Tag: Cardiac Arrest

Cryonics sets example for emergency medicine

One of the most neglected aspects of cryonics is that its procedures, and the research to support them, can have important practical applications in mainstream fields such as organ preservation and emergency medicine. Contrary to popular opinion, cryonics does not just involve an optimistic extrapolation of existing science but can set the standard for these disciplines. As a matter of fact, that is exactly what cryonics, and cryonics associated research, has been doing over the last 25 years.

The most striking example is the progress in vitrification as an alternative for conventional cryopreservation. Although the idea of eliminating ice formation at low subzero temperatures has been discussed since the beginning of cryobiology, vitrification as a serious research agenda was largely driven by the demand for ice-free preservation of the human brain. Over the last decades this research has culminated in the development of the least toxic vitrification agent to date, 21st Century Medicine’s M22.

The contributions of cryonics to mainstream science and medical practice are not confined to cryobiology. Researchers Jerry Leaf and Mike Darwin made impressive progress in the formulation of bloodless whole body organ preservation solutions to resuscitate dogs from ultraprofound hypothermic temperatures, an intervention that is increasingly being recognized as essential to stabilize trauma victims. In the mid 1990s, Mike Darwin and Steve Harris conceived and developed the idea of using liquid breathing with perfluorocarbons as a method to induce rapid hypothermia. They further validated a multi-modal medications protocol to resuscitate dogs from up to 17 minutes of normothermic cardiac arrest without neurological damage.

Although progress has slowed considerably in the non-cryobiology research areas over the last 10 years, it is encouraging to observe that some of the procedures that are routine in cryonics  stabilization protocol  are starting to catch on in mainstream emergency medicine practice as well. For example, contemporary cryonics stabilization protocol has been strongly shaped by the idea that the best strategy to limit brain injury after cardiac arrest is to combine a number of different interventions: cardiopulmonary support, induction of hypothermia, and administration of circulation-supporting and neuroprotective medications.

It is therefore very encouraging to learn that the Wake County EMS group in North Carolina has achieved impressive results in treating out-of-hospital cardiac arrest victims using a protocol that closely follows elements of current cryonics stabilization protocol. Systematic implementation of immediate induction of hypothermia, continuous compression CPR, and the use of an impedance threshold device (ResQPOD) produced an almost 400% improvement in survival and vast improvements in neurological outcome. A PowerPoint presentation about their experience and protocols are available at their website.

Such real world outcomes do not only inspire confidence in the procedures cryonics organizations can use to protect patients from brain damage after cardiac arrest, it should also serve as a wake-up call to relaunch an aggressive research agenda to push the limits of hypothermic and normothermic resuscitation. In absence of this, it will only be a matter of time before cryonics activists can no longer claim that “we did it first.”

HT Mike Darwin

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=-

The chemistry of neuroprotection

In a review of the 1998 21st Century Medicine seminars, Cryonics Institute president Ben Best writes:

“The presentations impressed upon me how much witchcraft and how little science has gone into the study of cryoprotectant agents (CPAs). This might be understandable in light of the fact that most cryobiologists are, in fact, biologists. I suspect that a great deal could be accomplished by a thorough study of the physics of the chemistry of CPAs.”

Such an observation could equally apply to the study of neuroprotectants in cerebral ischemia. There has been a growing literature investigating the potential of numerous molecules for the treatment of stroke and cardiac arrest. Although some approaches have been more successful than others, systematic reviews of the chemical and physical characteristics of effective drugs are lacking and discussion of the topic is  often confined to isolated remarks.

A number of examples:

“It is not surprising that all the agents which are effective in shock carry a negative charge. This applies both to heparin, which possesses a very strong negative charge, and to hypertonic glucose solution. The same may be said about a substance now in wide use – dextran – which has small, negatively charged molecules, and also about the glucocorticoids 21, 17, and 11, which also have a negative charge.” – Professor Laborit in: Acute problems in resuscitation and hypothermia; proceedings of a symposium on the application of deep hypothermia in terminal states, September 15-19, 1964. Edited by V. A. Negovskii.

“We report that estrogen and estrogen derivatives within the hydroxyl group in the C3 position on the A ring of the steroid molecule can also act as powerful neuroprotectants in an estrogen-receptor-independent short term manner because of to their antioxidative capacity.” Christian Behl et al. Neuroprotection against Oxidative Stress by Estrogens: Structure-Activity Relationship. Molecular Pharmacology 51:535-541 (1997).

“Minocycline’s direct radical scavenging property is consistent with its chemical structure, which includes a multiply substituted phenol ring similar to alpha-tocopherol (Vitamin E)” – Kraus RL et al. Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity. Journal of Neurochemistry. 2005 Aug;94(3):819-27.

“It is notable, however, that NAD+ and minocycline share a carboxamide and aromatic ring structure. A common structural feature of competitive PARP inhibitors is a carboxamide group attached to an aromatic ring or the carbamoyl group built in a polyaromatic heterocyclic skeleton. This structure is also present in each of the tetracycline derivatives with demonstrated PARP-1 inhibitory activity. Alano CC et al. Minocycline inhibits poly(ADP-ribose) polymerase-1 at nanomolar concentrations. Proceedings of the National Academy of Sciences of the United States of America. 2006 Jun 20;103(25):9685-90.

Systematic study of structure-activity relationship of neuroprotectants would not only contribute towards the development of a general theory of neuroprotection in cerebral ischemia, it would also contribute to the design of multi-functional neuroprotectants. Although it is now increasingly accepted that combination therapy offers more potential for successful treatment of stroke and cardiac arrest than mono-agents, parallel or sequential administration of multiple drugs present non-trivial challenges in research design and clinical application. Such problems may be better addressed by designing molecules with different mechanisms of action in the same structure, an approach that is currently recognized and investigated by forward-looking biomedical researchers.

Although the field of cerebral resuscitation has known some notable researchers  like Vladimir Aleksandrovich Negovskii and Peter Safar, who devoted their lives to a thorough study of the mechanisms of cerebral ischemia and its treatment, the field as a whole shows a never ending stream of trial and error publications to investigate yet another drug (before moving on to other areas in neuroscience and medicine). Although there is an increased interest in meta-analysis of all these experiments, meta-analysis that places its findings in a broader biochemical and pharmacological context is rare.

The emphasis on theory and research design can be taken too far. As Nassim Nicholas Taleb recently argued, the role of design in biotechnology is overestimated at the expense of chance observations and unexpected directions. But in the area of cerebral resuscitation the risk of too much theory and systematization is low at this point. As evidenced by the successful development of vitrification agents with low toxicity in cryobiology, a committed long-term and systematical effort to find solutions to human medical needs can pay off.

Critical cooling rate to prevent ischemic brain injury

Induction of hypothermia can reduce injury to the brain when it is deprived of oxygen. How fast do we need to cool a patient during cardiac arrest or stroke to prevent irreversible injury to the brain?

It is an established fact that induction of hypothermia prior, during, or after circulatory arrest can reduce brain injury. As a general rule, the lower the temperature is dropped, the longer the brain can tolerate circulatory arrest. The neuroprotective effects of hypothermia are often expressed using the Q10 rule which says that for every 10 degrees Celsius drop in temperature metabolic rate decreases by 50%. Or to put it differently, the Q10 rule states that ischemic damage susceptibility is decreased by a factor of 2 for every 10 degrees Celsius temperature drop.  Q10 may vary between species and in different organs and cells. For example, different temperature sensitivities were observed for release of the neurotransmitters glutamate, aspartate, glycine, and GABA during cerebral ischemia by Nakashima et al. Because even very modest reductions of brain temperature can have profound neuroprotective effects, the Q10 rule may not tell the complete story.

Other things being equal, it would be very useful to have a measure of brain injury when hypothermia is induced prior and/or during cardiac arrest. At least two authors have made an attempt to produce such a measure of ischemic exposure. In Cryonics Magazine (2nd Quarter, 1996), Michael Perry started initial work on this in an article called “Toward a Measure of Ischemic Exposure” (PDF).  Perry’s Measure of Ischemic Exposure (MIX) calculates how long the patient has been at a given temperature, with a higher weighting used for higher temperatures. A related measure has been proposed be Steve Harris called the E-HIT. E-HIT stands for Equivalent Homeothermic Ischemic Time. In his (unpublished) manuscript, Harris uses the E-HIT formula to calculate the equivalent normothermic ischemic time for different cryonics case scenarios and real cases. Clearly, the availability of such a measure (and its routine calculation in case reports) would constitute a major contribution to cryonics as evidence based medicine. It could aid in deciding if viability of the brain was maintained during cryonics procedures by estimating the equivalent warm ischemic time.

What makes such a measure complicated during cardiopulmonary resuscitation (CPR), or cardiopulmonary support (CPS) in cryonics stabilization procedures is that hypothermia may only constitute one intervention to mitigate brain injury. In an ideal cryonics case, pronouncement of legal death is followed by rapid restoration of oxygenated blood flow to the brain by (mechanical) cardiopulmonary support, administration of neuroprotective drugs and induction of hypothermia. Such a combination of interventions might avoid any injury to the brain, reducing the equivalent warm ischemic time to zero. A more realistic scenario is that such a combination of interventions may reduce the extent of ischemic injury compared to cooling only. Another complicating factor is that oxygenation in combination with low perfusion pressures might produce more injury than “anoxic cardiopulmonary support” (chest compressions without ventilation). It is clear that calculating a measure of equivalent ischemic time for real cryonics cases can become very complicated.

It would be interesting to know the cooling rate that would be necessary to stay ahead of brain injury, using contemporary medical criteria, during circulatory arrest. For this purpose we use some very simplifying assumptions:

1.The patient is not ischemic prior to pronouncement of legal death.

2. Cooling is initiated immediately after pronouncement of legal death.

3. There is no cardiopulmonary support or administration of neuroprotective agents.

4. Brain injury starts at 5 minutes of warm ischemia.

5. Q10 is 2.0: for every 10 degrees Celsius we decrease the temperature , metabolism is dropped 50% , which doubles the time a patient can tolerate ischemia.

6. No other forms of injury occur other than ischemic injury.

7. Ischemic injury is completely eliminated at the glass transition temperature of the vitrification agent M22 (-123.3°C).

8. A constant cooling rate is assumed.

Using these assumptions, Alcor’s Mike Perry calculates that a cooling rate of 2.89 degrees Celsius per minute is necessary to stay ahead of the equivalent of 5 minutes of warm ischemia.

Let Ehit = total ischemic time limit in hours, 1/12 corresponding to 5 min
Q10 = factor of decrease in metabolism per 10 degrees
Tdrop = desired temperature drop, from 37 degrees (body temp) down to -123.3= 160.3 degrees Celsius
ch=desired cooling rate in deg/hour
cm=desired cooling rate in deg/min = ch/60

Then

ch = 10*(1-exp(-Tdrop*ln(Q10)/10))/(Ehit*ln(Q10))

For Q10=2, Tdrop = 160.3, cm = 2.89 deg/min

If some of the assumptions are slightly changed we find the following for Q10=2.2

For Q10=2.2, Tdrop = 160.3, cm = 2.54 deg/min

If we assume negligible ischemic insult below 0 Celsius and only worry about cooling down to that temperature, so Tdrop is only 37 rather than 160.3, it doesn’t change these amounts drastically:

For Q10=2, Tdrop = 37, cm = 2.66 deg/min
For Q10=2.2, Tdrop = 37, cm = 2.40 deg/min

Clearly, such high cooling rates cannot be achieved during either conventional cardiopulmonary resuscitation or cardiopulmonary support in cryonics. The cooling rates we can hope for during the initial stages of cryonics procedures may exceed 1.0 degrees Celsius per minute at best. It is therefore not realistic to assume that cooling alone may be able to limit brain injury to a degree that allows resuscitation without adverse neurological effects using contemporary medical criteria. This should strengthen the case for the use of other interventions such as administration of neuroprotective agents and oxygenation of the patient. Although the latter intervention may produce adverse effects on the brain itself, the calculations above indicate that anoxic cardiopulmonary support is not compatible with maintaining viability of the brain as the objective of cryonics stabilization procedures. The case for rapid stabilization of cryonics patients remains strong.

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.

Cerebral ischemia and impairment of circulation

Cryopreservation of the brain depends on the removal of blood from the brain’s vasculature and its replacement with cryoprotective solutions in order to prevent ice crystal formation (freezing) during cooling (i.e., facilitate vitrification). Ultimately, the success of a good cryoprotectant is limited by perfusability of the brain, or the ability of cryoprotective solutions to penetrate all areas and cells of the brain via the cerebral vessels. Long periods of global cerebral ischemia detrimentally affect reperfusion of the cerebral vessels, thereby significantly degrading perfusability of the brain. Many possible causes for post-ischemic impaired perfusion have been hypothesized in the past, including swelling of the endothelial cells that make up the inside lining of blood vessels. However, a landmark 1972 paper by Fischer & Ames provided evidence implicating changes in the blood itself as the probable reason for post-ischemic reductions in perfusability of the brain.

Ames, et al. had already demonstrated impaired reperfusion in rabbits after cerebral circulatory arrest followed by infusion of a suspension of carbon black and examination of coronal brain sections. Brains undergoing less than five minutes of arrest perfused well and were evenly stained by carbon black ink. Ischemia in excess of five minutes resulted in patchy white areas where perfusion was impaired and blood vessels did not fill with ink. In an extension of this work, Fischer and Ames investigated the effects of perfusion pressure, anticoagulation, and hemodilution on post-ischemic perfusability.

In their experiment, the researchers induced cerebral circulatory arrest in rabbits and then perfused the head and neck with carbon black immediately following various ischemic periods. The perfusion solution was introduced to the cerebral circulation from a reservoir placed above the rabbit and through tubing that was inserted into and secured in the ascending aorta. Perfusion pressure may thus be modulated by varying the height of the reservoir above the animal. In some animals, acute hemodilution was achieved by rapid infusion (50 ml/kg) of saline into the femoral vein for moderate hemodilution or by a combination of saline administration and blood removal for extreme hemodilution prior to ischemia and carbon black infusion. A series of animals were also anticoagulated by giving heparin (500 units/kg) intravenously 15 minutes prior to ischemia. Brains were then removed and diffusion fixed in 10% formalin, allowing coronal sections of the brain to be examined macroscopically.

Brains from 5 groups of animals were studied:

Group 1: 4.5 minutes’ ischemia, reservoir at 28 cm above the heart (two animals), 40 cm (two animals), and 110 cm (two animals).

Group 2: 15 minutes’ ischemia, reservoir at 70 cm (six animals), 110 cm (eight animals), and 170 cm (seven animals).

Group 3: 30 minutes’ ischemia, reservoir at 170 cm (six animals).

Group 4: Hemodilution, 15 minutes’ ischemia, reservoir at 70 cm, hematocrit (HCT) 21 to 32 (five animals); HCT 4 to 13 (six animals).

Group 5: Heparin, 15 minutes’ ischemia, reservoir at 70 cm (six animals).

As previously observed, “animals with 4.5 minutes of ischemia failed to demonstrate impaired cerebral reperfusion even with perfusion pressures as low as 28 cm of water, all brains being completely and evenly black.” However, significant impairment of perfusion was observed after 15 minutes of ischemia. The effect was greatest in the thalamus and brain stem, while cerebral cortex remained adequately perfused after 15 minutes of ischemia at all levels of perfusion pressure. White (non-perfused) areas were significantly greater after 30 minutes of ischemia than after 15 minutes at comparable pressures and in all areas examined (including cortex). Hemodilution greatly improved reperfusion after 15 minutes of ischemia, but no difference between anticoagulated animals and controls was observed.

The authors speculate that blood viscosity, rather than clotting or cellular swelling, was the most probable cause of impaired reperfusion following ischemia. They further noted that “improved postischemic cerebral circulation has also been noted to follow the infusion of hyperosmolar agents,” which they speculated was also due to reducing blood viscosity. Red cell aggregation during blood stasis was assumed to be a major contributing factor to the increase in viscosity, and differences in vascular resistance throughout the brain manifesting as differences in circulatory impairment were thought to underlie the observation of impairment of discrete, macroscopic regions of the brain — particularly subcortical regions.

The results of Fisher et al. support rapid restoration of perfusion pressure (mechanical cardiopulmonary support) after cardiac arrest in cryonics patients, and hemodilution with agents like Dextran-40. It is harder to reconcile with the emphasis in cryonics to administer fibrinolytics and anticoagulants to eliminate and prevent blood clotting. The results of Fisher et al. are also at odds with those of Böttiger et al., who found that activation of blood coagulation after cardiac arrest is not balanced adequately by activation of endogenous fibrinolysis. Perhaps these findings can be reconciled if we allow for the possibility that cardiac arrest and cerebral ischemia induce formation of (micro)thrombi, but that these are not clinically significant, or at least do not affect reperfusion as greatly as other blood abnormalities such as red cell aggregation. And perhaps the formation of thrombi in small cerebral vessels can adversely affect cryoprotectant perfusion without being visible by gross examination. Formation of large clots may still be a problem after longer periods of circulatory arrest. Tisherman et al. have observed large vessel blood clots in rats and dogs after normothermic cardiac arrest of more than 20 minutes. Finally, cryonics patients may present with existing blood clotting problems as a result of (septic) shock.

Although the emphasis on antithrombotic therapy to maintain circulatory patency in cryonics patients seems to be warranted, more emphasis on other factors that affect cerebral (micro) circulation in cryonics patients seems desirable. As the work of Fisher et al. indicates, hypertension and hemodilution during cardiopulmonary support may be just as, if not more, important. The relationship between in vivo stasis of blood circulation and coagulation remains elusive and could benefit from more research.

Preventing vegetative patients through cryonics

The blog Practical Ethics reports on pioneering research from a group of scientists in Cambridge who are using fMRI scans to study the brains of people who have been diagnosed as being in a vegetative condition. A Persistent Vegetative State (PVS) is a condition that is characterized by a state of wakefulness without detectable awareness. The researchers found that some patients who have been diagnosed as being in a vegetative state were able to respond to certain stimuli, indicating the possibility of awareness. Although it is encouraging that new medical technologies can assist in preventing misdiagnoses of patients with severe brain injury, the fact remains that few of these patients will ever recover with their former personality and memories intact.

Patients who have been diagnosed with conditions such as Persistent Vegetative State (such as Terri Schiavo) or the Minimally Conscious State (MCS) often suffered serious damage to the brain as a result of severe stroke or cardiac arrest. Although there are rare cases of remarkable recoveries, most patients with such diagnoses have ceased to exist as persons because the parts of their brains that encoded their personalities have ceased to exist.

It is now a well established fact that brain cells do not immediately die after severe hypoxic insults such as stroke or cardiac arrest. Actual necrosis (or apoptosis) takes many hours, or sometimes even days (as a result of a phenomenon called “delayed neuronal death.”). Unfortunately, ischemic insults to the brain exceeding 5 minutes are often sufficient to set parts of the brain on an irreversible path to destruction of the person, even if resuscitation of the patient is possible. Currently, there is no single approved neuroprotective agent that can salvage these brain cells from destruction. Although hyperacute combination therapy may offer hope for people suffering severe hypoxic insults, most of such patients currently would be better served by placing them in a state of biostatis through cryonics before the complete ischemic cascade can run its course.

Although cryonics is often dismissed as speculative, it can be argued that long term preservation of the neuroanatomy of such patients through vitrification offers better hope of recovery as the same person (or any person at all) than immediate resuscitation after the insult. But for acceptance of cryonics as a treatment for patients at great risk of (delayed) severe brain damage to become acceptable, the general public will need more exposure to the technical feasibility of cryonics and perspectives on death that offer a more prominent place to the concept of personhood.

Combination therapy: The patient's view

One consequence of the growing understanding of the biochemical pathways involved in brain injury resulting from cardiac arrest, stroke, and brain trauma is that there is an increasing consensus among researchers that combination therapy is the most logical treatment for the multifactorial injury mechanisms responsible for neuronal death. In this context, combination therapy can mean either combining different forms of treatment, such as hypothermia and a neuroprotective agent, or the combination of multiple neuroprotective agents. But despite encouraging results with combination therapy in animal models, and disappointing outcomes for single neuroprotective agents (such as the recent free radical spin trap agent NXY-059) in human clinical trials, there are no indications that the current trend of investigating just one neuroprotective agent will be reversed soon.

One obstacle for successful combination treatment that is not often addressed is that cardiac arrest, stroke, and brain trauma are acute events that do not allow a vocal pro-active role of the patient at the time that this could benefit him. During the immediate post-insult period when the molecular events leading to neuronal death, and even higher brain death, play out, most patients are not able to communicate their wishes, or are in a coma. As a result, the patient is not present at the time when the most important decisions about his survival as a person are being made.

This predicament is different from patients suffering from serious but chronic diseases such as AIDS and cancer. In his book “Surviving Terminal Cancer: Clinical Trials, Drug Cocktails, and Other Treatments Your Oncologist Won’t Tell You About” psychology professor Ben Williams documents how he improved his odds of surviving a glioblastoma multiforme brain tumor by researching and pursuing his own treatment, which consists of a combination of conventional and “alternative” treatments.

Williams’ successful case of personalized combination therapy does not present strict scientific evidence that his treatment is the cause of his remarkable recovery (so far), but it does highlight the general benefits that may be obtained when patients demand some degree of control over their choice of treatments. Williams stresses that patients such as himself may have much to gain, and not much too lose, from pursuing such an experimental “cocktail” approach. A similar situation applies to patients who are at risk of severe brain injury and cannot afford to wait until the mechanisms and comparative efficacies of each individual component of a neuroprotective cocktail have been thoroughly investigated.

How can such an outcome driven treatment of cerebral ischemia gain acceptance? Since the patient will not “be there” to investigate and demand unorthodox experimental treatments, he can only influence his odds by leaving advance directives to medical care givers and relatives to request that such treatments are given to him. Such measures can only have a chance of succeeding, however, if experimental treatment options are documented for these patients.

In contrast, combinational pharmacotherapy and hypothermia have been core components of human cryopreservation stabilization protocol for many years. To date, researchers involved in cryonics have made record achievements in normothermic cerebral resuscitation and (ultra)profound hypothermic resuscitation. The applications of such research should not be limited to minimizing brain injury in cryonics patients but should be shared with the general public to help build a “supply” side of experimental treatments that can be consulted by medical care givers and relatives of the patient.

Individuals who are signed up for cryonics have a personal interest in stimulating such research, its documentation and dissemination because acute insults such as cardiac arrest, stroke, and brain trauma can produce (higher) brain death before the individual will present for human cryopreservation in the future. Indeed, cryonics may offer the only chance of personal survival for patients who are at risk of major brain damage if they are resuscitated and left to live at room temperature.