Medico-Legal Aspects of Human Cryopreservation Optimization

Introduction

Ongoing legal challenges and hostile interference of relatives have increased awareness among cryonicists that addressing the likelihood that one will be cryopreserved at all should take center stage among other strategies for survival. As a consequence, a number of individuals have recently taken on the task of working out the conceptual and legal challenges to minimize hostile interference (for a contribution on the ethical aspects of cryonics interference, look here).

One aspect of cryonics optimization planning that has received little attention to date is to develop legal strategies to deal with medical and legal issues surrounding one’s death, terminal illness, and the dying phase. In this memo I will outline some of the most important medical and medico-legal issues, how cryonicists could benefit from recognizing them, and suggest some legal and practical solutions. Before I get to the substance of these issues I would like to briefly identify all the stages in which proactive cryonics planning can improve our odds of personal survival.

Opportunities for cryonics optimization

The first and most obvious decision is to make cryonics arrangements. Alcor members face complicated decision making because the organization offers both whole body cryopreservation and neuro cryopreservation. From the perspective of cryonics optimization many members choose neuropreservation because it enables the organization to exclusively focus on what matters most; the brain. There is also a logistical advantage. In case transport of the whole body across state lines is delayed the isolated head can be released in advance as a tissue sample. Additionally, a number of Alcor members have recognized that it is possible to have the best of both worlds and combine neuro-vitrification and separate cryopreservation of the trunk. This allows the member to take advantage of the superior preservation of the brain that is available for neuro patients without having to forego whole body cryopreservation. This option is not widely advertised so one is encouraged to contact Alcor about revisions in funding and paperwork.

The other obvious decision is to have secure funding in place. Many members have given extensive thought about funding mechanism and wealth preservation so there is little need to discuss this here. From the perspective of cryonics optimization it is important to emphasize the importance of over-funding your cryopreservation. This not only protects you against future price increases, but also enables you to take advantage of technical upgrades that cannot be offered at the current preservation minimums. Another aspect to consider is leaving money to cryonics research. Although it is reasonable to expect that general progress in science will include general cell repair, there may be areas that will only be pursued by those who have a scientific or personal interest in resuscitation of cryonics patients. As in many areas in life, diversification is key. One should not solely depend upon Alcor or CI for successful resuscitation research or efforts.

Another important opportunity for cryonics optimization is to recognize the importance of proximity. From a technical point of view, there is simply no comparison to de-animating near the cryonics facility of your choice. This is not just a matter of reducing ischemic time. Remote standby and stabilization is a fertile ground for all kinds of logistical and legal complications. Most cryonics members do recognize the importance of reducing transport times but it is an established fact that as soon people become terminally ill they become more resistant to the idea of relocating and often prefer to die among friends at home. It is important to anticipate this scenario and to not delay relocation plans until the last minute. Another advantage of relocating at an earlier stage is that one is better protected in case of a terminal disease with rapid decline or sudden death.

As mentioned above, one issue that is getting increasing attention is how to protect oneself against hostile relatives and third parties. The take-home message is to alter cryopreservation contracts and your paperwork in such a matter that there is an incentive *not* to interfere.

Last but not least, something should be said about community building. Cryonicists can greatly benefit from becoming active in their local cryonics group. Often these meetings are open to members of all cryonics organizations. Most cryonics groups organize standby and stabilization trainings where members can familiarize themselves with the basics of the initial cryonics procedures. Such groups may not only play a part in your own future cryopreservation but are also useful to get a basic understanding about what you can do in the case a local member or a loved one needs to be cryopreserved. Another important aspect of participation in a local cryonics group is that one remains in contact with other cryonicists. When people get older their friends and family members die and the member has little communication with those who are aware of his desire to be cryopreserved. If you live in an area where there are no local cryonics groups contact your cryonics organization and/or start your own local group.

Physician-assisted dying

If there was more widespread acceptance of cryonics the harmful delay between pronouncement of legal death and the start of cryonics procedures would not exist. After a determination of terminal illness, preparations would be made to ensure a smooth transition between the terminal phase and long term care at cryogenic temperatures.

Some states have enacted legislation that allows a terminally ill patient to request the means to terminate their life.  Assisted suicide is currently legal in the following three states: Oregon, Washington, and Montana. Physician-assisted dying does not remove the current obstacle that cryonics procedures can only be started after legal pronouncement of death but it can bring the timing of death (and thus of standby) under the patient’s control. Utilizing such laws can also greatly reduce the agonal phase of dying and its associated risk of damage to the brain.

The legal requirements for utilizing physician-assisted suicide can vary among states but, as a general rule, require that a patient has been diagnosed with a terminal illness with no more than six months to live, that the patient is of sound mind, and that the request is made in written form and witnessed. The State of Oregon has a residency requirement to discourage physician-assisted dying tourism.

Since cryonics procedures are performed after legal death, there is no reason why cryonics patients are exempt from utilizing these laws. Despite rumors to the contrary, there is no evidence that utilization of these laws require mandatory autopsy. After all, the cause of death in physician-assisted dying is clear; self- administration of the lethal drug. To avoid any possible accusations that cryonics organizations encourage the use of such laws, it is recommended that no person associated with the cryonics organization should be a witness, let alone be the physician that prescribes the lethal drugs.

Sudden death and autopsy

One of the worst things that can happen to a cryonics member is sudden death. Especially when the patient is young with no prior heart conditions, an autopsy is almost guaranteed. There is little one can do to avoid sudden death aside from choosing a lifestyle that reduces cardiovascular pathologies. The only preparation for dealing with sudden death is to become a religious objector to autopsy. Some states (including California, Maryland, New Jersey, New York and Ohio) have executed laws to restrict the power of the state to demand an autopsy. Although exceptions can still be made in cases of homicide or public health there is little to lose in using such provisions. The websites of Alcor and CI have links to the relevant forms to execute. The Venturists are offering a card for their members stating that they object to autopsy. This card can be requested from Michael Perry (mike@alcor.org) at Alcor. An example of such a card is provided below.

Sudden cardiac death is not the only reason for ordering an autopsy. An autopsy is typically ordered if there are criminal suspicions (homicide) or suicide. There is also a greater risk of autopsy when a patient dies in absence of other people. Since many old cryonicists are single and spent a lot of time alone they are also at an increased risk for autopsy. This is another good argument to remain involved with local cryonics groups and in frequent contact with other cryonicists.

If autopsy cannot be avoided it is important that the cryonics organization is notified promptly. Cryonics organizations can make another attempt to persuade the authorities to abstain from an autopsy or to request a non-invasive autopsy that exempts and protects the brain. The cryonics organization can also issue instructions for how the patient should be maintained prior, during and after autopsy. It might be worthwhile to generate a template of general autopsy instructions for cryonics patients. Such a document may not be binding but it could be useful in limiting the amount of ischemia and injury.

The dying phase and Advance Directives

Most cryonics members have a basic understanding of the importance of time and temperature to protect a cryonics patient after legal pronouncement of death. Fewer people recognize the effect of the dying process itself on the outcome of a cryonics case. In best case scenarios (physician-assisted dying, withdrawal of ventilation) the dying phase is relatively rapid while in worst case scenarios extensive ischemic injury to the brain is possible. Little work has been done to outline recommendations for the terminally ill cryonics patient. One of the main objectives of this article is to recognize that cryonics members could benefit from a general template that can be used in their Advance Directives and to guide surrogate decision makers.

At this point it is useful to briefly describe how the dying phase itself can affect the outcome of cryonics procedures (for a more detailed treatment see the appendix at the end of this article). A useful distinction is that between terminal illness and the agonal period. A patient is classified as terminal when medical professionals establish that the patient cannot be treated with contemporary medical technologies. During this period the patient is usually still of sound mind and able to breathe and take fluids on his/her own. Unless the patient has suffered an insult to the brain or a brain tumor, there is no risk for ischemic injury to the brain yet. At some point, however, the body’s defense mechanisms will be overwhelmed by the patient’s disease and the patient enters the agonal phase. The agonal phase, or active dying phase, can be characterized as a form of general exhaustion. The body is still fighting but with decreasing success and efficiency. One of the biggest concerns for cryonics patients is the development of (focal) brain ischemia while the (core) body is still mounting its defense.

It would be impossible to design an Advance Directives template that is optimal for all cryonics patients, but there are a number of general guidelines that can inform such a document:

* All health care decisions should be guided by the objective of preserving the identity of the patient throughout the terminal and dying phase.

* Measures to prolong dying should only be initiated or accepted if they result in less ischemic injury to the brain.

* Life-sustaining measures should be withheld in case of traumatic or ischemic insults to the brain.

To ensure that sensible decisions are made in situations that are not covered by these Advance Directives, a Health Care Proxy can be executed that designates a person to make those decisions. It is understandable to give such power to the person closest to you but in the case of cryonics it is recommended that this responsibility should be given to a person with a strong commitment to your desires and a detailed understanding of the medical needs of cryonics patients.

Pre-medication of cryonics patients

If a critically ill cryonics member is at risk of ischemic brain injury during the dying phase it stands to reason that some palliative treatment options are better than others. One possibility for cryonics patients is to specify such options in one’s Advance Directives. Another scenario in which pre-medication is possible is where the medical surrogate is strongly supportive of such measures. It should be noted that such a decision rests solely with the member or his/her medical representative. Cryonics organizations should not be involved in the pre-mortem treatment of the patient.

There are two important questions about pre-medication of cryonics patients:

1. Is it safe?

2. Is it beneficial?

The answer to the first question has a lot to do with the status of the pharmaceutical agents in question. For example, a supplement like melatonin is less controversial than a prescription drug like heparin. The most important thing to keep in mind is that drugs that may be beneficial after legal pronouncement of death could have adverse effects in critically ill patients. Good examples are drugs that have effects on blood rheology and clotting. One would rather forego the hypothetical benefit of a drug if there is a non-trivial change of triggering major controversies about drugs taken during the dying phase. This leaves only certain supplements as relatively safe options for pre-medication of cryonics patients.

The answer to the second question is not clear. The rationale behind pre-medication is that it can protect the brain during agonal shock and its associated ischemic events. Evidence for this belief is usually found in the peer reviewed literature on neuroprotection in ischemia. However, there is a clear difference between the administration of neuroprotective agents during the dying phase and the administration of neuroprotective agents prior to artificially-induced acute ischemia. One perspective is that such agents are beneficial but only delay the ischemic phase of the dying period. In this case supplements have little neuroprotective effect. An alternative perspective is one where such supplements do not alter the agonal course as such but provide more robust protection after circulatory arrest. Obviously, this matter is not of concern to conventional medicine so there is little evidence to make rational decisions. In light of the previous discussion, the current (tentative) verdict should be that a case can be made for pre-administration of neuroprotective agents but that these agents should be confined to “safe” supplements like melatonin, Vitamin E and curcumin. Whether such a regime would be beneficial needs to be decided on a case by case basis and is, therefore, more in the domain of the Health Care Proxy than Advance Directives.

Do Not Resuscitate Orders

Do Not Resuscitate (DNR) orders present one of the most challenging issues for cryonics optimization. On the one hand, we would like to benefit from any attempt to resuscitate us in case of sudden cardiac arrest (or any other acute events that can lead to death). On the other hand, we would not like to be subject to endless rounds of futile resuscitation attempts that can damage the brain.

One would be inclined to think that resuscitation attempts should be made in case of sudden insults or during surgery but that no resuscitation attempts should be made during terminal illness. In reality things are not that simple. For example, resuscitation may be possible after 8 minutes of cardiac arrest but the patient can suffer severe brain damage as a consequence. Such a scenario can be minimized by executing a DNR at the cost of foregoing any resuscitation attempts at all. Would this outweigh the benefits of successful resuscitation attempts? It is hard to see how an objective answer to this question can be given without taking a specific person’s views on risk and treatment into account. One way to mitigate this dilemma is to make a distinction in your Advance Directives between pre-arrest emergencies (for example, resuscitation should be permitted in the case of labored breathing but presence of heart beat) and full arrest. An in-hospital situation where resuscitation of a critically ill patient would be helpful would be where it would allow a cryonics standby team to deploy at the bedside of the patient. As can be seen from these examples, good resuscitation instructions for cryonics patients require a lot of attention to context. Because confusion could arise whether Advance Directives would include pre-hospital emergency procedures it is recommended to execute an explicit document if you want these cases to be covered – such a document could be complemented by wearing a bracelet.

Creating a general template

This article has identified a number of important medico-legal issues that need to be addressed by cryonicists to optimize their cryopreservation. It has become clear that in the case of many topics we would all benefit from uniform and effective language. The next step is to translate the concerns discussed in this document in clear legal language so that templates can be offered to all members of cryonics organizations to draft their own Living Will and Advance Directives. One potential problem of such a general template is that it may not conform to state regulations and needs additional tweaking to make it valid in the state where the person lives.

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Appendix :  Neurological damage during the dying phase

Securing viability of the brain by contemporary criteria is the most important objective of cryonics standby and stabilization. Recognition of how pathological events in the central nervous system can defeat this objective is of great importance. As a general rule, the risk for increased brain damage is higher during slow dying. For example, when the ventilator is removed from the patient who is not able to breathe on his own the time between this action and circulatory arrest can be short. Conversely, when a patient is going through a prolonged terminal and agonal phase (regional) injury to the brain can occur while the body itself is still fighting for its survival.

The human brain has little storage of excess energy. As a result, hypoxia causes the brain to deplete its oxygen reserves within 30 seconds. The energy depletion that follows cerebral hypoxia during the dying phase has a number of distinct effects: 1) excitation or depression of certain processes in the brain, 2) alteration in the maintenance of structural integrity of tissues and cells, and 3) alteration of neuromediator synthesis and release. The depletion of oxygen leads to a switch from aerobic to anaerobic energy production. As a consequence, there is an increase in the metabolic end-products of glycolysis such as lactic acid which decreases pH in the brain. After 5 minutes no useful energy sources remain in the brain, which can explain why the limit for conventional resuscitation without neurological deficits is put at 5 minutes as well. Because the dying phase leads to progressively worse hypotension and hypoxia the metabolic state of the brain after the agonal phase is worse than if there would have been sudden cardiac arrest.

Light microscopic changes have been observed in brain cells after 5 minutes of ischemia. Prolonged hypotension, as can occur in the agonal patient, can lead to the appearance of “ghost cells” and disappearance of nerve cells. Such observations provide evidence that structural changes, including cell death, can occur prior to clinical death. Another manifestation of hypoxia (or hypotension) is the progressive development of cerebral edema. The resulting narrowing of vessels and decrease of intercellular space can, in turn, aggravate energy delivery to tissues. Of particular importance for cryonics stabilization procedures is the development of no-reflow which can prevent complete restoration of perfusion to parts of the brain during cardiopulmonary support. There is no consensus as to whether no-reflow can occur as a result of prolonged hypotension (as opposed to complete cessation of blood flow), but an extended dying phase can set the stage for cerebral perfusion impairment after circulatory arrest.

The central nervous system does not shut down at once. Throughout the terminal and agonal phase alternations in the brain progress from minor changes in awareness and perception to deep coma. As a general rule, more recent and complex functions of the brain disappear earlier than the most basic functions of the brain. The uneven brain response to hypoxia may reflect different energy requirements, biochemical and structural differences, and/or the activation of protective mechanisms to preserve the “core” functions of the brain. The CA1 region of the hippocampus has been demonstrated to be uniquely vulnerable to ischemia. This presents a problem for contemporary cryonics since the objective of human cryopreservation is to preserve identity-relevant information in the brain.

This article is a slightly revised version of a paper that was submitted for the 4th Asset Preservation Meeting near Gloucester, Massachusetts.

The RhinoChill: A New Way to Cool the Brain Quickly

We scientists are difficult, cranky, and above all, maddeningly frustrating people. Want to turn lead into gold? No problem, we can tell you how to do that, and in fact have even done it already: the only catch is that the cost of such ‘nuclear transmutation’ is many times that of even the most expensive mined gold. You say you want to travel to the moon? Done! That will be ~$80 billion (in 2005 US dollars). Want to increase average life expectancy from ~45 to ~80 years? Your wish is our command, but be mindful, you will, on average, spend the last few of those years as a fleshpot in the sunroom garden of an extended care facility.

And so it has been with an effective treatment for cerebral ischemia-reperfusion injury following cardiac arrest. Thirty years ago, laboratory scientists found a way to ameliorate most (and in many cases all) of the damage that would result from ~15 minutes of cardiac arrest, and what’s more, it was simple! All that is required is that the brain be cooled just 3oC within 15 minutes of the restoration of circulation. The catch? Well, this is surprisingly difficult thing to do because the brain is connected to the body and requires its support in order to survive. And the body, as it turns out, represents an enormous heat sink from which it is very difficult to remove the necessary amount of heat in such short time. Thus, the solution exists and has been proven in the laboratory, but it has been impossible to implement clinically.  This may be about to change as a variety of different cooling technologies, such as cold intravenous saline and external cooling of the head begin to be applied in concert with each other. Separately, they cannot achieve the required 3oC of cooling, but when added together they may allow for such cooling in a way that is both effective and practical to apply in the field.  A newly developed modality that cools the brain via the nasal cavity may provide the technological edge required to achieve the -3oC philosopher’s stone of cerebroprotection.

Read the complete article in PDF here.

Chemical preservation and cryonics research

In the 2009-4 issue of Alcor’s Cryonics magazine I review the technical and practical feasibility of chemical preservation. One of the most interesting aspects of chemopreservation is that it could play a useful role in the cryopreservation of ischemic patients.

There is accumulating evidence that vitrification agents cannot prevent ice formation in ischemic patients. This raises the question whether some cryonics patients could benefit from chemical fixation prior to transport and cryoprotective perfusion.

Such protocols raise a number of obvious concerns but the question is not so much whether these procedures are inferior to vitrification of non-ischemic patients, but whether fixatives can improve the situation of some ischemic patients compared to the prospect of substantial ice formation, or even straight freezing (cooling without cryoprotection). This is an empirical question which needs to be settled by experimental research.

Chemopreservation: The Good, The Bad and the Ugly

Reversible cryopreservation

On the forum of the Immortality Institute there is an interesting exchange about the feasibility and time line for reversible cryopreservation. Cryobiologist Brian Wowk weighs in with some interesting observations:

I think in the next 20 years more small animal organs, and perhaps some human organs, may be reversibly cryopreserved. The best scenario for cryonics would be improved, and possibly demonstrably reversible, cryopreservation of animal brains. It has been long observed that if reversible solid-state brain preservation could be demonstrated, then cryonics revival becomes a purely technical problem (albeit very complex one) of tissue regeneration. There would be no remaining doubt about whether the preservation itself was viably preserving human beings….Reversible solid-state cryopreservation of whole mammals is a very difficult problem with existing technology. This is why when asked about it people will often defer to nanotechnology. References to nanotechnology as a solution to a medical problem basically say, “We have no idea how to solve this problem with existing tools, but future abilities to completely analyze and repair tissue at the molecular level will be implicitly sufficient.” It’s a valid argument, but saying that a medical problem will be solved when someday technology exists to solve *every* medical problem is not very illuminating about time lines or nature of the problem.

Advocates of cryonics often push for demonstration of reversible small animal cryopreservation as  a means to persuade the medical establishment and the general public of the technical feasibility of cryonics. The limitation of this approach, however, is that this goal cannot be achieved until we are able to successfully vitrify all vital organs of the animal, including such difficult organs  as the lungs and the kidney. A more promising approach is to keep improving vitrification of the central nervous system. As argued in a recent piece for Alcor’s Cryonics Magazine, if organized electrical activity can be demonstrated after whole brain cryopreservation a strong case can be made for the acceptance of cryonics as a medical procedure and improved legal protection of cryonics patients.  It should be noted, however, that these research efforts constitute only one objective in cryonics. Another objective of cryonics research is to optimize procedures and protocols for existing patients, who invariably suffer some degree of circulatory arrest.

PLAC blood test for sudden cardiac arrest and stroke risk

Life Extension Foundation (LEF) unveiled a new blood test in an article in this month’s Life Extension Magazine (November 2008). Unlike cholesterol testing, which simply gives a measurement of high-density (HDL) and low-density (LDL) lipoprotein levels and provides little information about acute risk of stroke or heart attack, the PLAC® blood test “can accurately identify artherosclerotic plaque that is vulnerable to rupture,” essentially providing a direct assessment of sudden heart attack and stroke risk.

The PLAC® test, developed by diaDexus, Inc., provides this assessment by measuring levels of lipoprotein phospholipase A2 (Lp-PLA2), an enzyme that is directly involved in endothelial dysfunction leading to atherosclerosis (an inflammatory response of the blood vessel wall), plaque accumulation (build-up of lipid deposits inside blood vessels), and rupture (breaking loose of plaque which can then block a blood vessel, causing heart attack or stroke). The PLAC® test specifically measures Lp-PLA2 associated with oxidized LDL particles. In research studies, high levels of Lp-PLA2 have been determined to be highly specific for plaque inflammation: an elevated PLAC® test indicates an increased amount of inflamed atherosclerotic plaques and thus a higher risk of plaque rupture.

Because of the sensitivity and high specificity of the PLAC® test for such inflammation, the predictive value of the test for risk of cardiac arrest and/or stroke is higher than other markers for the prediction of acute events. Furthermore, the PLAC® test is inexpensive and convenient in comparison to CT and other imaging procedures since it involves only the collection of a blood sample.

In general, the PLAC® test is appropriate for those known to be at high risk for cardiovascular disease and stroke, and LEF recommends that it should be performed once a year in persons who are obese or are regular smokers, those with high blood pressure or cholesterol, type 2 diabetes, or a family history of stroke and coronary heart disease. The PLAC® test can be used to guide patient treatment options: from their article, the LEF panel “recommends that patients with high Lp-PLA2 levels be upgraded from moderate risk to high risk, or from high risk to very high risk. In these patients, a suitable goal is to lower LDL to 100 mg/dL in high-risk patients and to 70 mg/dL in very high-risk patients.”

The PLAC® test is currently the only blood test approved by the FDA to assess atherosclerotic risk for coronary heart disease and stroke. While this is useful for guiding patients in their use of known treatment options, it is not known whether lowering Lp-PLA2 itself will result in a reduction of this risk. A large study (IBIS-2 trial) is now underway to shed more light on this topic. In the meantime,  LEF claims that the PLAC® test is by far the most reliable, convenient, and inexpensive method for determining one’s risk of acute ischemic cardiovascular events and is undoubtedly a beneficial tool for helping patients to keep tabs on their risk level and to implement a more aggressive treatment strategy if indicated.

-=Get the PLAC® blood test=-

Dietary supplements induce neurogenesis after stroke

A recent study in Rejuvenation Research reports that a combination of dietary supplements confer neuroprotection in stroke. Over a 2 week period rats received either a proprietary formulation of blueberry, green tea, Vitamin D3, and carnosine  called NT-020 or vehicle (i.e., the same solution minus the compounds of interest) before stroke was induced through middle cerebral artery occlusion (MCAo). Two weeks after the insult the rats were subjected to behavioral tests and histological examination. Rats treated with the dietary supplements scored better on behavioral tests, had less histological damage, and showed evidence of neurogenesis.

This study is interesting for a number of reasons. Foremost, it highlights the possibility that dietary choices can positively affect outcome after ischemic insults. These findings complement research that found that caloric restriction improves behavioral and histological outcome after stroke.  The findings also reinforce that some of the most effective neuroprotective agents to date are ordinary nutrients, vitamins, and hormones. In this study the investigators combine a number of these agents to greater effect. Although the authors do not present specific data on bioavailability in the brain for these compounds, they argue that a multi-agent approach relaxes the dosage requirements for individual agents.

The paper reviews assays that demonstrate improved neurogenesis in the rats that received NT-020 such as endogenous birth of new neurons, neuronal phenotype expression of newly formed cells, and alterations in neurogenic factors. Pharmacological modulation of neurogenesis after ischemia is a young research field and the results reported in this paper provide additional evidence for the (only recently accepted) phenomenon of adult neurogenesis. Unresolved questions at this point include how neurogenesis differs among species and whether post-ischemic neurogenesis can improve long term outcome in humans.

The  design of the current study does not allow a rigorous answer to the question of whether neurogenesis contributed to or accompanied improved outcome. The possibility that other mechanisms (such as  increased free radical scavenging) were primarily responsible for the observed improvements cannot be ruled out based on this study.

Link: Dietary Supplementation Exerts Neuroprotective Effects in Ischemic Stroke Model

Cerebral blood flow during and after cardiac arrest

As discussed in a previous post, perfusion of the brain following long-term (>5 min) ischemia has been shown to be significantly compromised, particularly in subcortical regions. An interesting recent article by Ristagno, et. al in Resuscitation (May 2008) has added new data to the equation, using some of the most advanced technologies available for measuring cerebral microvascular blood flow.

To briefly summarize the experiment, pigs were subjected to 3 minutes of untreated ventricular fibrillation followed by 4 minutes of cardiopulmonary resuscitation and subsequent defibrillation. Blood flow in large (>20 micrometers) and small (<20 micrometers) cerebral vessels was measured during and after CPR by direct visualization using orthogonal polarization spectral imaging (OPS) together with cortical-tissue partial pressure of carbon dioxide.

Though prior studies implied a dissociation between microcirculatory flow and macrocirculation during CPR, Ristagno, et. al found “a close relationship between microvascular flows and the macrocirculation during cardiac arrest, during CPR and following return of spontaneous circulation (ROSC).” Interestingly, they also noted that cerebral blood flow was reduced, but did not stop, for more than 2 minutes after cardiac arrest, most likely due to residual compliance in the arterial circuit. After ROSC, flow progressively increased back to normal (pre-arrest) values within 3 minutes.

Importantly, the researchers also noted that cerebral cortical-tissue partial pressure of carbon dioxide (a measure of the severity of cerebral ischemia) increased progressively througout CPR, providing evidence for the fact that the pressure and flow generated during chest compressions “may minimise but do not reverse the magnitude of the brain ischaemia which preceded the start of CPR.”

Though many investigations, such as the previously reported study by Fischer & Ames reported no-reflow or hypoperfusion following ischemia, these authors observed no such phenomena, possibly because of the short duration of cardiac arrest. Indeed, they ultimately conclude that “a 3-min interval of ischaemia was therefore probably not long enough to induce alterations in blood flow during reperfusion.” Also of importance is the fact that OPS technology limits visualization of microvessels to within 1mm of the cortical surface. However, this paper still gives us better insight into the immediate effects of cardiac arrest, cardiopulmonary resuscitation, and reperfusion on microcirculatory flow in the brain.

Intranasal administration of medications

Experiments investigating the effects of medication administration via the nose are becoming increasingly common in scientific literature. Direct olfactory transport to the brain and the consequent lack of systemic side effects make nasal administration of neuroactive drugs a very attractive option for doctors and patients alike.

Neuropeptides such as insulin and melanocortins are known to play a role in central nervous control of energy homestasis, which in turn affects body weight regulation. Insulin receptors are also found in high concentration in the hippocampus, and insulin is known to influence memory consolidation. A recent paper by Hallschmid et al. studied the efficacy of intranasal neuropeptide administration in modulating both metabolic and cognitive disorders in humans, finding that administration of MSH/ACTH (i.e., melanocortins) induced weight loss in normal-weight humans, and that insulin administration “reduced body fat and improved memory functions in the absence of adverse peripheral side effects.”

Such results indicate a promising future for directed therapies in patients with central nervous system dysfunctions, and the potential of intranasal administration of medications in cryonics should not be ignored. As discussed in a previous post, intranasal administration of vasoactive medications could be a beneficial method to maintain blood pressure during stabilization. Similarly, intranasal administration of neuroprotective agents to the brain represents another time-saving means of reducing brain injury during cryonics procedures.

Neuroprotection for ischemic stroke

The journal Neuropharmacology recently published a new review of the current state of the art in neuroprotection for ischemic stroke. A strict definition of a neuroprotectant excludes agents that have as their goal circulatory patency or the reversal of vascular occlusion, such as thrombolytics and anticoagulants. As a consequence, the only medication that is approved for (ischemic) stroke patients, tPA, is not a neuroprotectant. Despite the explosion of interest and research in the field (as documented in Ginsberg’s review), no single neuroprotective agent has successfully survived human clinical trials. The author discusses a number of reasons why encouraging results fail to translate into human success and stresses the fact that most agents in clinical trials are administered too late to confer positive benefits, and even states that “there is practically no evidence that neuroprotection for acute ischemic stroke is possible with any agent beyond ~6h.” It is no surprise, then, that the author does not report many promising neuroprotective strategies except for therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy.

What does this mean for cryonics? As discussed in this review about medications in human cryopreservation stabilization, neuroprotection in cryonics has never been approached as a quest to find one single “magic bullet” to protect the brain after cardiac arrest. Cryonics stabilization medications protocol consists of a number of agents that intervene at different points in the ischemic cascade, reverse and inhibit blood clotting, and improve circulation. If rapid stabilization is possible, the time-window for treatment in cryonics is usually excellent in comparison to (focal) ischemic stroke where treatment within 1-2 hours is considered “hyperacute.” But cardiac arrest after an (often) long terminal and agonal period is not equivalent to (focal) ischemic stroke, and evidence that the medications that are given to cryonics patients are of great benefit is confined to a series of (non-published) experiments on (young) healthy animals in cryonics-associated laboratories.

When the author discusses future directions to find successful neuroprotective agents, he highlights the challenge of finding funding for neuroprotective trials that include metabolic treatment and combinations of (non-proprietary) drugs. In light of the predictable failure of mono-agents that the author reports, the discussion of the potential of combination treatment is remarkably brief and confined to the point that potential neuroprotectants need to be validated in combination with thrombolytic treatment. There is now an accumulating number of research papers on combination treatment in animal models that would warrant a more systematic analysis than the obligatory acknowledgement that combination therapy might produce better neuroprotection. Perhaps the most novel part of this new review of neuroprotective agents is the discussion of the author’s own research into high-dose human albumin therapy and the brief mention of a new paper (2007) that discusses the prospects of neuroprotective strategies that “are based on the principle that drugs should be activated by the pathological state that they are intended to inhibit.”

Stability and autolysis of cortical neurons in post-mortem adult rat brains

One scientific question that weighs heavily on the feasibility of contemporary cryonics is what happens to the brain after cardiac arrest. Common wisdom has it that the brain “dies” within 5-7 minutes after circulatory arrest. This is true in the sense that patients resuscitated from such insults die of brain death (or develop higher brain death) within days of the insult. It is not true in the sense that the neuroanatomy that represents the person disappears within 5-7 minutes. Even at room temperature the post-mortem ultrastructure of the brain is quite resistant to damage for hours after cardiac arrest.

Well designed post-mortem studies into the temporal aspects of brain structure after cardiac arrest are of great importance to the science of cryonics. Such studies will not only help establish the concept of information-theoretic death as a more rigorous definition of death than clinical or biological death, but can also assist cryonics organizations in formulating objective criteria for accepting patients with (very) long ischemic times.

Unfortunately, such studies are rare and many of the studies that have been done are unreliable as a result of compounding factors such as pre-mortem brain pathology, the terminal and agonal state of the patient prior to cardiac arrest, reperfusion injury after resuscitation, and hypo- or hyperthermia after cardiac arrest. As a result, it is hard to distinguish the histological and ultrastructural changes induced by permanent global ischemia from other factors such as failed resuscitation attempts or temperature.

These limitations can be overcome in well designed animal studies of permanent complete global ischemia. One such study was conducted by Sergey V. Sheleg et al. at the Alcor Life Extension Foundation. The authors report the results of a study investigating the progressive histological and ultrastructural changes in cortical neurons following cardiac arrest at room temperature (20 degrees Celsius) in rats. Brain samples were taken at 1, 3, 6, 9, 12 and 24 hours following cardiac arrest. Temperature of the rats after cardiac arrest was measured using a deeply placed esophageal temperature probe.

The authors did not find any autolytic changes in the ultrastructure of cortical neurons in the first 6 hours after cardiac arrest. After 9 hours disappearance of ribosomes was observed in ~ 55% of the neurons. Further progression of autolysis is seen from 12-24 hours. Light microscopy did not reveal any appreciable histological changes but rouleaux formation was observed in the microcirculation of the cerebral cortex after 1 hour following cardiac arrest. The authors also found caspase-3 (an enzyme that plays a key role in apoptosis) activation in a “significant number” of neurons of the cerebellum and neocortex 9 hours following cardiac arrest.

Although the authors state that their research reflects an interest in human cardiac arrest at room temperature, it is doubtful that this model is a realistic representation of this. As can be seen in the temperature graph in the paper, the temperature of the rats drops rapidly after cardiac arrest to room temperature. Humans will take a much longer time to cool to room temperature because of their lower surface to mass ratio. As a result, the biochemical and structural changes induced by cardiac arrest may proceed at a faster pace in humans. A model that would hold the body temperature of the rats closer to their pre-mortem temperature, or follow the typical cooling curve of a post-mortem human, would be a better model to investigate such changes. The authors also do not report a control/sham group for comparison.

Although the results of this study are encouraging for the science and practice of cryonics it needs to be kept in mind that many cryonics patients do suffer prolonged terminal and agonal periods that can contribute to brain injury prior to cardiac arrest. The authors also review evidence that reintroduction of blood flow after cardiac arrest can produce more severe damage (reperfusion injury) than permanent global ischemia. Currently, data is lacking to answer the question whether more rapid cooling and better circulation of medications outweighs the risk of more ultrastructural damage as a result of (prolonged) cardiopulmonary support in cryonics patients.