The Cryonics Institute’s 95th Patient
The Cryonics Institute's 95th Patient
by Ben Best
Cryonics Society of New York
(CSNY) President Henderson
The 95th patient of the Cryonics Institute (CI) is Curtis Henderson, an 82-year-old cryonics pioneer who was one of the 1965 founders of the Cryonics Society of New York. Historical details about Curtis can be found in a Wikipedia biography about him that I created. I have known Curtis for about 20 years. Curtis was among those who left Alcor to join CryoCare, and even in the 1990s I was worried about the quality of cryopreservation he would receive.
Curtis was often alone, and drove great distances across the United States — visiting and living-with different friends and family members at different times of the year. Curtis could have easily deanimated under very unfavorable circumstances. As it happened, Curtis deanimated under as favorable a set of circumstances as any of us could have hoped-for. Although Curtis had cardiovascular problems — he had recovered from a stroke and he had an artificial pacemaker on his heart — liver failure was what ultimately led to his demise.
Curtis' son Rob (named after Robert Ettinger) had a trailer on his New York farm that was Curtis' home when visiting. Curtis was visiting Rob's family at the time of his liver failure. While Rob was away on a business trip, Curtis went to Kingston Hospital complaining of stomach pains. The hospital performed paracentesis, draining about six liters of ascites. The next morning Rob visited Curtis in the hospital and found his father to be in a groggy "hazy" state. Soon thereafter, Curtis phoned Robert Ettinger saying that he "needs to be frozen". Displeased with the treatment his father was getting, after several days Rob took Curtis home and made an appointment with a hepatologist.
But the next day, Curtis was hazy and fainting, so Rob drove his father to Albany Medical Center. Curtis was unconscious when they arrived, but within 24 hours he regained consciousness and was lucid. It was the evening of Sunday, June 21 — Father's Day — the last day Rob was to see his father in a lucid state. Curtis complained of his pain, pulled-out his feeding tube and said that he wanted to die — screaming this to the physicians, according to Rob. Curtis lost consciousness thereafter, remaining in a coma, and was placed on palliative care (not given any more medical treatment).
Curtis, Robert Ettinger
and Andy Zawacki at CI
A team from Suspended Animation, Inc. was deployed to do a standby for Curtis. A detailed case report has been written by Suspended Animation, so I will only give a superficial review of their team's involvement. Albany medical center was amazingly supportive of Curtis' desire for cryonic preservation, and of Suspended Animation's requirements for standby. An ice bath with autopulse was allowed to sit by Curtis' bed in his hospital room.
Curtis was predicted to last no longer than 8 to 48 hours, but he outlived this prediction. Thereafter the physicians stopped trying to predict Curtis' survival time because they didn't know why he was still alive. But Curtis' heart stopped at 4:15am on the morning of Thursday, June 25th, 2009.
Curtis was given prompt pronouncement of death and placed in the ice bath with the autopulse cardiopulmonary support. But the standby team had to wait an hour for the funeral director before they could leave the hospital. It took another hour for the team to reach the funeral home, driving slowly in the van while the team gave Curtis cardiopulmonary support.
The Suspended Animation team consisted of Suspended Animation staff plus a professional perfusionist. For the first two-and-a-half days the team also included a surgeon, but the surgeon could not remain on the standby. Another surgeon was to join the team later in the day Thursday, but that was of no help early Thursday morning when the team needed to do surgery. Team-leader Catherine Baldwin had years of experience doing surgery on laboratory animals, but not humans. Catherine solicited the assistance of a funeral director to isolate the blood vessels.
Plans were made to ship Curtis by air to Michigan on Thursday afternoon, but the earliest available flight would not have arrived in Detroit until 10:40pm Thursday evening. Cargo processing stops at 10pm, so Curtis would have had to remain in the Detroit airport until cargo processing began again on Friday morning. There would be further delay with cargo processing and the drive from the airport. Curtis would not have arrived at the funeral home until mid-morning (when funeral services were already scheduled). A decision was made for Catherine Baldwin and a New York funeral director to drive Curtis from New York.
Catherine and the New York funeral director arrived at the funeral home of CI's funeral director Jim Walsh at about 3:30am on Friday morning. Mr. Walsh opened Curtis' chest with a median sternotomy. He could have perfused through the ascending aorta, but insofar as there was already a cannula in place in the femoral artery that had been placed by SA. Catherine told Jim that the cannula in the femoral artery extended all the way up to near the heart. Jim decided to use the existing cannula and take drainage from the jugular. Part of his rationale was concern about problems from pacemaker wires close to the heart. He clamped the axillary arteries as well as the descending aorta (thinking that the cannula in the descending aorta was not being constricted). In retrospect, the main advantage in opening the chest was the ability to clamp the descending aorta, because the decision to use the femoral cannula was only made after the chest had been opened.
In May of this year (2009) Melody Maxim, a professional perfusionist, came to CI to upgrade us to a centrifugal perfusion pump system, and provide us with training. Another modification to the perfusion system was to use two reservoirs rather than one reservoir, for safety and convenience. A filter and pressure guage could sit on the perfusion cart that is taken to the funeral home. This case was the first occasion for using the new centrifugal pump system (and dual reservoirs) on a patient.
The notes that I was given for this case did not make tabular presentation of data easy. The first nasopharyngeal temperature read was 1.3ºC at 3:49am, just before the beginning of surgery. By the time perfusion began at 4:12am the temperature had risen to 3.6ºC, and there was a slow increase toward 10ºC, but the highest nasopharyngeal temperature measured was 9.8ºC near the end of perfusion at 5:41am. The patient's head was resting in a pan filled with ice, but temperature increased as perfusion proceeded due to the access to burr holes required and rising perfusate temperatures. Higher temperatures increase the diffusion rate of cryoprotectants, but also increase the toxicity. The use of two reservoirs for this case may have increased the rate of temperature rise. I am investigating means of temperature control.
Perfusion began with 10% ethylene glycol. Cryoprotectant typically displaces blood from vessel walls — even after a washout — so it was not surprising that there was some initial blood. There were also what Mr. Walsh described as tiny clots (microclots), which could have formed during the slow dying process (low molecular weight heparins given prophylactically might have prevented this).
Over the years I have become increasingly disturbed over the amount of edema suffered by CI patients. Edema in tissues — notably in the brain — means that tissue bloated with water is compressing blood vessels, and thereby limiting fluid flow, limiting the ability to replace body water with cryoprotectant. Sometimes the edema becomes so bad during perfusion that blood flow stops altogether, and the perfusion must be halted. Warm and cold ischemia cause blood vessels to become increasingly leaky such that water flows into the interstitial space (spaces between cells). Thus, ischemia causes vasogenic edema (edema from leaky blood vessels). The other main form of edema is cytotoxic edema, where cells fill with water. Cells in ischemic tissues no longer have enough energy to pump sodium out of the cell. Sodium entering cells brings in accompanying water, resulting in cell swelling (cytotoxic edema).
We are not helpless against edema caused by ischemia. Conventional medicine has effectively reduced cerebral edema with sodium chloride and mannitol solutions. Rat experiments have generally shown sodium chloride to be superior to mannitol in reducing brain water content [CRITICAL CARE MEDICINE; Tong,TJK; 33(1):203-208 (2005)].
Even undamaged blood vessels can leak water into tissue if oncotic pressure is deficient. Blood contains albumin to prevent such leakage by maintaining oncotic pressure. Blood replacement solutions and organ preservation solutions often contain HydroxyEthyl Starch (HES) to play the role of albumin in maintaining oncotic pressure. Because HES is difficult to obtain and can cause microcirculatory disturbances, PolyEthylene Glycol (PEG) has been used as a replacement for HES with good results [THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS; Faure,J; 302(3):861-870 (2002) and JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY; Franco-Gou,R; 22(7):1120-1126 (2007)]. PEG is also fairly inexpensive.
For CI's 93rd patient I added 2.93 grams (100 milliosmoles) of sodium chloride and 20 grams of PEG to each kilogram of the 10% ethylene glycol (EG) solution. The 10% EG solution is the solution with the most water content, it is the first solution used in perfusion, and it is the most suspect for causing edema. Making this initial solution hyperosmotic and hyperoncotic would benefit all CI patients, not only those suffering from ischemic edema. It is easier to replace body water with cryoprotectant if the body water has been removed first.
Preparing for CI's 95th patient I made an even more aggressive effort against edema — and for increasing water-replacement efficiency — than I had made for the 93rd patient. I increased osmolality and oncotic pressure from all of the perfusion solutions (not just for the initial 10% EG solution), using the same carrier solution. The carrier solution contained not just an additional 100 milliosmols of saline to reduce cerebral vasogenic edema across the blood brain barrier, but contained an additional 50 milliosmols of mannitol to reduce cytotoxic edema. Moreover, I made the carrier solution hyperoncotic, by increasing oncotic pressure one-quarter above normal with extra PEG.
70% VM−1 is normally kept in the freezer. When I put the 70% VM−1 having the new carrier solution into the freezer, the solution turned milky white and became impossibly viscous. But when I moved this milky 70% VM−1 solution into the refrigerator, the viscosity returned to normal. There was no obvious precipitation, but the milky color should have been a warning of a problem. 70% VM−1 at refrigerator temperature would be more toxic than 70% VM−1 at freezer temperature, but I reasoned that the benefits of reduced body water would out-weigh the hazard of cryoprotectant toxicity.
The patient was perfused with more than 4 liters of 10% ethylene glycol and at least 8 liters of 30% ethylene glycol in the carrier solution shown in the table. Then, prior to any CI−VM−1 perfusion, burr holes were made in the skull. Both the right and left burr hole showed an initial shrinkage of the cerebral cortex 15 millimeters below the skull, considerably more than the maximum shrinkage of 5mm seen for the right burr hole of the 93rd patient — illustrating the effectiveness of the new carrier solution in removing brain water.
Perfusion was then attempted with the milky 70% VM−1 solution, but the filter immediately became clogged. The milky color had been due to PEG that had come out of solution to form tiny particles that were too small to precipitate. But the tiny particles were too large to pass through the filter. Fortunately, the particles clogged the 40 micron filter rather than plugging the capillaries of the patient. A new filter was put in place of the old one, and the patient was perfused with nearly ten liters of 70% VM−1 (in the usual iso-osmotic, non-oncotic carrier solution), more than had been deemed adequate to vitrify the 79th patient.
The notetaker observed some opacity of the 30% ethylene glycol and a decline in fluid flow, but this was not observed at the jugular. I later looked at the 30% ethylene glycol in the refrigerator at CI and observed some slight opacity, so I re-filtered the solution. Fluid flow cannot have been much affected by the 30% ethylene glycol because the brain continued to shrink during and after the 30% ethylene glycol perfusion.
The refractive index of the effluent was 1.366 after six liters of VM−1 had been perfused, and was 1.3586 at the end. Intermediate values were as low as 1.3586 and as high as 1.3651, but this was a small range with no trend, and is indicative of random variation. These values are well below the values of 1.416 for 60% VM−1 and 1.4275 for 70% VM−1 — and they showed no trend. After nine liters of 70% VM−1 the 93rd patient had an effluent refractive index of 1.424 — not unusual for a CI patient, and indicating adequate VM−1 concentration to produce vitrification. But the perfused 70% VM−1 was not affecting the effluent refractive index for some reason. I later tested the refractometer and it was working fine.
Perfusion was essentially over, but there seemed to be nothing to lose by bypassing the filter and trying to perfuse with the milky VM−1. Predictably, the capillaries immediately blocked fluid flow and the milky solution broke through the descending aorta. The pump was turned-off.
After perfusion the patient's face was visibly dehydrated. The cerebral cortex had shrunken 26mm below the skull at the right burr hole and 27mm at the left burr hole — indicative of considerable dehydration. This is an extremely hopeful sign that the brain was vitrified on cryogenic cooling by dehydration as well as by VM−1. It is believed that Alcor's M22 cryoprotectant achieves most of its vitrification by dehydration of the brain, insofar little M22 is believed to cross the blood-brain barrier. (Such concerns were what motivated Dr. Pichugin to spend so much time trying to find detergents that will safely open the blood-brain barrier.) Ice does not form without water, and the brain — as well as brain cells — does not contain many nucleators.
Alcor considers the brain to be vitrified by dehydration when the volume is 78% the original volume. Subtracting 2mm from the skull thickness, our patient's brain had shrunken 13mm after the ethylene glycol perfusions and an additional 12mm after the 70% VM−1 (both standard and milky) perfusions. The formula for the volume of a sphere in terms of the diameter is (1/6)πd3, which means that a 13mm diameter reduction of a 76mm diameter brain would give a volume 76% of the original, and a 25mm reduction would give a volume 58% of the original. If the brain is 80% water, then complete desiccation would leave a brain volume that is 20% of the original. Given the high tolerance for dehydration I have seen in many cell studied (especially when the cells are not quickly returned to isotonic, normothermic conditions), I think that the patient's brain was well preserved by dehydration, without harm.
A number of CI Directors have become concerned that I have been modifying the cryoprotectant carrier solutions without adequate testing. The components I have used have been extensively tested in animal experiments and in clinical trials, and I have an extensive collection of peer-reviewed journal articles documenting tests. But none of these articles mention putting PEG into a freezer. In response to concerns by CI Directors (and my own concerns) I will not make more modifications to the carrier solutions, and I believe we should return to using the traditional VM−1 carrier for the time being. I have paid for some research to be done on this by outside researchers. Given the excellent dehydration seen with this patient, I think it would be a mistake to return to an iso-osmotic, non-oncotic carrier solution for the EG solutions. But I am returning to ordinary m-RPS-2 carrier solution for the 70% VM−1.
When the cannula was removed from the femoral artery, it was clearly not long enough to have reached the descending aorta, much less the heart. Asked how perfusion had been possible, Mr. Walsh said that the descending aorta had not been completely clamped because of his belief that it contained the cannula.
The temperature probe in the nasopharynx, as well as temperature probes under the skin of the skull and in the chest, were stitched to the patient. The patient was then moved from the perfusion table to a moveable cart. The patient's head was placed in the plastic head enclosure with his neck resting on the edge of the box. Dry ice pellets were added to surround the patient's head. Then isopropyl alcohol was added to create a cold, head-cooling slurry. Then the patient was driven to the Cryonics Institute.
At the CI Facility the dry ice pellets were scooped out of the plastic head enclosure until the patient's head could be lifted free. The patient was then rolled to the computer-controlled cooling box and lifted into the box. When cooling-box cooling began the controlling temperature (under the skin of the skull) was just under −10ºC.
I was fortunate to be in dialog with a cryobiologist, who offered some useful suggestions for an improved cooling protocol to use for patients in the CI cooling box. Some new concepts leading to revisions of our previous protocol include the idea that holding periods ten or twenty degrees above glass transition temperature can provide significant stress relief because the viscosity and thermal stress can be very high at those temperatures. Also, cracking at higher temperatures results in larger, but fewer cracks than cracking at lower temperatures. So if cracking is inevitable, it is better to force cracks at larger temperatures by rapid cooling. Finally, rather than cool linearly from glass transition to liquid nitrogen temperature, it is better to cool exponentially — slowing the cooling rate as temperature declines because thermal stresses accumulate more rapidly as temperature declines. Thus, the cooling protocol recommended by the cryobiologist was:
cool as fast as possible to −100ºC
hold at −100ºC for 24 hours (stress relief)
cool from −100ºC to −110ºC in 1 hour (10ºC/hour)
hold at −110ºC for 24 hours (stress relief)
cool from −110ºC to −120ºC in 1 hour (10ºC/hour)
hold at −120ºC for 24 hours (stress relief)
warm from −120ºC to −118ºC in 1 hour (annealing)
hold at −118ºC for 2 hours (annealing)
cool from −118ºC to −145ºC in 30 minutes (rapid-cooling cracking step)
cool from −145ºC to −170ºC in 25 hours (1ºC/hour)
cool from −170ºC to −190ºC in 50 hours (0.4ºC/hour)
cool from −190ºC to −196ºC in 24 hours (0.25ºC/hour)
(For a more detailed explanation of these principles, see STRESS & STRAIN AT LOW TEMPERATURE and COOLING PROTOCOL NEAR Tg FOR VITRIFYING CRYONICS PATIENTS.)
There was a technical problem in implementing this protocol, however. Our computer program will not allow more than ten steps. So I ran the first two steps and skipped the third step (resulting in rapid cooling from −100ºC to −110ºC). After the first 26 hours I modified the program to drop the steps that had completed and inserted another holding step. As a result, a complete graph of the full protocol could not be completed. So the complete cooling is shown in two graphs below:
|First 26 hours||Last 140 hours|
The annealing step was not much different that what we have using for previous patients. But the end of cooling did not go as planned (or programmed). The cooling bottomed-out just below −192.2ºC rather than at −196ºC. The same effect had just been observed for the small cooling box when used for cooling a cat. I had assumed that the box was too inefficient to cool to −196ºC, but it was quite a coincidence that the same would be true for the large cooling box — and with such coincidence of inefficiency. Andy suggested that the thermocouple may be giving a wrong reading. Sure enough, when I placed a probe in liquid nitrogen, it gave a reading of about −192ºC. Dry ice (which is harder to stick a thermocouple into) gave a reading of −74ºC (although I trust this result less than the liquid nitrogen reading). Adjustments will have to be made to the programming to account for these errors until such time as the thermocouples can be re-calibrated.
|Annealing step||Final hours|
Robert Ettinger with the
Rob Henderson family
If I had made no adjustments the cooling box would have filled with liquid nitrogen — the valve continuously open in a futile effort to cool four degrees lower than the control probe was reading. I therefore changed the program to hold at −192ºC, which allowed the valve to open and close (giving a more spiked appearance to the cooling curve).
The net result of this was the Curtis Henderson received the best anti-cracking cooling that any patient has ever received in the history of cryonics. However, later cooling with cats revealed a danger of cooling mishap that may be associated with any cooling protocol that is longer than ten steps. So it may be a while before another patient gets such an excellent anti-cracking cooling.
Rob Henderson phoned to ask if he and his family could come see his father being moved from the cooling box to the cryostat. He drove from New York with his wife and two children, arriving in time for the move on Friday, July 3rd. Robert Ettinger drove to the facility from his nearby home so that he could meet with the family — giving Rob a chance to meet his namesake.
Rob Henderson asked to get a close, identifying look at Curtis. Rob seemed very apologetic in asking for this — reassuring us that he did not distrust us — but saying that he had promised Curtis that he would make sure that Curtis got into liquid nitrogen. We were not offended by the request, of course, but I was surprised that Curtis would feel the need for this kind of reassurance. In the past I have heard of requests for little windows on the cryostats so that the patient's faces could be seen. Only recently a lawyer told one of our Members that lack of ability to validate that patients are in liquid nitrogen — with periodic spot-checking and identification — rather than technology is the greatest obstacle to cryonics being more widely accepted by the public.
|Rob looks at Curtis||Curtis' Grandson gets close|
As patient family members have done in the past, Rob stood on a step-ladder and looked at his father in the cooling box. We had warned Rob that Curtis' face would be somewhat dehydrated. Rob looked at his father long enough to satisfy himself that it was Curtis. Rob's wife had no desire to look.
Curtis was wrapped in a sleeping bag and removed from the cooling box. Andy's brother-in-law, Dave, poured liquid nitrogen on Curtis from a bucket while Andy tied and strapped Curtis to his backboard. Rob watched as Curtis was lowered into liquid nitrogen in a cryostat.
On their way home to their New York farm, Rob Henderson's family stopped at Niagara Falls for the Fourth of July.