tasks. He was expressing regrets about having taken the case, partly because he thought that that cryonics is of no value. When he expressed this to me I told him that no one was expecting him to believe that what we are doing is going to work. I also gave my opinion that it would probably not be more than 15 minutes until legal death after the ventilator was removed because her respiratory muscles would probably be atrophied by disuse as a result of being on the ventilator.
Josh knew that he was taking on a huge project and that Timothy would not give any assistance. He considered seeking paid help from funeral director staff (not available) or elsewhere to give chest compressions with the Ambu CardioPump. I sent e-mail messages to all CI Members living near him asking if anyone would help. I received a positive response from a software engineer named Aaron as well as from a couple who had a psychiatric background, Jerry and Ruby. Ruby had been a psychiatric nurse. They all agreed to help with the case and all followed-up by donating almost a whole day.
At 30 minutes after midnight on the morning of January 16, 2006 the mother was given 975 mg aspirin, 20 mg Pepcid AC, 2 grams CoEnzyme Q10, 2000 IU Vitamin E (mixed tocopherols) 200 mg Melatonin and blueberry extract. Vitamin E was omitted from the usual 8 am supplement feeding, but the midnight dosing was repeated shortly after noon (except that 600 mg of Melatonin given separately would not dissolve). The Pepcid was given to prevent stomach acidity, which can cause erosion of the stomach wall during ischemia and cause massive bleeding -- especially in an anti-coagulated patient. This bleeding can even occur during CPS.
At the time of the 3:06pm removal of the vent the three CI Member volunteers waited in the lobby of the nursing home. Jerry was reportedly extremely helpful in speaking to the funeral director and making him more sympathetic to our efforts. Timothy departed. The physician injected both heparin and morphine prior to removing the vent, but refused to inject magnesium chloride or anything else. The funeral director and his assistant waited in a van outside. It took an hour and forty-five minutes for death to be pronounced after removal of the vent. The mother was given between morphine shots about every five minutes during that period. Morphine can cause respiratory depression in addition to relief of pain & distress. I believe the physician was trying to walk the fine line of trying to relieve distress while making a great effort to avoid hastening deanimation (as he indicated to Josh). Toward the end pulse was imperceptible and the mother was taking only one breath every five minutes, which means that hypoxia was already beginning.
After pronouncement at 4:51pm the three CI Member volunteers came into the room where the mother was located. The nursing home prohibited even the placement of ice on the mother. The CI Members all stood there for fifteen minutes waiting while the funeral director completed paperwork with the nursing home. Josh was very distraught that the nursing home and the mortuary people had so little sense of urgency. Once the mortuary people arrived with their equipment it took about ten minutes to get the mother into the van and the van moved to the hospital parking lot where CPS could begin in the van. Jerry phoned me and asked if CPS was still advisable. Total time without oxygen may have been as much as forty minutes, if the last ten minutes of hypoxia before pronouncement are included. Normally, this amount of ischemic time would raise concerns about ischemia-reperfusion injury, but the antioxidant, anti-inflammatory and anti-coagulant pretreatments caused me to decide they should proceed with CPS.
Josh had cut a U−shaped groove in the side of a styrofoam picnic cooler allowing his mother's head to rest inside the cooler which could be filled with both ice and water to facilitate more rapid heat exchange in her head. Josh's mother was placed in the Ziegler on top of lots of ice. With her head in the cooler he could add water to the cooler to benefit from the fact that a water/ice mixture cools much more quickly than ice cubes. The wire probe of an Acurite digital thermometer (obtained from WalMart) was placed down his mother's throat to facilitate monitoring of her cooling. Taking turns with the Ambu CardioPump, the team of four CI Members applied CPS from 5:23pm to 6:30pm at which time the mother's head temperature (as measured in her throat) was 75.6ºF (24.2ºC). (The funeral directors told them they must finish by 6:30pm if they did not want to miss the plane.) The van was too cramped for use of the bag mask valve, but the upward thrusts if the CardioPump provided very adequate ventilation because the tracheal tube eliminated the "deadspace" normally present in the upper airways. All were very pleased by the superior efficiency of the CardioPump over manual CPS. Jerry noted that the cold wet body would have been slippery and hard on the hands. He also said that the device would be helpful for those who felt the need to distance themselves from "bodies".
At one point there was a rise in the temperature of the throat which caused them to think that the thermometer was malfunctioning. The body has a large thermal mass and the CPS was probably pumping heat from the body into the head, reducing the benefit of the ice water in the cooler. Frankly, the delays were pushing close to the time when CPS could cause reperfusion injury, causing more harm than good (but the heavy load of antioxidants may have been very protective). If there was nutrient in the blood, circulating it could have been a benefit. It is a difficult call to say whether all of the teams efforts were more beneficial than if they had concentrated their energy on maintaining a flow of ice-water around the head. To the extent that the body was cooled more quickly that it would have been, it was prevented from warming the brain later. But quick cooling of the brain is very important.
The mother was driven to the funeral home (the CI Members are not licensed to ride in the van). The CI Members got several bags of ice at a convenience store on their way to the funeral home. Josh's mother was placed in a heavy duty, fabric-reinforced vinyl body pouch with ample quantities of ice. (These body pouches are normally used for shipment of highly decomposed or dismembered bodies, but the pouches are a standard part of CI body shipment.) Fiberglass building insulation was packed between the metal Ziegler shipping box and the cardboard container to prevent water condensation on the ice-laden Ziegler. (This is also a standard practice for CI patient shipment, but is unusual for funeral directors who don't normally ship ice.)
When the shipping box arrived in Michigan our funeral director was amazed by how heavy it was -- it was loaded with much more ice than usual. It might be as much as 150-200 pounds. The ice was not weighted by the shipper. At the funeral home we found the digital thermometer with its lead still in the mouth of the mother -- and reading a temperature of 35.2ºF (1.8ºC). Total time between patient deanimation and the beginning of perfusion was about 13 hours.
Jim Walsh, our funeral director expertly isolated the carotid and vertebral arteries on the left side of the patient and the carotid (with branching vertebral) on the right side. He clamped the subclavian artery on the right side and cannulated the other arteries he had isolated.
On the previous case I had brought the Compact FieldPoint and computer with LabVIEW software to monitor the patient temperature during the perfusion. Temperature was 6ºC when the perfusion began and 8ºC when the perfusion ended. The thermal mass of the patient is great enough that there is no great temperature change and the cold perfusate keeps the temperature down also. I decided that it is not worth the effort to monitor patient temperature during a perfusion. It was worth doing one time.
Jim was amazed at how well the blood washed-out with the m−RPS−2 washout solution. It was the best washout he had ever seen. The injection of heparin prior to removal of the vent made a big difference (heparin would not have been readily metabolized at low temperature and reduced circulation to the liver). But the pretreatment with aspirin, Warfarin and high doses of Vitamin E also undoubtedly reduced clotting. (Patients going for surgery are commonly told not to take Vitamin E in the hope of reducing bleeding.)
Bottles of the first three perfusates had been stored at 4ºC (refrigerator temperature), whereas the 70% VM−1 was at −7ºC (freezer temperature). Ramping of vitrification mixture into the patient also went smoothly. The effects of the "shrink-swell cycle" (initial dehydration of water from tissues followed by re-swelling as cryoprotectant entered cells) were readily visible in the face and eyes of the patient. (Water flows out of cells more readily than cryoprotectant enters cells to replace it.) After the first three perfusates were loaded there was an 8 minute delay while one burr hole was drilled into each side of the skull. These holes are about an eighth of an inch in diameter and only go deep enough to reveal the brain, without injuring it. The cryoprotectant causes the brain to shrink away from the hole. Classically burr holes have been valuable in cryonics to monitor for edema and blood washout in the brain. There was no trace of edema in this case and the burr hole functioned as a means of accessing vitrification mixture concentration in the brain. As the perfusion proceeded samples were extracted from the burr hole and analyzed them in his refractometer.
The left burr hole revealed a vitrifying concentration of VM−1 on the left side of the brain before the right side. Perfusate flow was reduced on the left side until the right side was fully saturated. Total time from perfusion beginning to perfusion end was one hour and twenty minutes. Jim suggested that most of the flow on the right side was going through the carotid and that superior perfusion might be achieved by cannulating both the vertebral and the carotid independently on the right side as well as the left. I think that this is an excellent insight and suggestion. We plan to implement it on our next perfusion.
After target vitrification saturation was reached on both
sides of the brain, a pillowcase filled with crushed dry ice was placed under
the head of the patient and another such pillowcase of dry ice was placed over
her face. Surrounding her head with dry ice was a means to facilitate rapid
cooling of her head, and thus facilitate vitrification. She was driven from the
funeral home to the CI facility, placed in a sleeping bag that exposed her head,
and put into the computer-controlled
|First Six Hours||First 130 Hours|
Temperature probes were placed deep into her nose, deep in her chest (between stitches where the incision had been made to access her blood vessels) and under the flap of skin of a burr hole. The probe down the nose (RED in the chart) was used as the controlling thermocouple because this gave the best reading of brain temperature. The cooling box brought the temperature of the controlling thermocouple down to −130ºC in 5 hours. Dr. Pichugin says that 60% VM−1 can vitrify if cooled to −130ºC within 4−5 hours, but will result in ice formation if held at −76ºC for 24 hours. Although we perfuse with 70% VM−1, which he says is more than adequate to vitrify at any cooling rate, there is a danger that some brain areas may have lower concentrations due to poor perfusion due to atherosclerosis or stroke. It is thus prudent to cool as rapidly as possible to prevent ice formation in poorly perfused brain areas that could lead to devitrification elsewhere.
The patient's brain was held at −130ºC for 18 hours to allow for "annealing" (relief of thermal stress) prior to a very slow (5 days) cooling to −196ºC. Body temperature only dropped a few degrees below 0ºC during the first six hours due to the large thermal mass. Not until 50 hours after the beginning of cooling-box cooling was the body temperature comparable to brain temperature.
The 40−50 degree oscillations of the temperature under the skin is due to the fact that superficial tissue has less thermal momentum than deep tissue -- resulting in greater warming and cooling when the liquid nitrogen gas valve shuts on and off. For the Cryonics Institute's 69th Patient we had used the thermocouple under the skin as the controlling thermocouple. This resulted a lot of thrashing, with the liquid nitrogen valve opening and closing very often. Worse, there was a lack of control over deep brain cooling, which continued more slowly after the controlling thermocouple was at a leveling-off temperature. Ideally, we would like to cool the whole brain as quickly as possible and then level-off at −130ºC. But the brain does not cool uniformly. The cooling pattern toward the more outward portions of the brain would be intermediate between the pattern below the skin and the deep thermocouple. There must be somewhere to place the probe that would compromise between large oscillations and early termination of the initial rapid cooling phase before all portions of the brain are below glass transition (solidification) temperature. It is hard to know which is worse, temperature oscillations at the surface, or initial rapid cooling which stops before the whole brain is below glass transition temperature. Good vitrification requires cooling to glass transition temperature (solidification) as quickly as possible.
The very last portion of cooling is not depicted on the charts. The cooling box will not go below -191ºC. The last 16 hours had oscillations between -189ºC and -191ºC, and finally a leveling at -191ºC when switched the cooling box to manual mode and kept the valve continuously open.
This patient was the last (the sixth) to be put into the HSSV−6−7 cryostat. Each patient has a rope tied to their backboard which allows for movement, placement and even removal, if a move should be necessary. These ropes are separated when adding a new patient, and then tied together again to be fished-out when need again (as when adding another new patient).
I have concerns about the risks we took in accepting
this patient -- despite the fact that they were "calculated risks".
I have had an idealistic vision of cryonicists
providing mutual aid for each other, of which Josh and the three
CI Members who helped him in this case were a beautiful model.
But there could be a serious
liability problem if one of the volunteers is injured or a disastrous
mishap occurs during the rescue effort. These considerations have led
Alcor down the path of "hold harmless" agreements for
volunteers, certification training for volunteers and
decreased reliance on volunteers.
|Andy's new Hoist||Andy Hoists the Patient into the Cooling Box||Last Phase of Computer-Controlled Cooling|
|Patient Removed from Cooling Box||Andy Sorts Ropes|