Tag: Perfusion

The future of Alcor

Alcor’s recent news item about its 2009 Annual Board Meeting and Strategic Meeting contains a number of encouraging statements. On the front of institutional reform, however, there is not much news to report. The passage about the need to balance recruiting new Board members and preserving institutional memory reads as a rather uninspired defense of the Board’s recent decisions. In light of the growing recognition that most of Alcor’s problems over the years can be tracked back to the composition and functioning of the Board of Directors, one would have expected more innovation on this front.  A major problem with a self-perpetuating Board of Directors remains that there are few mechanisms available in case a competent Board of Directors would change in an incremental fashion into a contra-productive Board. Perhaps the idea of term limits could prevent such scenarios.

In particular, there is an urgent need to adopt institutional changes that can prevent the highly variable quality of patient care that has been observed in the history of the organization.  Another challenge that remains is the recruiting of  additional Board members with a strong knowledge of Alcor’s technical operations and the delivery of standby services. Without this knowledge (and some degree of common sense) it is highly unlikely that the Board can do a serious job of overseeing such matters.

One of the most positive items in Alcor’s report is the recognition that Alcor would benefit from substantial cost savings in its operations.  Throughout most of Alcor’s history the organization has been dependent on (unpredictable) donations from wealthy members to sustain normal operations.  Obviously, this way of funding the operations of a cryonics organization (as opposed to long term patient care) constitutes an irresponsible gamble. Donors should be commended for being reluctant to contribute to Alcor (any further) until Alcor has shown evidence of getting its financial house in order. A number of sensible proposals were discussed to generate more structural income for the organization such as increasing membership dues, raising cryopreservation minimums, introducing a recommended funding level (as opposed to just a minimum funding level), and creating income-generating endowments.

One aspect that is largely ignored in this report, however, is the potential for substantial cost reductions in Alcor’s daily operations itself. For most of its history Alcor used to be rather transparent about staff member salaries in its communications and the magazine. It may not be a coincidence that this practice disappeared  during the period when Alcor saw substantial increases in compensation for (some of) its staff members. To give some perspective, the old Tim Freeman Cryonics FAQ included the following question and answer:

7-2.  Is anyone getting rich from cryonics?  What are the salaries at these organizations like?

In December 1990, Cryonics magazine reported that the Board of Directors of Alcor voted a 25% pay cut for all of the staff, so they could keep their budget balanced.  Many of the Directors are also on the staff.  The salaries after the cut ranged from $22,500 annually for the highest paid full-time employee (the President) to $14,400 for the lowest-paid full-time employee.  None of the Alcor staff are getting rich from their salaries.

It would be a worthwhile undertaking to do a comprehensive study of Alcor’s staff and consultant compensation history and policies (or lack thereof). There is never a shortage of arguments to justify higher compensation and ad-hoc decision making in cryonics, but it is doubtful that generous salary increases in the industry over the years were necessary to recruit or retain competent staff members. It might even be argued that a number of problems in cryonics are actually linked to offering wages that exceed what the employees who receive them would otherwise earn in the market place. Similarly, substantial cost savings can be obtained by increasing productivity and decreasing staff members. Issues of compensation and staff efficiency should be essential topics of consideration in any serious discussion about Alcor becoming more self-sustaining and less dependent on wealthy donors.

Another topic that deserves attention in this context is that all of Alcor’s major technologies (medications protocols, organ preservation solutions, vitrification agents) are licensed to the organization by independent research labs. Although Alcor itself is mostly to blame for not having developed competing technologies of its own since the mid-1990s, it is important to recognize this dependence. At the very least, Alcor could benefit from a cost-benefit analysis of some of these technologies and from developing contingency plans to deal with scenarios in which these technologies would no longer be available or cost-prohibitive.

During most of its history Alcor (and later, CryoCare) promoted the idea of cryonics as a medical procedure and criticized other cryonics organizations like the Cryonics Institute for being overly optimistic and reckless.  In an ironic twist of fate, some critics of Alcor now use this perspective to criticize the organization for not living up to the idea of cryonics as medicine. As a general rule, this is to be welcomed. Where this criticism can go off track, however, is when it is insufficiently recognized that knowledge of conventional medicine is a necessary, but not a sufficient, condition to do good cryonics. One of the worst scenarios for the future of cryonics is one in which regulators impose standards upon cryonics organizations that  actually increase the challenges of providing good patient care; something that has happened already in the case of the Cryonics Institute when the organization was forced to perform a complex technical procedure like cryoprotective perfusion at a funeral home.

Faced with the technical complexities of ramped cryoprotective perfusion, Alcor has decided to develop a system that not only uses software to record perfusion parameters (concentration, pressure, temperature, refractive index etc.) but to use the same software to control them as well. Provided that this new system lives up to its expectations, this development will be a major step towards a system that can use real-time feedback to adjust perfusion parameters in a manner that so far has only been available in small organ cryobiological research. The data that will be generated during cases can, in turn, be used to create cases reports that follow a consistent, formal standard. When these reports are used in an intelligent fashion, the prospect of developing technologies and protocols that can reduce the high variability in patient care will be feasible.

Experiment made on the mummy

As documented in David M. Friedman’s The Immortalists: Charles Lindbergh, Dr. Alexis Carrel, and Their Daring Quest to Live Forever, Lindbergh and Carrel considered the human body a living machine made of replaceable parts. A major reason why Carrel was interested in developing and refining equipment to perfuse isolated organs is because he believed that this would allow damaged tissue to be repaired outside of the body and ultimately substitute new organs for diseased organs. His ultimate objective was to conquer death itself.

In The Immortalists, Friedman writes about one experiment that should leave no doubts about Carrel’s personal commitment to the scientific conquest of death. When Lindbergh supervised the packing of Carrel’s property after his death they found:

..a 3,000-year-old Egyptian mummy the surgeon had tried to revivify  in 1925. (“A small hole was made in the abdomen of the mummy about 3 cm. from the right iliac spine. The skin was hardened and very tough,” Carrel wrote of his failed experiment.)

Without seeing the complete notes of these experiments, it is not possible to say what Carrel’s  specific intentions were. Although our knowledge about the ultrastructural effects of different preservation techniques has greatly improved since Carrel lived, it is hard to imagine that a  brilliant scientist like Carrel seriously believed in resuscitation of the 3,000-year-old Egyptian mummy. Perhaps his objective was more modest and involved recovery of material for cell and tissue experiments, an objective that would not have been unrealistic considering the recent reported findings of clonable DNA in an Egyptian mummy.

Carrel’s notes of this experiment, called “Experiment Made on the Mummy,” are included with his papers which remain at Georgetown University’s library in Washington DC.

Lindbergh and Carrel's quest to live forever

It’s difficult to follow up a best-selling book about the cultural history of the penis, but David M. Friedman has a knack for engaging readers in topics that others find difficult to broach. This time he tackles the touchy subject of death by relating the intertwined biographies of Charles Lindbergh and Alexis Carrel in his new book, “The Immortalists: Charles Lindbergh, Alexis Carrel, and Their Daring Quest to Live Forever.”

Like most people, I had only heard of Charles Lindbergh as an aviator and in the context of his first child having been kidnapped and murdered. Imagine my surprise, then, when I happened upon a passage in Cardiopulmonary Bypass: Principles and Practice outlining Lindbergh’s contributions to Alexis Carrel’s isolated organ perfusion research in the 1930s – contributions which, for the first time, “permitted sterile, pulsatile perfusion at variable ‘pulse rates’ and variable perfusion pressures.”

Wait a moment. How did the world’s most famous aviator become involved in organ perfusion? Although much information about Lindbergh and Carrel’s work exists online, Friedman’s book provides a much more personal history of these two accomplished men.

Lindbergh’s overnight catapult into fame and adulation as the first man to fly across the Atlantic ultimately culminated in his loathing the press and greatly valuing privacy. A few years after his groundbreaking flight from New York to Paris in the Spirit of St. Louis, Lindbergh began thinking about things other than aviation. In particular, he wondered why people should have to die. Always an ambitious person, he decided to enter the realm of biology in order to seek the solution to eternal life. Once he made his quest known, it was not long before he was introduced to Alexis Carrel.

Carrel, a French scientist working at the Rockefeller Institute in New York, had already been awarded the Nobel Prize in medicine in 1912 and was far along in his own personal quest for immortality when Lindbergh came along. Convinced that the body was little more than a machine with replaceable parts, Carrel had begun his research by culturing cells from animals and keeping them alive indefinitely after the animal had died, thus “proving” the immortality of man and inviting him to move on to the next step: culturing entire organs. So far, Carrel had been successful at keeping the organs alive outside of the body for a few hours by perfusing them with a nutrient medium, but infection invariably set in and caused the organs to fail.

Lindbergh tackled the problem of creating a better perfusion pump with gusto. Using his engineering expertise and an innate sense for biology he eventually developed a pump that kept the perfusate sterile, thus allowing organs to be kept alive for several days or even weeks. Carrel and Lindbergh published their preliminary results in Science (“The Culture of Whole Organs,” July 21, 1935) and Lindbergh described the perfusion pump in a separate article published later (“An Apparatus for the Culture of Whole Organs,” September 1935, Journal of Experimental Medicine). The entire effort was then written up for publication as a book (“The Culture of Organs”) in 1938. As a team, it was obvious that Carrel and Lindbergh were made for one another.

That was true in more ways than one. Carrel was a eugenicist through and through, and often expounded on his ideas and philosophies with Lindbergh when they weren’t in the lab. Lindbergh had long considered himself superior to the masses of people he sought to avoid (especially journalists), and Carrel’s theories provided him justification for his opinion of himself and other “great men.” Eventually, Lindbergh became so enamored with eugenics that he developed a profound respect for Nazi Germany, much to his protégé’s dismay. Eugenicist or not, Carrel (like most Frenchmen who lived through World War I) hated the Germans and cautioned Lindbergh against speaking too loudly in their favor.

But speak loudly Lindbergh did. In fact, he abandoned the laboratory altogether in order to promote his new cause: non-interventionism. Becoming the spokesman for the America First Committee, he toured the U.S. speaking against America’s involvement in World War II, arguing that we should instead allow the situation in Europe to play out on its own accord. But while he believed that America should not involve itself in foreign wars, he also said that he would be the first to defend his country if it were attacked.

When Japan bombed Pearl Harbor, Lindbergh tried to make good on his promise. However, having thoroughly irritated the Roosevelt administration with his anti-war rallies, he was prevented from serving his country as anything but a civilian. To prove his patriotism Lindbergh fought in the South Pacific, providing cover for American bombers and pilots and eventually shooting down a Japanese plane himself, with the knowledge that if he were caught he would receive no aid from the U.S. and would stand alone.

Carrel, meanwhile, returned to occupied France after retirement from the Rockefeller Institute and tried to create an organization of the brightest thinkers in France to create policies to guide and govern the common people and return his country to glory. Ultimately this project failed and Carrel died ostracized and under house arrest.

When the war was over, Lindbergh visited the concentration camps in Germany and saw the horror and devastation perpetrated in the name of supposed science. He was beside himself and couldn’t believe that the “neat” and “organized” Germans that he had admired would commit such atrocities. He returned to the U.S. to examine his life – and came to the conclusion that he, too, had allowed science to dominate his perspective. He documented his monumental change in attitude in a book called “Of Flight and Life” in 1948. Friedman documents:

“…Lindbergh was urging Americans to break free from the “grip of scientific materialism,” lest it lead them, shackled and helpless, to “the end of our civilization.” The choice facing America, Lindbergh wrote, was as simple as it was stark: “If we do not control our science by a higher moral force, it will destroy us.”

This about-face led Lindbergh to an even greater revelation: that he was no longer an immortalist. After spending time in Africa and coming to appreciate the beauty of nature, Lindbergh dedicated the remaining years of his life to environmentalism. Friedman writes that “The person who once tried to save the world by saving white civilization would now try to save the world from white civilization.” Lindbergh wrote:

“When I watch wild animals on an African plain, my civilized [method] of measuring time gives way to a timeless vision in which life embraces the necessity of death.” I see individual animals as mortal manifestations of immortal life streams; and so I begin to see myself. I am not only one, I am also many, a man and his species. In death, then, is the eternal life which men have sought so blindly for centuries, not realizing they had it as a birthright.”

When faced with a cancer diagnosis in 1974, Charles Lindbergh had already made his peace with death, believing now that it was only through death that man may become immortal. With the same determination that he had done everything in his life, he planned his funeral down to the last detail. When the time came, he flew to his home in Maui and reminisced with his wife and children about his life – one of the most accomplished lives of the 20th century. Then, the man who was the first to fly solo across the Atlantic, who made the “Model T” of perfusion pumps, and who became a great political activist turned environmentalist, finally abandoned science…or, as he told the doctors who wished to continue treating his cancer in its last stages, “no, science has abandoned me.”

Remote blood washout in cryonics

One argument that is often raised in favor of “field vitrification” (or vehicle based vitrification) is that it will reduce the time of (cold) ischemia and eliminate the harmful effects of remote blood washout and transport of a patient on water ice to a cryonics facility. A related argument is that field vitrification will eliminate stabilization.

In fact, field vitrification will not eliminate the need for stabilization because patients need to be protected from warm ischemic injury after cardiac arrest until a location to carry out cryoprotectant perfusion has been secured and surgical access to the patient’s vessels has been established (a procedure that, in cryonics, takes at least fifteen minutes under the best of circumstances). During that period the patient will still require prompt cardiopulmonary support, induction of hypothermia, and administration of anticoagulants and neuroprotective agents. As a consequence, stabilization times should not differ between field vitrification or remote blood washout. In light of the possibility that field vitrification will likely require more demanding and time-consuming surgery, field vitrification might even necessitate longer stabilization times. The only procedure that could reduce or eliminate stabilization would be hospital-based vitrification.

Field vitrification will reduce the period between cardiac arrest and the start of cryoprotective perfusion. But whether this is a clear advantage or not depends on the question of whether remote blood washout and transport on water ice introduces additional injury to the patient. Recent anecdotal observations of cryoprotective perfusion of patients who have been washed out in the field indicate that the procedure of blood washout itself may be harmful. It is not clear, however, whether this is an intrinsic element of remote blood washout and cold transport or the result of poor perfusion techniques and flawed composition of the organ preservation solutions that are used to replace the blood.

In cryonics, remote blood washout is done for at least three reasons: (1) to eliminate the possibility of blood clotting and hypothermia-induced red cell membrane rigidity, rouleaux formation, and cold agglutination; (2) to remove ischemia-induced inflammatory products and endotoxins from the circulation; and (3) to protect the patient from hypothermia-induced cell injury and edema by substituting the blood with an organ preservation solution.

The organ preservation solution used today is called MHP-2. The original MHP solution is a modification of RPS-2 (an organ preservation solution for hypothermic kidney preservation created by Greg Fahy at the American Red Cross) and stands for Mannitol-Hepes-Perfusate. It is designed as a so called “intracellular” organ transplant solution. In order to reduce passive ion exchange as a result of hypothermia-induced cell membrane pump inhibition, its composition more closely resembles the composition of the solution inside the cell rather than the interstitial fluid or blood plasma. MHP also contains molecules to provide oncotic support, prevent acidosis, and reduce free radical damage. In a series of groundbreaking experiments by Jerry Leaf and Michael Darwin, MHP was successful in resuscitating dogs from up to 5 hours of asanguineous ultraprofound hypothermia. MHP-2 is a modification of MHP that is believed to produce superior results.

A number of arguments have been put forward why remote blood substitution with MHP-2 is not successful in securing viability of the brain during transport, and may even produce adverse effects. The most obvious reason is that MHP has been validated for up to 5 hours of ultraprofound hypothermia, which is not the typical transport time of a cryonics patient. A related problem is that MHP has not been validated in a model that reflects the typical cryonics patient who experiences variable periods of hypoperfusion and warm ischemia prior to and after cardiac arrest. And, unlike the canine asanguineous ultraprofound hypothermia experiments, in cryonics MHP is used as static cold preservation solution instead of being continuously perfused at low flow rates. Although MHP can reportedly recover dogs from up to 3 hours of asanguineous circulatory arrest (clinical death), such a protocol further reduces the time that viability of the brain can be maintained during transport.

Although the MHP patent and the notebooks from the original washout experiments are clear that MHP should be prepared as a hyper-osmolar perfusate (~ 400 mOsm), it has been established that in recent years many batches of MHP have not been mixed with hyper-osmolality as an endpoint, due to a lack of osmometry quality controls. The exact effects of this are unknown but have been hypothesized to explain why recent remote blood washout has produced worse results than in the past, possibly by aggravating, or in the case of a hypo-osmolar perfusate, producing edema. This problem, and the confusion about the exact composition of MHP-2, is briefly discussed in the Suspended Animation case report of Cryonics Institute patient CI-81.

Field vitrification is not the only solution to the limitations of remote blood washout and transport on water ice. Another solution would be to improve the composition of hypothermic organ preservation solutions and perfusion protocols to secure extended periods of cerebral viability during transport. Instead of substituting the patient’s blood with an organ preservation solution, after which the patient is shipped on water ice, the organ preservation solution can be continuously (or intermittently) perfused at low flow rates, similar to machine perfusion in conventional organ preservation, while the patient is being driven in a rescue vehicle to a cryonics facility. This has a number of advantages, including the possibility to sustain aerobic metabolism, improve microcirculation and administer cytoprotective agents.

Although cerebral viability of the brain may be extended by improved organ preservation solutions, there seems to be a fundamental limit to shipping patients in hypothermic circulatory arrest because the remaining energy demands of the brain will need to be satisfied by oxidative phosphorylation (or other energy substrates) at some point. Although it is not known how far these limits can be pushed by static use of organ preservation solutions, it is likely that a protocol of continued hypothermic perfusion of remote cryonics patients will exceed these limits. Like field vitrification, such a protocol will present non-trivial technical and logistical challenges.

This still leaves the question of whether remote blood washout can aggravate injury in ischemic patients unanswered. Since the original canine experiments investigated MHP in healthy animals we do not know if some patients would be better off without a blood washout. Dr. Southard, one of the inventors of Viaspan (also called the University of Wisconsin solution in the scientific literature), discussed similar concerns in a recent interview:

“In clinical organ preservation/transplantation, there are many unexplained incidents of reperfusion injury. This is characterized by delayed graft function in the liver and kidney. We do not see this in our animal models. Thus, there are some differences between how experimental animals and human donor organs respond to organ preservation. The difference may be related to the fact that the UW solution was developed to preserve the “ideal organ.” This is one taken from a relatively young and healthy lab animal donor and transplanted into a healthy recipient. In the clinics, the donors are usually brain-dead (brain trauma), remain in the ICU for periods up to a day or more, are treated for hypotension, and come from an uncontrolled group of donors. Therefore, we are now studying how UW solution preserves organs from the “less-than-ideal” donor. We are simulating the clinical condition by inducing warm ischemia or brain death in experimental animals to determine if UW solution is suitable for these types of organs. If not, we will develop an ideal method to preserve these less-than-ideal donor organs.” (quoted on the old Viaspan website).

Similarly, organ preservation solutions used in cryonics need to be investigated in models that better reflect the typical pre-mortem pathophysiology and post-mortem procedures encountered in cryonics. Developing stabilization technologies and procedures for “less than ideal patients” is an important element in an approach known as “Evidence Based Cryonics.”