Case reports in cryonics

This article was originally published in Cryonics magazine, 4th Quarter, 2010.

Introduction

The most important reasons for writing case reports are:

1. To provide a transparent and detailed description of procedures and techniques for members of the cryonics organization and the general public. A cryonics organization that never writes anything about its cases and procedures should be treated with more caution than an organization that does.

2. To validate current protocol and procedures in general, and its actual implementation in particular. A case report should not only record what happened but should be used for guidance as to what should happen in the future. A detailed case report, especially when a variety of physiological data has been collected, contains a wealth of information that can be analyzed for the team members’ and patient’s benefit. Cryonics cases are relatively rare (compared with other medical procedures), so we should try to learn as much as we can from the cases we perform.

3. To serve as a medical record to assist with future attempts to revive the patient. Although advanced future medical technologies may make it possible to determine the physiological condition of the patient down to the molecular level, it is important to provide as much medical information as possible to help in efforts to revive patients. Having a detailed record of the patient’s condition prior to pronouncement, subsequent stabilization, and cryoprotection, may also help the organization in establishing the desired sequence of revival attempts.

4. To gain more scientific credibility. If we want scientists and physicians to take us seriously, we need to convince them that we attempting to cryopreserve our patients in a scientific manner.  Professional case reports can provide this kind of credibility.

This article will mainly concern itself with the general question of how a case report can help a cryonics organization in improving protocol, techniques and skills.

Protocol

To be able to assess the quality of patient care in a cryonics case, it is important to specify what the intended protocol was prior to writing about the case. Only if we know what the organization was supposed to do will we be able to assess how successful the care was. For example, if there is no mention of collecting (and analyzing) blood gases during a case this may have been because it is currently not a part of the organization’s protocol, but it may also be the result of a shortage of skilled personnel, defective equipment, or other problems or deficiencies. Unless the writer of the report specifies what should have happened, it is difficult to assess the quality of preparation and performance. If preparation for the case was poor and there was no (functional) extracorporeal perfusion equipment available, the case report should not simply state that the organization attempted to do a

case without substituting the blood with an organ preservation solution, but also why the blood washout was not attempted.

In reality there will be many deviations between the organization’s protocol and what actually happens. Human cryopreservation cases are not controlled laboratory experiments, and as many people who have extensive experience doing cases know, unique situations present themselves, including frustrating events that are beyond the control of even the most skilled medical professional. Nevertheless, the inherent unpredictability and uniqueness of cryonics cases is too often used as an excuse or justification for failing to follow established protocol, or for serious errors and omissions in the care of the patient. Documenting the prospective protocol will help us to gain a more systematic understanding of what is possible (or essential) and within our control, versus that which is not.

Detail

The importance of writing detailed descriptions of the procedures and techniques employed during a case cannot be overestimated. This not only enables the reader to gain a comprehensive understanding of the techniques used, it also allows detailed analysis of the difficulties that were encountered during a case that would not have been noticed if there is only a brief mention of it. For example, instead of simply noting that medications were administered, providing comprehensive details is essential. There are many reasons why this is the case.

Case reports should be prepared with the possibility in mind that what may seem mysterious, or inexplicable, to the writer may be crystal clear to an expert or perceptive reader when provided with sufficient detail.

Providing as much detail as possible also serves to allow for replication of the techniques used by others. This is a critical component of the scientific method. Other investigators or practitioners must be able to duplicate the procedures and obtain the same outcome. Yet another consideration is that factors not now perceived or considered to be important may become so in the future. There are many examples of this in the history of cryonics that have proved essential to improving patient care. For example (1), in the early days of cryonics bags of ice were used to facilitate external cooling. It was not until comprehensive and consistent core cooling data were collected that it became apparent that this technique required 6-8 hours to cool a patient to ~ +20°C (room temperature!) with the patient cooling at a rate of 0.064°C/min. Documentation of these appallingly slow cooling rates provided powerful incentive to develop stirred water ice baths which increased cooling rates to between 0.15°C/min  and 0.33°C /min, allowing cooling to ~15°C within 90 minutes to 2 hours after the start of cardiopulmonary support (CPS) (see graph below).

Comparison of Cooling Methods: Above are actual cooling curves for three adult human cryopreservation patients on Thumper support, using ice bags, the Portable Ice Bath (PIB), and the PIB augmented by SCCD (squid) cooling. Patient A-1133 weighed 56.8 kg, patient A-1169 weighed 57.3 kg, and patient A-1049 weighed 36.4 kg. As this data indicates PIB cooling is approximately twice as efficient as ice bag cooling. The SCCD appears to increase the rate of cooling by an additional 50% over that of the PIB (roughly adjusting for the difference in the patients’ body mass).

This example is even more instructive because continued diligent and comprehensive monitoring of cooling in multiple patients made clear other factors that were critically important to good outcome or, conversely, prohibited it. A large-framed obese male with heavy fat cover and a large amount of thermal inertia will not cool at anywhere near the rate that an emaciated, petite woman will. Evaluating the patient for fat cover and body mass index before deanimation allows reasonably accurate prediction of the cooling rate and may suggest the need for the addition of other cooling modalities such as peritoneal lavage with chilled fluid. Favorable results from application of peritoneal cooling in turn will suggest that even greater rates of cooling are possible for all patients and lead to the addition of the modality as a standard part of the protocol.

Failure to gather and promptly analyze data as basic as cooling rate precludes realization that problems exist as well as any possibility of solving them.

It is important to note that an incomplete case report doesn’t necessarily indicate failure on the part of a cryonics organization. In a case where the number of team members is limited, all resources may have to be devoted to doing the case, instead of collecting data, or assigning an essential person to the job of taking notes. In the case of limited personnel it is better to do a good case without documentation than to document a bad case. To some degree this conflict between tasks can be avoided by having some of the team members (the team leader, paramedic, etc.) use a voice recorder with a clip-on microphone. But if the number of team members is insufficient, and data collection is not possible, this should be reported in the case report and recommendations should be made and implemented to prevent this situation from occurring again in the future. Good data acquisition and scribe work are essential for a good case report and, if feasible, should be a full-time job during a case.

Analysis

Specifying the protocol and describing the case in great detail is necessary but is not sufficient. A critical review of the information and data culminating in a list of desired changes and specific plans to address them should complement this. Ideally every discrepancy between protocol and reality that has been observed during the case should be discussed. Even in a case where stabilization started promptly after pronouncement, and the protocol was followed to the letter, there is still a lot of (physiological) data that, once analyzed, may require a change in the protocol in future cases.

To assess skills, identify critical failures, formulate solutions, and compare cases in a meaningful and valid way, a consistent and systematic format of reporting cases is essential. A typical case report should be divided into sections describing protocol, patient assessment, preparation and deployment of standby assets, the details of the case (divided in sections such as  airway management, cardiopulmonary support, external and other cooling methods, blood washout, cryoprotective perfusion, and cooling to storage temperature), analysis, recommendations, and a variety of (public or non-public) appendices. Such appendices should include time-lines and graphic presentation of data, medications, cryoprotectants, and statistical analysis and comparisons to other cases.

Each case report should not only present solutions, or suggest tests and experiments to identify solutions, but provide a plan of action as to how these things can be accomplished. One approach to ensure that research and tests to validate solutions are implemented, and appropriate remedial action is taken, is to appoint an officer in the organization who is responsible for quality assurance and quality control. This individual’s job will be to ensure that case reports are written in a manner consistent with the guidelines as outlined by the organization, as well as to ensure implementation of required changes.

Another critical role of case reports is to educate the organization’s staff as well as consultants and, where appropriate, the patients’ physicians and other health care providers about protocol, procedures and techniques. Although case reports are not and should not be a substitute for comprehensive written protocols, standard operating procedures (SOPs), and thorough training of personnel, sometimes solutions to problems can only be found in case reports where a team member was presented with an unusual problem. Consistent and systematic organization of case reports will greatly enhance the utility of case reports for this purpose. For example, if a reader wants to know about surgical techniques, and problems encountered in gaining access to the circulatory system for blood washout, consulting a case report will be far easier if they’re organized in a consistent and predictable manner.

Answering Objections

One objection to writing up a case report is that it is not a controlled experiment and at best provides only anecdotal evidence. This is not the case for the following reasons.

Not all the mistakes and issues identified are of a hypothesis testing nature. For example, if a patient presents the human cryopreservation team members with a problem that could not be managed with the equipment at hand, the cryonics organization doesn’t necessarily need a larger number of cases to decide to make a change to their equipment, and to start teaching employees the necessary skills.

Similarly, what may be perceived as anecdotal evidence for the cryonics organization may be a consistent finding in nearly identical settings in mainstream medicine. For example, some issues during a human cryopreservation case may be well known in hemodynamic management of potential organ donors in hospitals, or, for example, a medication in the protocol that is undergoing trial as a stroke therapy may demonstrate the same adverse effects observed during transport of a cryonics patient.

Of course, such lessons are impossible to learn without both broad and deep knowledge of medicine and the relevant research literature. Considering the ever growing number of publications and hyper-specialization, case reports may increasingly become collaborations between numbers of people with expertise in diverse areas. The individuals with the most valuable input do not necessarily have to be the ones who did the case. A physician dealing with similar issues in a neuro-intensive care unit may identify problems and propose solutions not obvious to those delivering cryonics care to the patient.

Monitoring

We don’t know how our patient is going to fare in the future but we can know a lot about how our patient fared up to the point of long term low temperature care if we monitor his condition continuously. This starts from collecting detailed pre-mortem medical data to monitoring fracturing events during cooldown.

It is tempting to say that a case went very well if all the steps of the protocol were followed in a timely manner. This is not unreasonable because one would expect a strong correlation between an evidence based protocol and optimal care. But it is important to keep in mind that the goal of stabilization and cryopreservation is to treat the patient and not the book (as a saying in emergency medicine goes).

Without comprehensive monitoring of the patient through all parts of the procedures a case report will only document a predictable series of mechanical steps and some crude visual indicators of (relative) success at best. The things we are really interested in, like (quantitative) end-tidal CO2 measurements, cardiac output, pH, and cerebral oxygenation, cannot be observed without sophisticated equipment.

Not only do we want to know how the patient is doing after the fact, we would also like to be able to intervene during a case if we observe a trend that suggests (alternative) treatment. Only in-depth reporting and analysis combined with a sound understanding of the physiopathology and available treatments will enable us to do so.

Presentation

A comprehensive list of dos and don’ts in writing case reports is not something that can be explored in this article, but some things are worth mentioning. Stylistically, a human cryopreservation report should resemble a medical or research report rather than a sensationalized adventure for the patient or the standby team. This should apply to the organization of the material as well as the choosing of words. As a general rule mainstream medical terminology should be used instead of cryonics jargon. Editorializing should be limited, and if perceived necessary, be moved to the proper section of the report. For example, jumping from a technical description of procedures to quarrelling among relatives or complaining about government regulation doesn’t look very professional.

Protocol, procedures and techniques should be the subject of the report, not people. Cryonics preparation and procedures are very demanding and exhausting for all people involved and mistakes are made and will be made. Errors should be presented as dispassionately as possible to avoid a culture of blame and personal conflict. Experience also teaches that (potential) participants are more open to transparent reporting if a case report will not single out individuals in describing procedures.

No matter how competent the writer of the report is, each report should be proofread by most or all individuals who were involved in the case and, if possible, a variety of outsiders with appropriate technical and medical knowledge, before it is released to the general public.

Patient Care

Writing case reports as presented in this article may be more demanding and time-consuming than generally has been done in human cryopreservation, but the results may improve patient care to a degree not previously seen.  Ultimately, the most ambitious use of case reports will be one in which the case reports are analyzed as a series, measurements are compared, and patterns are established. Reading (and evaluating) a series of case reports in a systematic manner  will even enable us to answer some very fundamental questions as to whether, or the degree to which, protocol, procedures and techniques  have improved over the years.

Providing the best patient care possible for current and future patients is the reason why cryonics organizations exist, and considering how powerful a tool a good case report can be, a responsible cryonics organization should devote considerable resources and time to writing them.

As our members and resources increase, and human cryopreservation gradually becomes a part of mainstream medicine, the successful transition from basic algorithm, volunteer driven case to evidence-based cryonics will be an important mandate.

Case reports and increasing caseload

One of the biggest challenges facing a growing cryonics organization is that the organization will be faced with a growing number of cases per year. This challenge is further amplified if all these cases need to be documented. As a consequence, a cryonics organization will find itself allocating an increasing amount of time to writing case reports and falling behind publication schedule. One of the most unfortunate responses to such a development would be to make an attempt to keep writing case reports in the old style but to lower standards and take short cuts.

An alternative approach is to develop a new format for case reports that allows for a shorter report but still captures the essential objectives of case reporting. One approach is to eliminate all the narrative that is not essential for following the mechanics of the case and evaluating the quality of care. In the past there have been a number of case reports with excessive narrative but little technical reporting or analysis. For a cryonics organization with a growing caseload the opposite approach should be followed. Another approach is to eliminate detail about procedures that were performed without deviations from past protocol and expectations, provided that this is made explicit in the report. As a result, case reports will increasingly read as a description and commentary on events that diverged from protocol or new observations about existing procedures.

To establish a template for such case reports the following approach can be followed. First, it is established what kind of information is essential for doing a meta-analysis of all cryonics cases. Then these parameters are reverse-engineered to create a template for writing case reports that reconcile the need for economy of expression and documenting all the relevant aspects of a case.  One important advantage of producing such case reports is they permit easier consultation of the technical details of the case and still meet the fundamental objectives of writing case reports.

The history of case report writing in cryonics shows an erratic potpourri of approaches and styles. One of the most unfortunate victims has been the objective of using case reports to improve the practice of human cryopreservation and to formulate meaningful research questions for the sciences that inform cryonics. But if systematic thought is given to the objectives of case reporting outlined in this document, steps can be taken to leave this unsatisfactory situation behind while meeting the needs of a growing cryonics organization.

Notes

(1) I am grateful to Mike Darwin for this example and for reviewing earlier drafts of this article.

Interview with cryonics funding specialist Rudi Hoffman

hoffman formalThis is the fourth in a series of interviews with individuals in the life extension and cryonics movement. Rudi Hoffman is an Alcor and CI member and the most prominent seller of cryonics life insurance policies.  His website with information about how to fund cryonics can be found here.

Did you find out about cryonics before or after you became an insurance agent? How has each field impacted the other in your life?

In 1978 and 1979…Gee, that seems like a long time ago…I was teaching 5th grade math and science. Since I was making the, even then, paltry sum of $6,200 a year teaching, a friend of mine recruited me into the insurance and investment field.

I was recruited by a very controversial, but consumer oriented, company called “A.L. Williams Corporation” to sell term life insurance and mutual funds. The first several years in the business, I managed to decrease my already low income, while increasing my personal overhead dramatically.

A very uncomfortable combination. Perhaps some of your readers can relate, either currently or in their early careers. If you are frustrated, if you are broke, if you are worried…believe me, I have been there. It is supposed to be character building, and maybe it was, but mostly it was simply terrifying.

I recall an exciting day when one of the people who I was renting a room to called me at the office to inform me that our water had been shut off due to late payment. At the time I was also three months late on my house payment, had fixed costs thousands of dollars higher than my income, and was in truly desperate and uncomfortable financial straights. But, due to both a crusader’s zeal about the concept that A.L. Williams was championing financially for the consumer, and an abysmal lack of the good sense to quit and “get a good job,” in a matter of a few more years I eventually proceeded to do something called “making a living.”

So, I have been selling life insurance and securities investments since 1979. At some point, starting somewhere after the 25 year point of ridiculous dues paying, I have been approaching what some may call successful at it.

I have been selling cryonics life insurance, starting with my own cryonics policy, since 1994, when I signed up with Alcor.

Do you think that having cryonics arrangements yourself helps you write more policies?

Yes, I do.

It is a proverb in the sales business that “sales is a TRANSFER OF FEELING.” I was personally signed up and ideologically on board with cryonics well before I sold anyone else a cryonics policy. Being a signed cryonicist is a serious decision for me, and I think that cryonics is SUCH a rational and reasonable gamble that nearly everyone should at least consider this option.

What is the most common/pervasive myth or fallacy about cryonics you hear from people contacting you for insurance?

The general feeling of the uninformed populace is that “Cryonics is only for rich guys.” It is my passion, as well as my profession, to dispel this pernicious and potentially deadly lie. Cryonics is AFFORDABLE for most people who are in good health living in a developed country. This is because of the magical leverage of life insurance, in which a few dollars a day can create a fund of literally hundreds of thousands of dollars exactly when these funds are needed.

I recall that you have been turned down by at least one insurance company because they did not like the cryonics industry. Some people fear that progress in the science of human cryopreservation will make insurance companies less inclined to write policies. Do you agree?

I have been running my more traditional financial planning practice for about thirty years. During the last fifteen years we have incorporated the cryonics life insurance, and increasingly cryonics estate planning, as part of the financial planning practice.

ARGUING WITH IDIOTS

In this time, I have learned some astounding facts. Here is one. “Insurance company executives, and their legal staffs, can be stunningly stupid, remarkably retrograde, and frustratingly fickle.” In short, some are TRULY idiots. Here’s why I know this.

As an independent broker and Certified Financial Planner (R), I have access to literally hundreds of life insurance companies to write for my friends and clients. One would think, logically, that insurance companies would be THRILLED to have a market composed of cryonicists. We are, demonstrably and documentably, one of the most highly educated, prosperous, and long lived niche markets anyplace. We tend to be nonsmokers, health enthusiasts, seat belt wearers, and not take life threatening risks. We are proactive in our own self-care and health maintenance. We take vitamins and anti-aging nutrients, practice reduced calorie diets, and see our doctors prophylactically and often.

But, because the cryonics organizations require that they be the OWNERS as well as the partial beneficiaries of the cryonics funding policies, insurance companies by a huge majority do NOT want our business!

If you find this counter-intuitive, surprising, and virtually unbelievable, I would not blame you.

But, because cryonics is still far from mainstream, and because the insurance companies confuse the cryonics OWNED policies with a category of policies they do not like called “Stranger Owned Life Insurance” (STOLI) policies, most carriers will not provide a letter of approval for this type of business.

And, I don’t just want to “slide a policy in under the radar” of the legal or compliance department at an insurance company. I insist that the insurance company UNDERSTAND and acknowledge in writing that these are cryonics policies. I believe in business candor and transparency, and I have sometimes worked for years to get a letter of approval for our cryonics business.

Moreover, I have personally been FIRED, literally received a termination letter, from at least three major companies because I had sent them virtually exclusively cryonics related policies.

A MORE PROFESSIONAL SOUNDING CAVEAT

To be fair, like other generalizations, there are exceptions to the trend. There are companies and organizations who are very supportive and professional in helping us fund cryonics. I am privileged to work with some outstandingly talented colleagues and collaborators who do indeed, “Get it.”

With reference to the second part of the question, as cryonics becomes more mainstream, and even further proof of concept emerges in the scientific world, we will have carriers enthusiastic about this wonderful block of business. It is my intention to have full departments within major insurance carriers who will help us fund suspension and cryonics estate planning.

What is the minimum amount of life insurance that you recommend for cryonics (in 2009)?

The short answer would be $250,000.

If you are a full body vitrification client at Alcor, you need $150,000 currently. If you are at CI, and you have the funding for Suspended Animation and air ambulance services, you need a minimum of about $110,000. Here are the three LOGICAL and RATIONAL reasons to have a generous amount of OVERFUNDING over the above figures:

REASON NUMBER ONE: The traditional reason people own life insurance:

You probably have loved ones you care about, and possibly provide income for. This would include spouses, partners, children, pets, friends, and even causes you are passionate about. If you have NO ONE, and NO ORGANIZATION, you care about and want to see thrive financially, you are probably screwing up your life pretty badly and need to make some changes.

There is a difference between being an Ayn Rand Objectivist who understands ideologically the “Virtue of Selfishness,” and being a selfish jerk who is too dumb, lazy, or shortsighted to have some life insurance to help take care of those you care about. Especially if one of those people you care about is yourself…or, more precisely, your FUTURE self.

Life insurance, especially modern permanent policies, are “LONG TERM SMART” leverage of resources. If you make $30,000 a year, it would take a lump sum of $300,000 to replace your income, even assuming a generous 10% after tax return on investment.

I am far from wealthy. But I own 2 million, three hundred thousand dollars of life insurance on my life. I pay for this personally, like any other consumer. It costs me a substantial part of my annual income. But, I have a wife I truly love and want to care for, and organizations doing great work I want to support, and several cryonics trusts I want to fund with life insurance proceeds.

You, dear reader, surely care about SOMETHING outside of your skin. This is because we hope you are RATIONALLY SELF INTERESTED. Life insurance is your love made visible. It is a document of long term love and commitment to those you care about.

REASON NUMBER TWO: Due to inflation and technological progress, the price points in cryonics almost certainly will rise over time:

Although cryonics organizations have historically grandfathered earlier client rates, this is not contractually guaranteed going forward.

And the preliminary research on the next technological enhancement in cryonics, Intermediate Temperature Storage (ITS), looks to be a major improvement in saving your precious self. But, like other major improvements in medicine, this will come at a price. Due to increased engineering challenges and much higher liquid nitrogen boiloff rates, the price will almost certainly be higher even for current members. NOT to charge an increase for even existing clients would be irresponsible.

It makes sense to lock your current good health and younger age rates in now. You may not be able to get more coverage in the future at ANY price, and it will certainly be at a higher price.

REASON NUMBER THREE: You can specify a portion of your life insurance policy go to one or more CRYONICS TRUSTS:

Cryonics trusts exist. They may not be perfected or tested. Like cryonics itself, they are our BEST EFFORTS at finding a way to solve a huge and previously intractable problem. But, they can be funded with LIFE INSURANCE, a much smarter way of leveraging your money, as well as providing tax and creditor advantages. This is the exact kind of thing wealthy and smart people have done for literally centuries with their money. The distinction is that we are using these marvelous tools to help fund cryonics, and preserving and creating future wealth for ourselves and those we care about.

You are currently writing a book. What can you tell us about it?

I have been working on this book since 2002. I hope to have it published in 2010. I also hope to make it available as a download on the web at minimal or no cost to my cryonics prospects and clients. The book is called, “THE AFFORDABLE IMMORTAL: THE EMERGING SCIENCE OF CRYONICS AND YOU.”

It is designed as an easy to read resource for folks potentially interested in cryonics. It explains, in a straightforward way, the fascinating world of life insurance, and how to use life insurance for cryonics.

It deals with some of the ideology of cryonics. And, an estate planning lawyer I work with who is an expert on cryonics trusts has a section on cryonics legacy planning that is the clearest explanation I have ever seen on this topic.

What is your take on the current state of wealth preservation for cryonics members?

HEY, LET’S BEAT BOTH DEATH AND TAXES!

The idea of “taking it with you” is not out of the bounds of reality anymore.

Cryonics itself is a “best efforts” intervention designed to enable whatever makes up “you” to take a time travel ride to the future. Cryonics trusts exist to enable your funds to grow at a rate somewhat higher than taxes and inflation, and compound and grow. These funds are earmarked to both enable the cryonics resuscitation process, and enable you to have funds to provide you with enhanced options in the astounding future that you may be revived in.

Of great concern, of course, are the details of cryonic estate planning. Including the question, “How do I find a trustee to manage and grow the money, who understands the concept of cryonics and my wishes, and who won’t run off with the money?”

There are structures in place to have oversight in depth for trustee arrangements. Currently, a small group of cryonicists are in process of developing a cryonics oriented trust company employing younger cryonicists as trustees for the accounts.

The bad news is that legitimate cryonics estate planning is not cheap. The better news is that some groundwork has been laid out by pioneers of this idea to make it more affordable than it used to be. And the actual funding of the cryonics trust can come from the leverage of life insurance. You can have a separate life insurance policy to fund the cryonics trust, or name the trust as a partial beneficiary of your cryonics policy. Setting up the cryonics trust has in the past involved tens or even hundreds of thousands of dollars. Current trust prices range from 10,000 down to a few thousand for setup. And maybe a thousand a year for maintenance. The Hoffman Prototype Cryonics Trust has been made available at no cost to my clients, to be used by their attorneys as a template.

Part of the reason for the current emphasis on developing legitimate and solid cryonics trusts is this: Wealthier and older cryonicists CARE about being able to execute such trusts. And we NEED wealthier cryonicists who are willing to DONATE money to research optimal cryonics protocols.

There are literally MILLIONS of MILLIONAIRES, in the United States alone. Plus millions more throughout the world. Cryonics as a field is DESPERATE for the money these folks have in their pockets. The individuals are DESPERATE to find a legitimate way they can both make a positive difference in the world and have a chance for themselves and their loved ones to continue living.

We MUST find a way to help MERGE these highly motivated entities to develop the synergy that will fund the RESEARCH that will save your life.

You are a member of both major cryonics organizations (Alcor and CI). Why?

They are both excellent organizations. Alcor is my primary cryonics vendor. If there is a problem in the future with Alcor, or logistics or technological issues deem it optimal, I also wanted to be a member and have my funding set up for the Cryonics Institute.

I have friends and clients with both organizations. I also want to say what a remarkable job Ben Best and Andy Zawacki are doing at the Cryonics Institute to further the cause of genuine science and evidence based cryonics.

What do you consider the biggest challenges in today’s cryonics?

There are perhaps millions of forward thinking people who would sign up today if there existed clear documentation of a small animal returning from cryonic temperatures with all it’s systems and memories intact.

Yet, as large as the “no clear evidence for effective cryonics” problem is, there exists one that is even larger, in my opinion.

What could be a bigger detriment to the science and adoption of cryonics than “Hey, we can’t even prove this works?”

I’ll get to this below, in a later question.

Do you think that members should be more involved in Alcor’s formal decision making?

Not just “Yes,” but “Heck, yes!”

Especially at the pioneering stage this “long term startup” operations exists in, cryonics NEEDS genuine MEMBERS. A member is involved, engaged, pro-active, takes initiative to help the organization, volunteers time and money to further the organizations goals, and just, in general, PARTICIPATES in the organization.

For a whole series of reasons, some of which may be fixable, and some which may be intrinsic to growth and geography, many current cryonics members behave more like buyers of a commodity.They pay their life insurance, member dues, and think that this magically will be sufficient to give them a chance of indefinite lifespan. You people need to grow up out there. We are STILL in the pioneering phase of this movement. The appropriate metaphor is that we are in the same cryonics lifeboat…but it has numerous leaks.

We need members who ENGAGE in their own cryonics advocacy. Members who enable local networks of like minded people. Members who set up pre-planning with local doctors, funeral directors, and emergency medical personnel. Members who call their cryonics organization and say, “What can I do to HELP this movement, and what can I do to help secure a better suspension for myself and my loved ones?”

The readers of this website are the exceptions to the rule. Your readers, I suspect, are active proponents of this concept with their colleagues, out of the closet cryonicists who have the courage to be candid with their wish to not die in a mere few decades.

Alcor keeps growing but it has a lot of member cancellations as well. What can be done to prevent this?

Growth has been steady, but modest, for decades in cryonics. I would not be the first to describe cryonics as a “thirty year startup company.” Alcor recently passed the 900 member mark, and should go over 1000 in 2010.

WHY WE AS INDIVIDUALS NEED TO DEVELOP INTO CRYONICS ADVOCATES:

For whatever reason, only a low percentage of the cryonicists I am aware of REALLY feel like, “Hooray! We are part of a GRAND and MIND-BOGGLING experiment in indefinite life extension! We must pull together, develop networks and friendships, do INCONVENIENT and sometimes somewhat COSTLY events in which we get together. We must read the cryonics bulletin boards, help our organization recruit the BEST management talent for roles at Alcor and CI, and simply do what we can to make cryonics an EVIDENCE BASED SCIENCE”

Instead, we have the classic “Free rider” problem. Most cryonicists, and most everyone else as well, are extremely busy, wrapped up in their own trip, dealing with careers, family concerns, larger social concerns.

We are happy to see that Bill Faloon and Saul Kent are committing a reported ten million dollars a year to aging and cryonics research. But we can’t ALL be free riders on their largess. It is challenging to get free-thinking, anti-authoritarian, atheist oriented cryoncists to agree on a goal we can all get behind. There is currently NO thought leader who has defined a program that cryonicists can agree to support.

We need the equivalent of a Kennedy saying, “Before this decade is out, we commit to landing a man on the moon and returning him safely to earth.”

The cold war was the motivation behind the golden era of space development. (Of course, Kennedy could coerce millions and spend billions of coerced contributions…so the analogy is not perfect.)

SOME GOOD…MAYBE GREAT NEWS:

There is some behind-the-scenes work which can’t be announced yet that will excite even the most jaded and cynical of cryonicists. Leadership will be exercised, and progress will be shown, and a vision will be laid out that will generate a HUGE buzz in both the cryonics world and larger outside world.

Do you agree that Alcor should be able to sustain itself from membership dues without relying on outside donations?

Conceptually, yes. But raising dues to accomplish this is problematic for many at this juncture. The Alcor board has basically decided to do this, and I understand the rationale, but the timing is unfortunate.

How successful have you been in relating to others on the topic of cryonics? Do you think there are better or worse strategies for piquing interest in cryonics among the general public?

I am an unabashed cryonics advocate. I talk about it with most of my friends, family, and colleagues. Here is the hard teaching. It does not matter. Unless someone is READY for this idea, you probably are NOT going to get them interested. It does not matter how credible, enthusiastic, compelling, or intellectually rigorous you are.

Again, there are exceptions to this rule. Mostly they are these: An individual convinces his less enthusiastic spouse/partner to sign up. Parents pay for coverage on their children. And, a member pays the full cost of a life insurance AND dues AND startup fees for a friend or colleague, and handles most of the paperwork hassle for them.

I continually think about ways to promote this meme. The reality, learned after fifteen years of hurt feelings, potentially damaged relationships, and lots of intellectual hand-wringing and conversations with myself about how I can be more compelling, is that MOST people just are NOT interested.

Deal with it.

There will be some that are…and they will probably self-select the way you did.

I am hoping the current tabloid style “whistle blower” book by the almost certainly fraudulent huckster Larry Johnson will have a long term positive effect on cryonics awareness.

And, if I can get off my butt and get my book published and or promulgated somehow, this may help.

How long have you been married to Dawn and did she initially share your enthusiasm for cryonics?

I am happily married to Dawn, the love of my life, for 25 years last April. While she did not share my enthusiasm and initially declined to sign up, we WERE smart enough to buy an extra life insurance policy on her, initially naming me as beneficiary. When, in a wonderfully romantic event five years later on Valentine’s Day, she DID elect to surprise me with a sign-up, she just changed the beneficiary of her policy.

There is a lesson…perhaps several of them…for those perceptive enough to get it, in this true story.

Your writings are often critical of religion. Were you raised in a religious family? If so, what events had the most bearing on your development as an atheist?

OKAY! Here we go!

NOW we come to the real reason that cryonics is not a more popular idea and medical produce. Now we come to the “elephant in the room” that few dare even notice, let alone have the guts and political incorrectness to criticize.

Here’s the thing. If you REALLY believe you are going to heaven when you die, or even have some other vague and fuzzy brained notion of the reality of an afterlife, the odds are low that you are a very good cryonics prospect. This statement is based on PERSONALLY talking about these very ideas with literally HUNDREDS of cryonicists.

“Oh,” the accomodationists squeal, “Science and Religion don’t REALLY conflict. Cryonics and traditional religion are not remotely antithetical to each other. These two arenas deal with different areas of human experience, these are “non-overlapping magisteria”.

Well. There is no other word for the above paragraph but “BULLSHIT.” Sorry if this isn’t academic or erudite enough for you. Stephen Jay Gould was a smart man. But he was not smart enough to sign up for cryonics before he died of cancer…and he was not smart enough to see the OBVIOUS conflicts in epistemology and world view that exist between the religious mindset and the scientific worldview.

Of course, we’d expect most of us to be in something like the agnostic category, leaning toward the atheist end of that category.

What is more puzzling to many of us in the skeptical, rationalist, agnostic, atheist, bright, humanist, secular community is that the folks fitting these categories are STILL mostly not interested in cryonics!

Undamnbelievable!

Like many of your readers, I spend a huge amount of time thinking and reading in the areas of psychology, cognitive science, philosophy, religion, history, science, epistemology, and self improvement.

Some of the most influential thinkers in my worldview will be familiar to many of your readers. The “four horsemen of the rationalist atheist non-apocolypse” are the best selling authors Richard Dawkins, Sam Harris, Daniel Dennet, and Christopher Hitchins.

While all these guys are compelling, perhaps the most paradigm shifting read for me was Sam Harris’s “The End Of Faith.”

In this brilliant work, Harris documents not only the pernicious and evil effects of faith, (defined as believing without adequate evidence), but that the very IDEA of faith as a VIRTUE is intrinsically and deeply flawed.

Like many cryonicists and free thinkers, I was raised in a (rather wonderful) Christian family. My grandfather was the president of a Christian college (Anderson University, where I graduated from in 1975). I personally taught at Warner Christian Academy during 1977 and 1978.

While I did not believe the extremely unlikely and clearly cultural theology of these institutions, for many years I felt that the sense of community, and the genuinely positive effects of being a part of a community of folks trying hard to do “good,” superseded the negatives of believing in superstitions and nonsense.

I no longer feel this way.

As Sam Harris documents in his classic short book, “Letter to a Christian Nation,” the effects of believing in things that defy reason are, for lack of a better word, EVIL.

It is just plain WRONG to believe things without good reason to do so!

You have not only been a vocal advocate of cryonics but of limited government as well. As an insurance agent, what do you make of the ongoing attempt to transform health insurance companies into highly regulated providers of entitlements?

Wow…sounds like a political question I will graciously defer till I can get your readers around a table with some beers and coffee and we can rant about this! I will mention that cryonicists are disproportionatly of a libertarian mindset…again, not a surprising fact.

hoffman costumesEveryone who knows you is familiar with your holiday-themed greeting cards (where you and your dogs are completely decked out in holiday-specific costumes and surrounded by festive holiday decor) — do you actually own all the costumes and scenery, or is it rented just for the photos?

We love holidays, and enjoy decorating our yard, selves, and dogs. Over many years of scrounging, we have managed to find some way cool bits of yard decor. As I write these words, we have some 35 yard “blowups” with a Halloween theme…and a huge blow up Shrek on the roof!

Along with dancing, biking, reading, and traveling, these activities help make a full and fun life. Most of the time…

Now we all just need to figure out how to have more life…and more fun.

Anyone who has put up with this deeply personal and hopefully somewhat interesting article in order to read to this point deserves my most sincere gratitude. Next time, let’s talk about you…

Response to Aschwin de Wolf's 'Evidence Based Cryonics'

In his article entitled ‘Evidence Based Cryonics’ Aschwin de Wolf unassailably argues that: “There is an urgent need to move from extrapolation based cryonics to evidence based cryonics. This will require a comprehensive research program aimed at creating realistic cryonics research models. It will also require vast improvements in the monitoring and evaluation of cryonics cases. The current debate should no longer be between advocates and opponents of standby and stabilization but about what stabilization procedures should be used by cryonics organizations given our current knowledge”.

Unfortunately, much of the rest of what he has to say is incomplete or lacks the necessary context required to allow for a fair and technically sound evaluation. Perhaps the brevity of the blog format was the reason for these shortcomings? In any event, I would like to comment on these remarks and provide a somewhat different perspective on the complex and important issues discussed in ‘Evidence Based Cryonics.’

The best place to start is to define what evidence based medicine is, and then proceed to attempt to describe what might constitute ‘evidenced based cryonics.’ Webster’s New World Medical Dictionary, 3rd Edition (2008) defines evidence-based medicine as, “the judicious use of the best current evidence in making decisions about the care of the individual patient. Evidence-based medicine (EBM) is mean to integrate clinical expertise with the best available research evidence and patient values. EBM was initially proposed by Dr. David Sackett and colleagues at McMasters University in Ontario, Canada.” Having defined what EBM is, the next question is, what constitutes “the best current evidence?”

The United States uses the U.S. Preventive Services Task Force (USPSTF) system for evaluating evidence about the effectiveness of medical interventions. The USPSTF classifies evidence in terms of reliability for use in decision making as follows:

* Level I: Evidence obtained from at least one properly designed randomized controlled trial.

* Level II-1: Evidence obtained from well-designed controlled trials without randomization.

* Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.

* Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence.

* Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

* While beyond the scope of discussion here, it is worth noting (and referencing) the work of Guyatt, et al., and the GRADE Working Group in further defining what constitutes the quality and strength of scientific evidence; a formidable and controversial task (1- 6).

* To anyone knowledgeable in the areas of medicine applicable to human cryopatient stabilization and transport procedures (i.e., resuscitation/reanimatology, ischemia-reperfusion injury, solid organ preservation, deep hypothermic cardiopulmonary bypass and whole animal asanguineous perfusion) it will immediately be apparent that none of the 5 classes of evidence presented above can be directly applied to cryonics cases. Arguably, Level III evidence, the “opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees” might apply were there any acknowledged ‘respected authorities’ in the sphere of cryonics standby, stabilization or transport patient care. Alas, no such authorities, respected or otherwise, are currently ‘acknowledged’ to exist.

Thus, the first statement Aschwin makes in opening his article, “Cryonics patients can greatly benefit from rapid stabilization after pronouncement of legal death,” which he defines as “procedures that aim to rapidly restore blood circulation and drop the patient’s temperature” is itself unsupported by either conventional medical research or by cryonics research or case reporting using EBM criteria. If the information-theorertic criteria, as validated by ultrastructural preservation of the brain (7), or the demonstrated recovery of function of the brain are to be used as the gold standards for determining the efficacy of cryonics stabilization and transport procedures, then there currently exists no EBM quality (scientifically robust) data to support “restoration of blood circulation” following pronouncement of medico-legal death in cryopatients.

More specifically, assuming such an intervention is warranted, the question then becomes,’ under what circumstances and in which patients should it be applied?’ Is the patient with 30 minutes of post-arrest warm ischemia better off with simple external cooling followed by cryoprotective perfusion, as opposed to undergoing in-the-field reperfusion using closed chest cardiopulmonary support? What about the patient with profound peri-arrest hypoperfusion with evidence of failed or inadequate brain perfusion, such as the presence of fixed and unresponsive pupils for many minutes, or even for an hour or more, before cardiac arrest occurs and medico-legal death can be pronounced? At what point in the complex and difficult to quantify spectrum of warm ischemic injury should cardiopulmonary support be withheld? Or, given that the benefits of rapid post arrest cooling are unequivocally supported by Level II-2 and Level II-3 evidence from conventional medicine, should such support be modified to mitigate or prevent oxygen-driven reperfusion injury by carrying out CPS under anoxic conditions, and if so, under what circumstances and by what procedures? We have no rigorous answers to these questions and Aschwin is certainly on-point in calling for well designed, cryonics-appropriate studies to answer these and myriad other questions of great importance.

The problem is, as it has been since the inception of clinical cryonics in 1967, “what, if anything, do we do in the meantime?” Indeed, forty-two years later, we have little direct evidence even that cryoprotective perfusion results in superior conservation of identity-critical information under the real-world conditions encountered by today’s cryopatients than would be the case were they subjected to more timely straight freezing!

Is a patient who has suffered hours of warm ischemia better off simply being rapidly cooled and rendered into the solid state, as opposed to being subjected to 24, 48 or 72 hours of cold ischemia, followed by cryoprotective perfusion and freezing or vitrification? How do we even determine what the ultrastructural condition of a brain is following straight freezing? Freezing in the absence of fairly large amounts of colligative cryoprotectant agent(s) results in the collapse of tissue ultrastructure into dense channels of material, the structural condition of which it is currently not possible to determine by techniques such as transmission electron microscopy. Reaching conclusions based on the post-thaw ultrastructure (or lack thereof) of straight frozen tissue is complicated by the potentially myriad artifacts introduced during rewarming, thawing, fixation and embedding required to image tissue ultrastructure.

Given the extreme resource constraints that have historically been present in cryonics, and the lack of directly applicable mainstream medical research, the answer to the question of ‘what to do’ has been to apply reasoned extrapolation of high quality, peer-reviewed biomedical research to the care of the individual cryonics patient, and where possible, to conduct on-point in-house research to validate such armchair speculation.

It is important to point out that since the inception of cryonics in 1964, until approximately 1976, efforts to establish patient care protocols were a group effort between the then extant cryonics societies. The first of these efforts was organized by Robert Ettinger in 1966 and resulted in the protocol developed by Dante Brunol (8). Beginning in 1972, Fred and Linda Chamberlain, Art Quaife, Greg Fahy, Peter Gouras, M.D., Robert Ettinger, and I engaged in an extensive and largely public effort to reach a consensus about what should constitute a good standard of care for cryonics patients based upon extrapolation (and where feasible) experimental validation of findings in the peer-reviewed biomedical literature. This was done via extensive private correspondence, via publication of findings and recommendations in Manrise Technical Review and The Immortalist, as well as in the form of a detailed procedure manual for administering human cryopreservation entitled Instructions for the Induction of Solid State Hypothermia in Humans published by Fred and Linda Chamberlain and available, in part, on-line at: http://www.lifepact.com/mm/mrm001.htm (Readers interested in obtaining a copy of the full manual, for private use, may contact the author at m2darwin@aol.com).

During the 1980s this effort continued and was both documented and subjected to review by the American Cryonics Society, Trans Time, Alcor and Cryovita Laboratories in the form of detailed technical presentations made at the annual Lake Tahoe Life Extension Conferences hosted by Fred and Linda Chamberlain’s Lake Tahoe Life Extension Festivals from 1979 to 1985[1.] An example of such disclosures is available at: http://www.lifepact.com/tahoe.htm.

In short, these efforts were public, largely collegial, and consisted of a best effort to apply insights from the scientific literature to human cryopatients. Furthermore, both Jerry Leaf and I made a sustained and detailed effort to document, by both presentations and publications, the outcomes achieved in detailed human cryopatient case reports (10-20) and in animal studies of post-cryopreservation ultrastructure, including those designed to reproduce conditions encountered under real-world conditions (21, 22).

These efforts resulted in a number of cryopatient stabilization protocols that incorporated multiple drugs to address the multiple mechanisms of ischemia-reperfusion injury as identified in the literature; an approach which Aschwin describes as administration of “an unorthodox number of medications to protect the brain and prevent impairment of circulation. While there are peer reviewed papers that combine a number of medications, there is no precedent in mainstream medicine or biomedical research in using such a large number of medications (in contemporary cryonics, medications protocol exceeds 12 different drugs and fluids).” This statement deserves further scrutiny.

Are poly-drug approaches to treatment unprecedented in medicine? As an example, let’s consider the case of a hyperkalemic hemodialysis patient who experiences cardiac arrest while preparations are being made for emergency hemodialysis. How many and what kind of medications will this patient likely receive in the setting of refractory cardiac arrest? Per the American Heart Association (AHA) Guidelines the patient will initially receive 1 mg epinephrine IV every 3 to 5 minutes during CPR. This may be substituted (after the first dose) with 40 IU of vasopressin IV. Since the patient is in aystole 1mg atropine IV is also given. Concurrent with the administration of these drugs the patient is given 30,000 IU of sodium heparin to allow for the institution of hemodialysis to definitively reduce the serum potassium level. The patient is given an unsuccessful 360 Joule shock at this point. Point of care evaluation of blood electrolytes discloses blood potassium of 12 mmol/L: a level that is incompatible with the return of spontaneous circulation. A decision is made to administer calcium chloride: 5 mL of 10% solution IV over 2 min and 2 amps (60 mlL) of 50% dextrose in water along with 10 IU regular insulin IV (glucose and insulin facilitate a transient profound cellular uptake of potassium from the interstitial and intravascular spaces). CPR is continued for 8 cycles and the patient is again defibrillated with a resulting non-perfusing rhythm consistent with hyperkalemic cardioplegia. CPR is continued while hemodialysis proceeds. After 4 minutes of hemodialysis a third defibrillation attempt is made with the result being coarse ventricular fibrillation. Following another unsuccessful defibrillation attempt, and confirmation by point of care testing that serum potassium has decreased to 7.8 mmol/L with blood pH at 6.95, 300 mg of amiodarone is given in addition to 1 mEq/kg sodium bicarbonate: by slow IV push; the latter to correct the acidosis that has resulted from prolonged CPR and dialysis with a low pH bicarbonate-acetate dialysate.. Following 5 additional cycles of CPR the patient is successfully defibrillated and recovers with a mild neurological deficit as a consequence of extended, low flow perfusion during CPR.

This patient, undergoing routine resuscitation from hyperkalemia cardiac arrest, has just received 9 discrete drugs, all of them indicated, and all of them within the current guidelines for the treatment of hyperkalemic cardiac arrest (23-24). Interestingly, none of these drugs was administered to ameliorate vital organ ischemia-reperfusion injury. The reason for this is that no such drugs are currently clinically available for this indication.

Similarly, patients undergoing acute fluid resuscitation and initial; treatment for septic shock may receive a dozen or more drugs including pressors, ionotropes, a vasodilator, 2-3 antibiotics, insulin, rAPC, and any ancillary drugs required to facilitate renal replacement therapy or mechanical ventilation (see: http://www.leedspicu.org/Documents/Septic%20shock.pdf). So, it is clearly not the case that, “there is no precedent in mainstream medicine” for a multimodal drug treatment approach to complex illness, since multi-drug interventions constitute the standard of care for resuscitation from both cardiac arrest and septic shock and increasingly serve as the backbone of a wide range of successful cancer chemotherapies.

However, it is the case that, at least until recently, multi-drug interventions in biomedical research to treat cerebral ischemia-reperfusion injury have been virtually nonexistent. This is beginning to change as there is increasing understanding of the complex, multifactorial nature of cerebral ischemia-reperfusion injury. Examples of this are the recent successful work of Buckberg, et al in recovering piglets from 90 minutes of deep hypothermic circulatory arrest using a protocol that employed 5 primary therapeutic drugs (plus leukodepletion using a Leukoguard filter in the arterial line during cardiopulmonary bypass) (25), the work of Liu, et al., demonstrating the effectiveness of a combination of cerebral blood flow promoting drugs and the administration of phenyl-N-tert-butyl-nitrone (a free radical inhibitor) and cyclosporine-A (a mitochondrial poration inhibitor) in improving 24 hour neurological outcome after 8 min of experimental normothermic cardiac arrest in pigs (26) and the work of Gupta, et al., combining melatonin and poly (ADP-ribose) polymerase inhibitors in a rat model of stroke – a study that employed 6 drugs in the most successfully treated group (27).Other research combining multiple drugs and other interventions, such as mild therapeutic hypothermia, have also shown positive results (28, 29).

Aschwin goes on to state, “The only existing justification for using current protocol reflects work done at Critical Care Research (CCR) in the 1990s. Although scattered reports exist about the effectiveness of this protocol in resuscitating dogs from up to 17 minutes of normothermic global ischemia, no detailed (peer reviewed) paper has been published about these experiments “

I do not know what is meant by the term “scattered reports” to describe disclosure of this work and would note that there have been two formal public disclosures, the first in the form of United States Patent 5700828 issued on 12/23/1997, and the second in the form of a public seminar which was subsequently distributed as a videotape: Darwin M, Harris, SB, Russell, SR, O’Farrell, Rasch, C, J, Pengelle, C, Fletcher, M. Routine Resuscitation of Dogs from 15-17 Minutes of Normothermic Ischemia (37.5°C) With Long Term Survival (>6 weeks). In: 21st Century Medicine Seminar on Recent Breakthroughs in Cryobiology and Resuscitation Research, Ontario, CA; 1998.

As the principal investigator on this study, I would be the first to agree that it is both regrettable and unacceptable that it has not been either peer reviewed or published. However, as I do not have access to either the primary or the reduced data from this study, I am personally powerless to remedy this situation. Further, I think it extremely unlikely either that I will be given access to this data, or that the results of this study will be published in any meaningful time frame, if at all, by those at CCR who control the study data.

The question thus arises as to whether the drugs identified in this study are of use, either singly or in combination, in the stabilization of cryonics patients? The only certain way to answer that question is to apply them in well designed animal models that closely approximate the spectrum of real-world conditions under which cryopatients eligible for cardiopulmonary support and pharmacological treatment of ischemia-reperfusion injury present for care. Such studies will take tens of thousands of dollars and several years to complete. So, again, the questions arise, ‘what do we do in the meantime ‘and ‘how do we judge the evidence that we use to justify any interventions we undertake?’

It is not possible to answer these questions without considering the specifics of the work in question. Aschwin states that, “in contemporary cryonics, medications protocol exceeds 12 different drugs and fluids” with the implication that the CCR canine resuscitation series (CRS) research was the source of these 12 drugs/fluids, presumably those described by Aschwin in his January 2007 article Human Cryopreservation Stabilization Medications (http://www.alcor.org/Library/html/stabilizationmeds.html).

In fact, the original CRS protocol included a total of 22 drugs!

o Hemodiluent: defined electrolyte-dextran-40 containing solution
o Hypertensives: 3 primary drugs, 1 secondary drug
o Buffer: tromethamine (THAM), 1 drug
o Antiglycemic: 1 drug
o Free radical inhibitors: 6 drugs
o Excitotoxicity Inhibitors: 3 drugs
o Ca++ Antagonists: 1 drug
o Bradykinin Inhibitor: 1 drug
o Leukotriene Antagonists/Inhibitors: 2 drugs
o COX I&II Inhibitors: 1 drug
o Phospholipase Inhibitor: 1 drug
o Antiplatelet: 1 drug
o PARS Inhibitor: 1 drug
o Metabolic Support: 2 drugs

TOTAL: 22 drugs

Of these, 6 drugs (not including the anticoagulant heparin, the hyperosmotic agent mannitol, the flow promoting agent dextran-40, and the buffer THAM, all of which were previously in use in cryonics) were retained in the protocol licensed by CCR to Alcor and to Suspended Animation, Inc. These drugs are s-methylthiourea (SMT), d-alpha tocopherol (Vitamin E), melatonin, alpha Phenyl t-Butyl Nitrone (PBN), kynurenine, and carprofen. How should the utility of these drugs be judged? The first step in such a process is to determine which patients might benefit based on the available information. By definition, only patients eligible for CPS can be treated, since effective use of all of these drugs requires thorough systemic distribution. Patients with 20 minutes or less of normothermic cardiac arrest are probably the only suitable candidates based on the limited ability of closed chest CPS to generate adequate pressure and flow over increasingly long intervals of cardiac arrest. Beyond this general criterion, it is necessary to consider the evidence for the utility of each drug individually, on the basis not only of the CCR study, but in the context of the published literature.

The patent which first discloses the core drugs used in the CCR protocol was United States Patent 5700828 which was filed on 12/07/1995. This is significant because two of the primary cerebroprotective drugs described in this patent, melatonin and PBN, had not been previously demonstrated to be neuroprotective in cerebral ischemia-reperfusion injury. It was not until 2003 that the first peer-reviewed paper documenting the effectiveness of melatonin in ischemia-reperfusion appeared (30) and not until 1999 that the effectiveness of PBN in cerebral ischemia was documented in the literature (31). Since these papers first appeared a vast literature supporting the effectiveness of melatonin in both focal and global cerebral ischemia-reperfusion injury has appeared, and the PBN analog NXY-059 was demonstrated as effective in a wide range of animal models of cerebral ischemic injury (32)., although the drug failed in a RCT of stroke (33).

The utility of vitamin E, mannitol and of dextran-40 in cerebral ischemia reperfusion injury predate the 1995 patent and are extensively documented in the cerebral resuscitation literature. There are few papers documenting the effectiveness of kynurenine, and no papers supporting the effectiveness of carprofen in cerebral ischemia-reperfusion injury, although there are many papers documenting the utility of other non-steroidal anti-inflammatory and NF-kappa B inhibiting drugs in cerebral resuscitation.

Should any or all of these drugs be applied to cryopatients? Aschwin raises a number of possible contraindications which merit consideration: “The lack of relevant published data to support the administration of large numbers of drugs…in cryonics is not just a matter of risking performing redundant procedures. A lot of time and resources are being spent in cryonics on obtaining and maintaining equipment and supplies for these procedures, in addition to the licensing fees paid to use some of these technologies and the training and recruiting of people to perform them. But perhaps the most troublesome problem is that the preparation and execution of these procedures during actual cryonics cases can seriously interfere with rapid and effective cardiopulmonary support and induction of hypothermia.”

It is clear from the foregoing that Aschwin considers immediate post arrest cooling in the presence of CPS to be an essential element of effective cryopatient stabilization. Unfortunately, the use of CPS in this setting carries with it the risks of return of consciousness (33) as well as the return of ‘signs of life’ such as agonal gasping (34, 35), spontaneous movement (36, 37) and even the return of spontaneous circulation. (38). This implies that the cryopatient undergoing CPS must be protected against these undesirable effects by pharmacological intervention. At a minimum, this means that intravenous (IV) or intraosseous (IO) vascular access must be established and at least 3 drugs must be administered (e.g., an anesthetic, a paralytic, and a cardioplegic). Thus, much of the skill, equipment and added personnel required to administer cerebroprotective drugs to cryopatients are, in fact, a requirement of delivering CPS assisted cooling. When Aschwin writes: “the preparation and execution of these procedures during actual cryonics cases can seriously interfere with rapid and effective cardiopulmonary support and induction of hypothermia” it is not clear what he means? Is it establishing IV or IO access, or the administration of a large number of drugs, or both that constitutes a threat to rapid post-arrest CPS and cooling?

CPS and vascular access must, necessarily, proceed together, with CPS (properly) trumping vascular access where any conflict occurs. It should also be noted that CPS, given in the absence of an effective pressor, and (in most cryopatients) volume expansion, will not achieve perfusion that is effective; either for supplying adequate cerebral blood flow to prevent ongoing ischemic injury, or to facilitate heat exchange. CPS implies not only vascular access and the attendant skills, complexity and hardware, but also the administration of at least half a dozen drugs in order to render it both safe and effective. Given this requirement, what are the additional burdens and costs of delivering cerebroprotective medication?

Currently, melatonin, PBN, vitamin E, and carprofen are combined into a single parenteral product by CCR (Vital-Oxy) which can be administered IV or IO via a stopcock manifold using a pressure infuser. Heparin (anticoagulant), vercuronium (paralytic), magnesium sulfate (cardioplegic) and the first dose of vasopressin (pressor) can similarly be combined to create a single parenteral product shortly before use and may be administered ‘push’ via the stopcock manifold. Dexrtran-40 and mannitol may also be combined into a single parenteral product with a total volume of ~550 mL which can also be given via pressure infuser and the stopcock manifold. Bolus, or continuous doses of vasopressin and THAM (buffer), can be given via the same stopcock manifold using battery operated infusion or syringe pumps.

The broader issue to be addressed is how these multiple medications may be given rapidly, accurately, and with the least use of personnel. Compact, battery operated infusion pumps for in-field use are now available, but they cost a fortune. The same is true of programmable, battery operated syringe pumps. I think the solution to this problem is to computerize it. A laptop computer should already be in use during cryopatient stabilization and transport to acquire data from the patient and it can and should be used to give the meds as well. One simple system for doing this would be to use pressure infusers, and syringes under pressure, with open/close line-clamp solenoids under computer control. Meds would be dispensed by the interval of solenoid opening; push meds would be a full open solenoid, and interval bolus meds would be given by briefly, and for a fixed time, opening the solenoid(s). This is an extremely simple system to implement from both the hardware and software standpoints. A schematic of this type of system is shown below:

darwin_meds

Of course, this presumes that the multidrug approach to cerebroprotection of the cryopatient is economically justified. I would be the first to agree that it is not necessary to pay costly licensing fees to derive most of the benefit from the CRS protocol. It is clear from reviewing the literature that the most widely validated and likely most potent drugs in this protocol (in the context of preventing ultrastructural injury secondary to ischemia-reperfusion injury) are melatonin, PBN[2], and, arguably, vitamin E. These are readily available molecules and may be used by any cryonics organization, absent licensing, on the basis of their documented protective effects in the literature. Other likely useful drugs such as dextran-40, THAM and mannitol have a long history of use in cryonics which predates the CCR research and these drugs may also be used at little cost (Darwin M. Transport Protocol for Cryonic Suspension of Humans, Fourth Edition. 1990, http://www.alcor.org/Library/html/1990manual.html).

In the nearly decade and a half that have elapsed since the CCR canine resuscitation series was undertaken many other promising experimental drugs for the inhibition or moderation of cerebral ischemia-reperfusion injury have emerged. I am in complete agreement with Aschwin that the best way to evaluate the potential utility of these drugs to cryopatients is in animal models that are truly relevant and which simulate the actual condition of cryonics patients who present for stabilization and transport. Such patients are typically suffering from extensive activation of the immune-inflammatory cascade, are often severely dehydrated or fluid overloaded, and invariably suffer from serious disturbances in cerebral microcirculation which begin hours or even days before medico-legal death is pronounced. As a consequence, these patients will typically have pre-arrest ischemic injury which will likely be compounded by post-arrest reperfusion. Evaluation of pharmacological interventions should, and indeed properly must be, carried out in animals models that reflect these facts.

Finally, Aschwin writes: “Even more complexity is introduced when cryonics organizations make an attempt to wash out the blood and substitute it with a universal organ preservation solution. The rationale for this procedure is found in conventional organ preservation and emergency medicine research. The question in organ preservation research is no longer whether hypothermic organs benefit from blood substitution with a synthetic solution, but what the ideal composition of such a solution should be. In emergency medicine research asanguineous hypothermic circulatory arrest is increasingly being investigated to stabilize trauma victims. But it is a major step from these developments to the practice of remote blood washout of ischemic patients with expected transport times of 24 hours or more. At present the only sure benefit of remote blood washout is that it enables more rapid cooling of the patient, a benefit that should not be underestimated. But when liquid ventilation becomes available to cryonics patients, rapid cooling rates will be possible without extracorporeal circulation.”

There can be no argument that blood washout followed by long delays to cryoprotective perfusion is deleterious (as currently practiced) on the basis of both clinical experience with cryopatients and recent unpublished animal research by Fahy, et al., of 21st Century Medicine (39). This practice should probably be abandoned until such time as effective solutions are developed for use in cryopatient transports. The statement that “when liquid ventilation becomes available to cryonics patients, rapid cooling rates will be possible without extracorporeal circulation,” is by no means assured. As the primary inventor of fractional tidal liquid assisted pulmonary cooling (40), I feel it is critical to point out that this technique has been validated only in the setting of healthy animals with spontaneous circulation. The reduced flow state attending external CPS and the typically severely injured lungs of the cryopatient present the twin challenges of greatly reduced blood flow coupled with greatly reduced pulmonary surface area (as a consequence of pre-existing or emergent lung injury; i.e., acute respiratory distress syndrome or acute lung injury resulting from closed chest CPS). which will dramatically reduce the efficacy of heat exchange achievable with this technique.

Once again, as Aschwin correctly notes in the context of pharmacological intervention, it is imperative that modalities developed for application in conventional clinical medicine be validated in the very different setting of the patient presenting for cryopreservation after succumbing to prolonged terminal illness – as well as the added insults of peri- and post-arrest systemic and cerebral ischemia.

REFERENCES:

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ENDNOTES:

[1] The Cryonics Institute declined repeated invitations to participate in these colloquiums.
[2] It is important to note that the PBN used in the CCR study was prepared by dissolving it in boiling water with concurrent microwave heating in the presence of atmospheric oxygen. This is very likely significant because such handling would inevitably create breakdown products of PBN, such as NtBHA and its oxidation product the spin-trap MNP. As Proctor, et al., have pointed out, (Peter H. Proctor and Lynsey P. Tamborello, SAINT-I Worked, But the Neuroprotectant Is Not NXY-059, Stroke 2007 38:e109; published online before print August 23 2007.) it is possible that the failure of NXY-059 in the SAINT-II trial was due to the fact that material used in this trial differed from that used in the successful SAINT-I trial in that it was stabilized and protected against oxidation. It may well be that it is not PBN, per se, that is cerebroprotective, but rather its oxidation and/or break-down products.

Evidence based cryonics

Cryonics patients can greatly benefit from rapid stabilization after pronouncement of legal death. One fortunate feature of stabilization procedures is that the most effective and validated procedures are relatively inexpensive and easy to perform.  The difference between no stabilization procedures at all and procedures that aim to rapidly restore blood circulation and drop the patient’s temperature is likely to be bigger than that between such basic stabilization and procedures that include administration of a large number of medications and remote blood washout.  This observation gains even more importance when it is considered that there is a serious lack of empirical data to support these more advanced procedures.

To date, no single neuroprotective agent has been approved for the treatment of global or focal ischemia. Despite this fact, cryonics organizations like Alcor and Suspended Animation administer an unorthodox number of medications to protect the brain and prevent impairment of circulation. While there are peer reviewed papers that combine a number of medications, there is no precedent in mainstream medicine or biomedical research in using such a large number of medications (in contemporary cryonics, medications protocol exceeds 12 different drugs and fluids). The only existing justification for using current protocol reflects work done at Critical Care Research in the 1990s. Although scattered reports exist about the effectiveness of this protocol in resuscitating dogs from up to 17 minutes of normothermic global ischemia, no detailed (peer reviewed) paper has been published about these experiments.  Another concern involves the extrapolation of these findings to cryonics. It would go beyond the general nature of this piece to document all the differences between these controlled experiments and cryonics as practiced in the real world, but suffice it to say that the factors of shorter and longer delays, longer  drug administration times, suboptimal “post-ischemia” circulation, and induction of hypothermia introduce many unknowns about the efficacy of these drugs for cryonics patients.  In the case of some medications, like streptokinase, heparin, and dextran 40, a case could be made that the potential benefits outweigh the unknowns, but should this argument be extended to all medications?

Even more complexity is introduced when cryonics organizations make an attempt to wash out the blood and substitute it with a universal organ preservation solution. The rationale for this procedure is found in conventional organ preservation and emergency medicine research. The question in organ preservation research is no longer whether hypothermic organs benefit from blood substitution with a synthetic solution, but what the ideal composition of such a solution should be. In emergency medicine research asanguineous hypothermic circulatory arrest is increasingly being investigated to stabilize trauma victims. But it is a major step from these developments to the practice of remote blood washout of ischemic patients with expected transport times of 24 hours or more. At present the only sure benefit of remote blood washout is that it enables more rapid cooling of the patient, a benefit that should not be underestimated. But when liquid ventilation becomes available to cryonics patients, rapid cooling rates will be possible without extracorporeal circulation.

The lack of relevant published data to support the administration of large numbers of drugs and remote blood washout in cryonics is not just a matter of risking performing redundant procedures. A lot of time and resources are being spent in cryonics on obtaining and maintaining equipment and supplies for these procedures, in addition to the licensing fees paid to use some of these technologies and the training and recruiting of people to perform them. But perhaps the most troublesome problem is that the preparation and execution of these procedures during actual cryonics cases can seriously interfere with rapid and effective cardiopulmonary support and induction of hypothermia.

There is an urgent need to move from extrapolation based cryonics to evidence based cryonics. This will require a comprehensive research program aimed at creating realistic cryonics research models. It will also require vast improvements in the monitoring and evaluation of cryonics cases.  The current debate should no longer be between advocates and opponents of standby and stabilization but about what stabilization procedures should be used by cryonics organizations given our current knowledge.

Viewing cryonics as an experimental medical procedure does not necessarily commit one to the position that substantial amounts of money and resources should be allocated to recruiting medical professionals and expensive equipment. The most common sense implication of the views outlined above is that the most effective measures to improve the care of cryonics patients are encouraging members to relocate to the area of their cryonics organization, improved health tracking of existing members, and cryonics training aimed at teaching the basic procedures and techniques that confer real evidence based benefits.