Table of Contents and Disclaimer

STANDBY:

END-STAGE CARE OF THE HUMAN CRYOPRESERVATION PATIENT

by Michael G. Darwin
Copyright 1994 by Michael G. Darwin. All rights reserved.

Chapter 7: Premedication of the Human Cryopreservation Patient

Disclaimer: Alcor cannot provide medical care for living patients and must regard the care and medication of legally living members as the sole responsibility of members and their treating physicians.  To avoid conflict of interest Alcor cannot advocate premedication protocols for cryonics patients.


"The physician must be able to tell the antecedents, know the present, and foretell the future--must mediate these things, and have two special objects in view with regard to diseases, mainly to do good or to do no harm."

--Hippocrates Of The Epidemics

The Way It Is

Because of the medicolegal constraints imposed upon cryonics now, and most likely in the foreseeable future, cryopreservation procedures cannot begin until clinical and legal death have occurred. It is generally argued by proponents of human cryopreservation that significant intervals of ischemic injury need not be catastrophic, nor result in the irreversible compromise of mentation and identity. These arguments are made largely on the basis of laboratory experiments where global ischemia is induced in healthy animals without prior pathology.

There can be no argument that such experiments have contributed greatly to our understanding of the biology of ischemia and to bounding the limits, as it were, of the “theoretically possible” with respect to recovery of cryopatients who experience ischemia. Clearly, the persistence of neuronal membrane integrity and the conservation of central nervous system (CNS) ultrastructure after significant periods of normothermic ischemia is encouraging and provides a reasonable basis for the hope that structures encoding human identity are still intact after such insults. However, it is critically important to realize that experiments conducted in the laboratory under tightly controlled conditions are designed to answer highly specific questions, in fact, they are usually designed to answer only a specific few questions. Such experiments cannot be expected to tell us much about the condition and prognosis of cryopatients who die in very complex and uncontrolled ways in the real-world.

Unlike laboratory experiments, cryopatients do not typically experience global ischemia from a well-timed jolt of electricity to the heart after bounding into bed in previously good health. Some will die from sudden, unexpected arrhythmias and do so free from serious multiorgan or systemic disease which can cause extensive antemortem brain damage. But such patients will pay for the "scientifically clean" nature of their ischemic insult by being subjected to uncontrolled reperfusion during futile resuscitation attempts, long post-arrest delays attendant to unwitnessed cardiac arrest, and/or medico-legal examination (autopsy or seizure by the medical examiner (ME) or coroner). While two-thirds of cryopatients will die "expected deaths" (i.e., not from sudden cardiovascular compromise, suicide, accident or homicide), only half of these will die in settings or under conditions that make prompt high quality post-arrest intervention possible.

Thus, approximately one-third of cryopatients will die from degenerative disease in a setting that will allow for a reasonably good chance of prompt post-arrest intervention. However, this number is also misleading if it is taken to be an indicator of an optimum chance at recovery or a laboratory-like model of global cerebral ischemia.

The reality is that of this 35% or so of patients who present for cryopreservation with adequate warning to mount a full standby, somewhere between 7-10% of them will suffer from some major pre-cryopreservation compromise to their brains. Many of these patients will have organic brain syndrome from Alzheimer's, multi-infarct dementia, HIV or HIV related CNS infections (i.e., toxoplasmosis, tuberculosis, meningitis, etc.), stroke, brain tumor (primary or secondary) or other causes. At this time, little can be done to improve these patients' chances. Of the remaining 25% of cryopatients without prearrest primary brain pathology, most will suffer a prolonged period of agonal shock characterized by hypoxia, activation of the immune-inflammatory cascade, and regional cerebral ischemia. As a consequence, these patients will experience global brain insult before cardiac arrest ever occurs. Only a small minority of cryopatients, perhaps as few as 2-10%, will present for cryopreservation under conditions that allow for an optimum standby and will experience legal death in a way which results in little or no antemortem hypoxic-ischemic injury.

It should also be kept in mind that so far we have considered only the effects of ischemia in a laboratory setting as our guide to how we should visualize the condition of the "typical" cryopatient. This scenario or model does not take into consideration the behavior of the ischemically injured brain in response to resuscitation (acute reperfusion), induction of hypothermia, introduction of cryoprotectants during an extended period of perfusion, and finally, the effects of cryoinjury during cooling to -196°C.

All cryopatients, no matter how well or how poorly they experience medicolegal death will, indeed must experience medicolegal death before cryopreservations procedure can commence. This fact alone means that all patients presenting for cryopreservation will experience some period of ischemic insult: even if the insult is only 1-2 minutes of global ischemia and 3-5 minutes of inadequate blood flow and gas exchange during the initial minutes of CPR.

This is the sad reality of how cryonics is practiced today, and anyone who doubts this reality need only peruse the case histories of those cryonics organizations that choose to publish them in sufficient detail to allow a meaningful evaluation.

An Alternative

So, what can be done? Even in the best of cases there will be a period of ischemia which reaches or exceeds the current 4-6 minute envelope of clinical recovery. The problem of mitigating ischemic injury upon reperfusion and after the declaration of legal death is dealt with in great detail elsewhere. And, as has been previously noted, it is not possible to start cryopreservation procedures on people not yet legally dead. So, it would seem that this Chapter might well end here. And so, in effect, it will for many cryopatients for diverse reasons that will be discussed below.

But this need not be the case. The common event which all cryopreservation patients experience is hypoxia-ischemia. Whether global or incomplete, whether in the presence of underlying systemic disease or not, all will experience ischemia. And so we can, as Hippocrates admonishes us to do, "tell the antecedents, know the present, and foretell the future." And with such knowledge of the past, present and future comes the power to act.

While it is certainly the case that postmortem aspects of cryopreservation (induction of hypothermia, cryoprotective perfusion, and cooling and solidification) cannot be undertaken before legal death, much of what determines the likely utility of these "postmortem" procedures will occur prior to medicolegal death. Furthermore, many of the physicochemical events that will result in ischemic injury after cardiac arrest and upon reperfusion can best be moderated or even inhibited by pre-insult pharmacological intervention.

Defining Premedication

The basic definition of premedication in the context of this text is pharmacologic intervention during the patient's terminal illness to moderate or inhibit ischemia-reperfusion injury that would otherwise occur as a result of cardiac arrest and the delays attendant to the pronouncement of legal death.

Encompassed by this definition is a wide range of behaviors ranging from providing the patient with nonspecific information that pharmacological intervention is an option, to providing the patient with detailed verbal or written information, all the way through to establishing a specific protocol for dispensing drugs. Please note that all biologically active compounds, including nutrients in excess of the Reference Daily Intake (RDI), which are taken by or given to the patient with the intent to modify the patient's response to ischemia-reperfusion injury or the dying process will be considered, for the purposes of this text, to be medications or drugs.

Risks

Is antemortem premedication of patients to inhibit agonal and postmortem injury legal? Is it moral? Will it harm the unequivocally living patient in order to provide supposed benefit for the equivocally dead one? These two questions must be asked and answered before we proceed further.

Legal Risks to Patient and Staff

Ironically, the legality of premedication is an easier question to address than the question of "will it do no harm?" To be sure, neither question has a black-or-white or all-or-none answer. The answers come in shades of gray, and as with all such gray-state answers, there is the associated hazard of mistaking dusk for dawn.

In the United States (the only country which I will consider here) there are six broad classes of pharmaceuticals:

  • 1) Vitamins, nutrients, and minerals (i.e., vitamins E and C, selenium, magnesium)
  • 2) Over the counter (OTC) drugs (aspirin, naproxyn, cimetidine)
  • 3) Ethical prescription drugs approved by the US FDA (l-deprenyl, Dilantin, misoprostol)
  • 4) Ethical drugs available in non-US countries which may be legally imported for personal use (Zileuton, piracetam, ketotifen)
  • 5) Unclassified drugs and drugs approved for veterinary but not human use (PBN, FBP)
  • 6) Underground or contraband drugs (Thalidomide, GHB)

The legal risks associated with thoughtful and prudent use of drugs in categories 1 and 2 (vitamins and OTC drugs) with the patient's informed consent under the direction of a physician and with the knowledge and consent of the patient's personal physician and caregivers, are minimal (but not nonexistent).

The legal risks associated with thoughtful and prudent use of drugs in category 3 (ethical US FDA approved drugs) under the direction of the patient's physician are somewhat greater but still probably small.

Risks associated with thoughtful and prudent use of drugs in category 4 (ethical non-FDA approved drugs) imported by the patient for personal use under the direction of a physician with the knowledge and consent of the patient's personal physician and caregivers is considerably greater.

Use of drugs in category 5 with knowledge and consent of the patient's personal physician is high. Without the involvement of the patient's primary care physician, use of such agents is contraindicated.

Any use of drugs in category 6 is normally contraindicated and always carries with it the risk of autopsy of the patient and serious legal repercussion for any cryonics personnel involved in such activity.

More detailed considerations of the legal risks involved in premedication will have to await discussion of specific drugs and specific medical and social scenarios later in this Chapter.

Medical Risk to the Patient

The issue of medical and psychosocial harm to the patient in the context of premedication is a far more difficult one. At first glance it might seem a simple issue. Some drugs like aspirin and vitamins E and C which might provide substantial cerebroprotection if given in advance of the ischemic insult would seem to carry no downside. They are commonly ingested by healthy people, are widely endorsed by physicians in moderate amounts, are essential nutrients found in food, and are freely available OTC without a prescription.

However, the hidden caveat in the above paragraph is the qualifier "they are commonly ingested by healthy people." In patients with iron overload from hemochromatosis or with diminished urine output, moderate doses of vitamin C could cause serious injury or death. In the patient who is platelet depleted or suffering from bleeding secondary to cancer or gastrointestinal (GI) ulceration, vitamin E or aspirin may precipitate a hemorrhage causing morbidity or mortality.

Thus, even the most seemingly innocuous agents may cause direct physical harm. Beyond the issue of physical injury or death are the even thornier issues of social cost (impact on the quality of remaining life) and economic cost, both of which may feed back in unexpected ways to affect the patient's physical well-being. Thus, as with all medicine practiced upon living people, the admonition to "first do no harm" looms large and weighs heavy on its practitioners.

The point of this discussion is very simple: premedication of cryopreservation patients carries with it cost, uncertainty, and the potential for considerable harm as well as some benefit (to both the patient and the cryonics personnel). The cost-benefit ratio will be something that can only be established on a case-by-case basis with careful and thoughtful interaction between all of the parties involved. Such parties will necessarily include the patient and the Standby personnel, but may (and usually should) include the patient's family, physician(s), intimate friends, and others involved in the patient's care.

In some situations it will be an imperative for the patient's physical and psychological well being (quite apart from any advocacy or involvement of cryonics organization or Standby staff) to use category 6 drugs and this will be undertaken by the patient with the full support and active cooperation of all caregivers (including the physician) and the family. Ironically, such a situation may pose only the most minimal risk to the patient and staff where, by contrast, the use of a single category 1 drug such as vitamin E in a situation involving a hostile physician or family member may result in a medicolegal disaster. There are no hard and fast rules and good judgment is the only protection. Good judgment, however, is hardly an assured commodity and it must stated clearly and without qualification that premedication of any patient with any drug carries with it risk which cannot be eliminated. Be forewarned!

Evaluating the Patient

Psychosocial Considerations

As the above discussion should make clear, premedication carries with it risks which are determined to a large degree by the patient's medical condition, and psychological and social situation. Determining the most beneficial (or lowest risk) approach can only be done after the patient is carefully assessed in all these areas.

Psychosocial evaluation and intervention are covered in considerable detail elsewhere in this text. However, a few words specific to premedication are in order. Patients who have family and/or primary caregivers who are hostile to cryonics are generally not candidates for premedication. The same is true of patients who have diminished capacity, diagnosed psychiatric problems or who are obviously not fully capable of giving informed consent. The only exceptions to this rule are situations where:

  • Patients who are no longer competent have left an advanced directive or have a Durable Power of Attorney for Health Care (DPAHC) which specifies premedication.
  • The patient's medical surrogate (as appointed in their DPAHC) is aggressively supportive of premedication.
  • The spouse or parent(s) or guardian of the patient are cryonicists and are aggressively supportive of premedication.

Situations where unresolved hostility, paranoia and mistrust exist on the part of any of the key players in the patient's personal, social or medical milieu, whether directed at cryonics or not, are absolute contraindications to premedication.

Ideal situations are ones where the patient and family are long-time cryonicists, or where the patient has been pursuing alternative treatments that involve self administration of unapproved parenteral or category 6 medications. The latter situation, such as is often the case in HIV patients and younger patients with cancer or other unexpected degenerative diseases, almost invariably implies a person and caregiver(s) who have become knowledgeable about the mechanics of administering parenteral drugs, are willing to take risks, and are generally (but not always) capable of independent judgment and the ability to absorb and draw conclusions from the primary biomedical literature. Such a patient and caregiver(s) will be able to use the Internet and access biomedical databases and illness-specific special interest groups (SIGS) and thus get a wide range of independent information. The ability to critically evaluate the peer-reviewed scientific literature supporting premedication for ischemia-reperfusion injury is a strong plus in favor of providing the patient with information on premedication.

Medical Considerations

In addition to the psychosocial situation, the patient's medical condition and treatment will determine whether premedication is appropriate and if it is, what its specifications will be. Clearly a patient who is dying in a hospital will not be a candidate for intervention with category 4, 5 or 6 drugs. Similarly, a patient with gut failure, GI obstruction, or other contraindications to p.o. medication will not be able to benefit from many of the drugs likely to be of use in premedication. Beyond these logistical considerations come more subtle and potentially dangerous ones.

An exhaustive medical evaluation of the patient by his personal physician and by a physician knowledgeable about premedication (including the pharmacology of the drugs to be used) is absolutely essential. The purposes of such an evaluation are to:

  • 1) Rule out the possibility that the patient has a potentially treatable illness and is not terminally ill in the first place.
  • 2) Rule out underlying medical conditions which may contraindicate premedication in general or the use of specific agents.
  • 3) Provide medicolegal documentation of the appropriateness (i.e., anticipated benefits and lack of contraindication) of a given premedication protocol for the patient.
  • 4) Provide a sound basis for determining the appropriate medications as well as their dose and route of administration.

The medical evaluation of the patient prior to premedication should include the following elements without exception:

  • 1) A comprehensive gathering, duplication (and retention) by the Cryonics Organization's Medical Director (COMD) of all of the patient's available medical records.
  • 2) A thorough medical review of the records gathered by the attending physician and the COMD with specialist consultation as necessary.
  • 3) Evaluation by a clinical laboratory (which the COMD has confidence in) of the patient's CBC, clotting status, TSH level and serum chemistries, at a minimum.
  • 4) Evaluation of current and projected nutritional status, caloric intake, assessment of macronutrient intake (with special attention to fat intake), and assessment of dietary micronutrient intake.
  • 5) Determination of baseline serum antioxidant levels and redox status (Pantox Profile).
  • 6) Infectious disease screen including testing for HCV, HBV, HIV, TB and other etiologic agents as circumstances may indicate.

Pantox Panel

Determining the patient's antioxidant status is a crucial first step in formulating a plan for premedication. In some cases, patients may already be supplementing with vitamins or trace minerals which are central to the basic premedication protocol discussed below. In all cases it is desirable to titrate the dose to the desired levels. This will be especially important in cases of compromise to the gut, malabsorbtion syndrome, noncompliance, and poor nutritional status. Poor nutritional status will mean low intake of macronutrients including fats, which act as facilitators of absorption for lipid soluble medications.

Pantox Profile

The patient's serum antioxidant profile will serve several functions in addition to establishing a baseline for premedication. It serves as a marker for overall nutritional status and it provides easy to understand visual feedback for the patient, showing him graphically where he is now versus where he needs to be. Response to premedication as evaluated by serum antioxidant levels also contributes to our understanding of the effectiveness of premedication both in acutely raising blood levels of these drugs and in moderating ischemic injury.

Below is a table giving the normal range of serum antioxidants and pro-oxidants (such as serum ferritin) evaluated by Pantox testing. [Pantox Laboratories, San Diego CA (619) 272-3885].

Lipid Soluble Antioxidants     Normal Range   Units

Coenzyme Q10 (Ubiquinol)       0.33 - 4.37     *M
Alpha-tocopherol (Vitamin E)   23.0 - 78.0     *M
Gamma-Tocopherol               1.50 - 7.50     *M
Lycopene                       0.07 - 0.66     *M
Beta-Carotene                  0.25 - 4.20     *M
Alpha-Carotene                 0.04 - 0.50     *M
Vitamin A                      1.60 - 3.51     uM
Lipid Protection Ratio         4.70 - 15.8	


Water-Soluble Antioxidants

Vitamin C                      22.0 - 137      *M
Uric Acid                       246 - 569      *M
Total Bilirubin                1.71 - 20.5     *M
Direct Bilirubin               0.00 - 5.13     *M


Iron Status

Serum Iron                     7.17 - 26.8     *M
Iron Binding Capacity          44.8 - 71.6     *M
Percent Saturation             11.2 - 51.7      %
Available Binding Capacity     32.9 - 75.0     *M
Serum Ferritin                 27.0 - 450     ng/ml

Table 7-1: Normal limits for serum antioxidants and pro-oxidants.

The results of an individual's Pantox panel are displayed graphically so that the patient can meaningfully evaluate where s/he stands and see progress towards reaching predetermined goals. Below are graphic examples of a Pantox profile on a typical 51 year-old smoker with end-stage primary adenocarcinoma of the lungs. The "ideal" levels shown on the graphics for antioxidants are the lower limits considered desirable for premedication for cerebroprotection.

Formulating a Program

Generalities

Once a complete evaluation of the patient is done, including Pantox testing, it is time to meet with the patient and his family to determine if premedication is an option that they wish to pursue and whether it is one which is practically open to them. In other words do they have not just the will but also the financial and logistic ability. Can they afford the medication? Will their physician object? Are there family members or other key players who might create serious problems? And finally, does the patient really want to do this?

This last consideration may seem a given but it is not. Dying people are remarkably refractory to taking medication. This is particularly true of oral medication. Lack of appetite and psychological withdrawal are normal elements of dying. As the patient deteriorates physically his threshold for any kind of inconvenience or discomfort will decrease dramatically. As energy for important daily activities disappears the patient will most often become extremely protective of how that energy is used. Even the simplest acts such as bathing, eating a meal or swallowing pills on a schedule can become an unacceptable burden. Add to this normal alteration in physiology and psychology the presence of GI dysfunction, nausea or malaise and you have the perfect recipe for noncompliance. Thus, it is important to go over in considerable detail with the patient what is involved in premedication. It is also important to negotiate with the patient in advance for how much pressure should be brought to bear on the patient by caretakers to maintain compliance.

Patients considering premedication need to know that very few patients remain committed to this course of action till the end. They need to understand that those around them will allow them to stop premedication when it is no longer psychologically or physically possible for the patient to continue. And, just as importantly, the patient needs to know that benefits of premedication will likely extend well beyond the time it is stopped. This is particularly true of fat soluble drugs such as vitamin E, co-enzyme Q10 (CoQ10), PBN and melatonin.

If appropriate (i.e., they are long term cryonicists using alternative parenteral medications), the use of parenteral premedications can be generally discussed. It is not recommended that Standby personnel or cryonics organizations provide or recommend unapproved parenteral medications, however, if this is something the patient is aware of and intends to pursue, information may be given about how to avoid complications and injury as a result of inappropriate use of injectable drugs. Similarly, determining dosages on parenteral products to achieve the desired serum and tissue levels is something that can be addressed on a case-by-case basis carefully, and without advocacy.

Once the general kind of premedication program is determined, the next step is to determine the specific elements of the program. If the program is a multi-drug one which includes water soluble drugs with short half-lives then it is very important to keep dosing simple, uniform and an integral part of the normal daily routine. The best way to achieve this is by specifying that all medications be taken with meals or with two meals and at bedtime. This has two added advantages in that it is likely to decrease GI side effects of the medication (heartburn, nausea, diarrhea) and increase the length of time which the program can be followed. It is almost never acceptable to have the patient taking any medication more than three times a day or at times other than mealtime or bedtime.

If the patient is inclined he should be encouraged to note side effects, problems or questions so they can be addressed and rectified (say sleepiness during the day or stomach discomfort with bedtime medicine).

In any event, and this is very important, the patient's medication intake should be charted or, if that is not possible, a day-by-day pillbox set up so that medicines taken or not taken can be reliably determined by looking at the container at the end of the day, end of the week, etc. Pantox levels should be run, if financially possible, at least three times during the course of premedication: at two weeks after the start, at the estimated "mid-point" of the patient's terminal course, and during the agonal period.

Specifics

An Exposition of Putative Cerebroprotective Drugs and Their Pharmacology

A discussion of the comprehensive pharmacology of each of the cerebroprotective premedications discussed below would consume a full volume. The approach used here will be to divide the medications by category type and give a brief account of the drug's pharmacology both as it relates to its traditional use and to its use as a putative premedication for ischemia-reperfusion injury.

Category 1 Drugs

400 IU d-alpha tocopherol (vitamin E) p.o., t.i.d. Vitamin E is a naturally occurring lipid soluble free radical scavenger and antioxidant which has been shown to be cerebroprotective in a variety of experimental models of cerebral ischemia and in spinal cord injury and head trauma. The cerebroprotective effects of vitamin E are greatest when given as a premedication where it becomes incorporated into cell membrane lipids before the ischemic insult occurs. Vitamin E comes in a variety of dosage forms as an over the counter product. The packaging, chemical formula and source all affect its bioavailability and activity. Several chemical forms of vitamin E are marketed: natural mixed tocopherols, d-alpha tocopherol (synthetic) and esterified tocopherols.

The esterified versions of the tocopherols (usually the succinate or the acetate) are resistant to auto-oxidation and may be safely stored at room temperature. This is by far the most common way vitamin E is sold in the United States whether it is packaged dissolved in oil in gelcaps, as a powder in capsules, or as an emulsion in chewable tablets or elixirs. In a healthy individual the vitamin E is de-esterified in the liver (and to a lesser extent in other tissues) and becomes fully biologically active only 7-10 days after ingestion. The likelihood of impaired hepatic metabolism and the need for immediate protection (terminal patients often die far earlier than expected) make the use of esterified vitamin E problematic. The use of gamma enriched mixed tocopherols is the ideal; we will still refer to this as “vitaim E” supplementation.

At this time it is recommended that nonesterified mixedtocopherols and preferably gamma tocopherol obtained fresh from a reliable supplier be used for “vitamin E” premedication.

In addition to its antioxidant and neuroprotective effects, vitamin E is an essential nutrient which is involved in immunity, wound healing, and cardiovascular health. Vitamin E has antiplatelet activity and is a moderate antagonist of vitamin K1 and thus has coumadin-like effects in doses much above 40 IU. At doses of 400 IU and above the coumadin-like effects of vitamin E can cause potentially serious bleeding in a patient with gastrointestinal ulceration. High dose vitamin E can also interact with coumadin, warfarin and related anticoagulants to potentiate their effects, thereby increasing the risk of hemorrhage into joints or bleeding in the CNS. The antagonistic effect of vitamin E on vitamin K1 can be reversed by vitamin K1 supplementation using vitamin K1 obtained from health food stores.

Ascorbic acid (Vitamin C) CAUTION: Do not administer to patients with iron overload! 1 g p.o., t.i.d. Ascorbic acid is a water soluble antioxidant which is distributed throughout the tissues of the body and is accumulated in the CNS. Approximately 80% of the total body ascorbate load is in the brain. Ascorbic acid reacts directly with hydroxyl and peroxyl radicals as well as superoxide radicals and singlet oxygen. Of significance to this protocol, ascorbic acid is important to the regeneration of oxidized d-alpha tocopherol to the reduced form. The use of ascorbic acid as a cerebroprotective agent is an empirical one. While ascorbic acid is important in regenerating vitamin E and glutathione (two critical ischemia protective antioxidants), it is also one of the most effective hydroxyl radical generators present in the brain in high concentrations. Ascorbic acid participates in hydroxyl radical generation by its central participation as a reductant in the Fenton reaction. The Fenton reaction is driven in the CSF and interstitial fluid of the brain by the massive release of ascorbate as a result of the exchange of intracellular ascorbate for extracellular glutamate as one of the first physiochemical events of ischemia.

The other critical ingredient in the Fenton reaction is iron. Approximately 10% of the population has a defect in iron metabolism or a blood dyscrasia that results in hemochromatosis (iron overload). In a normal person the total body iron stores (including hemoglobin) amount to about 5 grams. In hemochromatosis, total body iron is in the range of 50 grams. To normalize such massive iron overload would require therapeutic phlebotomy of 1 unit of blood (450 cc) every 6 weeks for five years!

Administration of ascorbic acid to patients with hemochromatosis can result in massive free radical injury resulting in serious morbidity or death. A primary target of injury is the CNS with seizures and cardiorespiratory arrest as the proximate cause of death. Serious injury to the lungs and the liver is also likely. Thus, it is critical to evaluate the patient's free iron levels and total iron binding capacity before supplementing with ascorbic acid.

There is some empirical evidence that ascorbic acid provides neuronal protection in ischemia by improving regional blood flow and oxygen consumption in the injured spinal cord and by protecting cultured cortical neurons from NMDA-mediated toxicity in vitro. Ascorbic acid has been repeatedly shown to be cerebroprotective when given in advance of ischemia. Much like vitamin E, ascorbic acid is provided in a bewildering array of dosage forms, packaging and chemistries. Vitamin C has been esterified, made fat soluble by reacting it with palmitate, and delivered to the stomach and intestines as almost every salt imaginable in capsules, tablets, time-released granules, and flavored elixirs. The esterified (palmitate) form of ascorbic acid is the preferred form of ascorbic acid for premedication. While de-esterification to ascorbic acid salts will occur in the liver, the esterified form has fewer GI effects and will (before de-esterification) reach a steady state in cell membranes and body fat stores where it may be more effective in preventing ischemic injury than in the unesterified (water soluble) form.

In addition to driving the Fenton reaction, ascorbic acid (as either the acid or the salt) causes stomach upset in some people. Taking it with a meal almost always eliminates this side effect. In patients with diminished urine output, ascorbic acid can precipitate out of the urine and form stones or painful crystals. Dosage should be adjusted in patients with renal failure or in patients who are dehydrated. An occasional patient is intolerant to significant doses of ascorbic acid due to either GI side effects (including diarrhea) or due to back or flank pain. These are additional reasons for using the esterified form of vitamin C). One popular brand is Ester-C.

Melatonin 10 mg p.o. before retiring (or with the evening meal as the patient desires). Melatonin is a hormone secreted by the pineal gland which is involved in circadian rhythms in a wide range of animals and appears to be central to the initiation of sleep in man and other mammals. Melatonin's biological activity is only now beginning to be understood. Exogenously administered melatonin rapidly crosses the blood brain barrier and induces sleepiness in normal human subjects. Melatonin is also a powerful free radical scavenger and antioxidant which appears to readily cross mitochondrial membranes where it may exert a protective effect in ischemia.

Melatonin acts differently from all common chain-breaking antioxidants including the naturally occurring thiol compounds cysteine and glutathione (the two mainstays of water soluble free radical buffering chemistry). In contrast to d-alpha tocopherol, glutathione, and melatonin's precursor (serotonin), melatonin does not participate in redox cycling, cannot generate hydroxyl radicals in the presence of iron or other transition metals (such as ascorbic acid), and is extremely resistant to auto-oxidation. Melatonin specifically interacts only with highly reactive species such as hydroxyl radicals or transition metal complexes which have the same or greater electroreactivity. In short, melatonin is the most potent endogenous hydroxyl radical scavenger identified to date and because of its solubility in both water and lipids, it provides broad spectrum protection to a wide range of biomolecules including proteins, lipids and nucleic acids.

Melatonin has been shown to provide in vivo protection against kainate-induced neurotoxicity, inhibiting both the behavioral and biochemical effects of kainate and thus presumably acting as an inhibitor of neuronal excitotoxicity. This neuroprotective effect is apparently a result of the inhibition of hydroxyl radicals which are generated as a result of NMDA receptor activation. Melatonin is currently a "fad" drug used primarily as an OTC treatment for insomnia and jet lag. It is also being used as an "anti-aging" hormone and as an adjunct to the treatment of breast and prostate cancer as well as a primary treatment for benign prostatic hypertrophy (BPH).

The most significant side effect to melatonin supplementation is sleepiness and sedation. Inhibition of prostacyclin and gonadatropins has been known to occur during sustained use of high doses with the possibility of sterility and gonadal atrophy. At doses of 20 mg, morning sleepiness is a likely side effect.

Sodium Selenite 100 to 250 micrograms per day p.o. with the evening meal or before retiring. Selenium is an essential trace mineral found in drinking water and a wide range of foods. It is essential for the proper functioning of the selenium, glutathione, peroxidase free radical scavenging system. At high doses it is toxic, but it is well tolerated at doses of up 1000 micrograms per day. Selenium has been shown to be cerebroprotective in models of head injury and cerebral ischemia. Selenium is an exceptionally well tolerated nutrient, the only common side effect being a metallic taste at high doses (over 500 mcg per day).

Sodium selenite is available inexpensively in capsules from Twinlab Company of Ronkonkoma, New York.

Magnesium Oxide 300 mg p.o. t.i.d. with meals. Magnesium is an essential trace mineral which is known to decrease platelet aggregation, decrease cardiac arrhythmias in marasmus and myocardial infarction, stabilize cell membranes and act as a cytoprotectant in cerebral and coronary ischemia. It is also an antihypertensive, decreases vasospasm in catecholamine storm, reduces peripheral vascular resistance and profoundly reduces both acute and 1 year mortality following myocardial infarction.

Magnesium should not only provide primary cerebroprotection in ischemia, but it should greatly reduce the chance of a patient dying from wasting disease, congestive heart failure, arrhythmias secondary to increased myocardial irritability and platelet activation from elevated levels of tumor necrosis factor (TNF) and related cytokines.

Magnesium is available in many forms as salts and organic chelates (such as magnesium orotate), however the oxide form is by far the cheapest and appears to have adequate bioavailability with minimal side effects.

The principal side effect of magnesium oxide is diarrhea, but this occurs infrequently at the doses suggested here. Very high doses of magnesium result in muscle weakness with the possibility of respiratory arrest at very high doses. Magnesium supplementation must be used only with caution and should be monitored in patients with renal disease or in patients with oliguria or anuria secondary to dehydration.

Co-Enzyme-Q10 (Co-Q10, ubiquinone) 150 mg in vitamin E or other oil t.i.d. with meals. Co-Q10 is a mitochondrial electron transport molecule which is critical to aerobic metabolism. It is a potent free radical scavenger that is profoundly protective against myocardial, cerebral, renal and skeletal muscle ischemia, especially when given prior to the insult. Co-Q10 is a quinone, a family of brightly colored cyclic organic compounds that are phylogenetically very old. Co-Q10 is an integral part of the mitochondrial membrane in all eukaryotic cells and of the chloroplasts in plant cells. So common is Co-Q10 that the name ubiquinone refers to its ubiquitousness in living systems. Co-Q10 is closely related to vitamin K1 and vitamin E which have in common with Co-Q10 a number of quinone-like features.

Because Co-Q10 is a critical molecule that is central to the generation of ATP in mitochondrial metabolism, serum and tissues levels below 75% of the normal baseline (0.33 micromoles as given in the Pantox panel) are associated with death from infection or cardiac arrythmia. Co-Q10 is known to be a key up-regulator of immune function and is used clinically in Japan as a treatment for myocardial ischemia, atherosclerosis, and idiopathic cardiomyopathy. In fact, Co-Q10 is the most prescribed cardiac drug in Japan.

Co-Q10 is only sparingly soluble in water but quite soluble in lipids. Its absorption after p.o. administration is greatly facilitated by consumption with fat containing foods. Not only should Co-Q10 be administered in oil or as micellized product, it should always be given with meals to facilitate absorption.

Co-Q10 is remarkably well tolerated even in very high doses. It substantially extends the mean lifespan of animals chronically fed the drug as 0.1% of their diet and its toxicity is essentially zero in doses in the therapeutic range. The only known side effect of Co-Q10 administration is occasional cardiac palpitations.

Co-Q10 is available from most health food stores as an OTC nutrient. The drug is a fine granular yellow powder that is usually packaged in gelatin capsules. Recently, Co-Q10 has become available dissolved in oil in soft gelcaps and this the preferred form of the drug for premedication of human cryopreservation patients. If health food stores or retail stores are used as a source for the product it is recommended that the Kirkland brand be used (150 mg/capsule in oil)which is sold in Costco/Price Club stores nationwide.

Not only is Co-Q10 likely to be cerebroprotective, it also likely to greatly reduce the risk of sudden cardiac death from arrhythmias during terminal illness (a not uncommon occurrence).

Based on the author's personal experience with dying patients, Co-Q10 will usually benefit patients during the course of their terminal illness. Most patients in the end stage of wasting diseases who are supplemented with Co-Q10 report substantial increases in energy and stamina.

Ginkgo Biloba extract 80 mg t.i.d. with meals. Ginkgo biloba is one of the few trees surviving from the Mesozoic period (200 million years ago). It is an Asiatic tree of modest proportions with distinctive bi-lobed fan-shaped leaves (hence the name biloba). The leaves contain a variety of biochemically complex and pharmacologically active substances which are profoundly cerebroprotective when administered both before and after cerebral ischemia. A quality ginkgo extract is typically a 50:1 concentration containing a minimum of 24% ginkgo flavonglycosides, 6% terpene lactones, and 0.8% ginkolide B.

The ginkolides have been chemically purified into discrete compounds for use as investigational new antiplatelet agents. Structural analysis of these compounds has lead to the synthesis of a variety of derivatives (which have the advantage of being patentable as pharmaceuticals, which naturally occurring ginkolides are not) such as BN 50739 which is an effective antiplatelet agent (platelet activating factor (PAF) inhibitor). Administration of BN 50739 following 14 minutes of global normothermic ischemia in the dog brain facilitates recovery of adenyl nucleotide to levels to 100% of control (versus 50% in controls), reduces polyunsaturated fatty acid (PUFA) levels to 30% of control, and markedly inhibits excitotoxicity and allows for recovery of EEG activity (there is no recovery in control brains). BN 52021 is a naturally occurring ginkolide with antiplatelet and cerebroprotective properties similar to its synthetic cousin BN 50739. It is not as effective as BN 52021 milligram for milligram but its effect is dose dependent and doses of ginkgo extract specified in this protocol should yield a comparable effect. It should also be noted that the natural extract contains many biologically active compounds and other inkolide variants which have not been evaluated under the same rigorous conditions as the monoagents both isolated from natural sources and synthesized.

In addition to its anti-PAF activity, ginkgo extract contains flavonglycosides which have strong anti-inflammatory activity and are especially effective at inhibiting increased capillary permeability, perhaps by preventing the destruction of the normally present inhibitors of elastase and collagenase which occurs during ischemia.

Two quality sources of ginkgo biloba extract are Gingold and NOW brands. Ginkgo is extremely well tolerated and the only side effect reported has been insomnia from caffeine-like effects at high doses.

While the ginkolides, flavonglycosides and terpene lactones all posses antioxidant and anti-inflammatory activity, the pharmacology of ginkgo is not well understood. Ginkgo acts as a cerebral vasodilator and improves cognitive function in human and animal subjects, both young and old. It's cognitive enhancing effects and it anti-PAF effects increase with the length of administration. Therefore, it is important to start ginkgo administration as early as possible. Despite its anti-PAF effects, ginkgo is not associated with increased bleeding time, coagulopathy or other alterations in hemostasis.

FlavonAll (multibioflavonoid supplement) 1 tablet t.i.d. with meals. (10 mg pycnogenol, 65 mg proanthocyanidins, 30 mg anthrocyanins, 180 mg polyphenols, 125 mg citrus bioflavonoids, 140 mg silymarin, and 80 mg ginkgo extract). FlavonAll tablets contain a wide variety of bioflavonoids which are nonessential nutrients that improve capillary integrity (reduce edema formation) in injury from a variety of insults. Bioflavonoids are derived from a variety of botanical sources (primarily citrus, grape seed, ginkgo and green tea). Bioflavonoids are known inhibitors of the pro-inflammatory compounds prostaglandin A2, thromboxane and the leukotrienes all of which are known to play a major role in the pathophysiology of ischemia, particularly the development of interstitial edema and protein leakage through capillary membranes during reperfusion.

The bioflavonoids are well tolerated and are not known to have any side effects in the dosages specified in this protocol. The bioflavonoids have antidiarrheal activity by virtue of their anti-inflammatory and capillary hyperpermeability inhibiting effects.

ALCAR (Acetyl-l-Carnitine) 500 mg t.i.d. with meals. Several mitochondrial enzyme systems such as adenine nucleotide translocase and those involved in oxidative phosphorylation are damaged in ischemia. As a consequence, there is a marked accumulation of free fatty acids, long-chain acyl CoA, and long-chain acyl carnitines.

Many of the metabolic derangements known to occur in cerebral ischemia are apparently a result of the accumulation of acyl CoA which is known to damage many different enzyme systems. Acyl carnitine analogs such as acetyl-l-carnitine can penetrate the blood brain barrier, the cell membrane and the mitochondrial membrane. They are readily metabolized and appear to normalize mitochondrial metabolism by removing long chain acyl groups from a variety of mitochondrial CoAs. ALCAR has been shown to greatly reduce neurological injury in a canine model following 10 minutes of normothermic global cerebral ischemia.

ALCAR improves cognitive function in organic brain syndrome secondary to Alzheimers, atherosclerosis-related cerebrovascular insufficiency, and advanced age (i.e., nonspecific dementia). ALCAR's absorption will be decreased if taken at meals. ALCAR is not a medication which is central to cerebroprotective premedication.

Alpha Lipoic acid 400 mg b.i.d. with AM and PM meals. (ALA) is a potent mitochondrial antioxidant and preliminary data indicate that it may act synergistically with ALCAR and vitamin E to provide cerebro- and systemic-protection against ante and post arrest ischemia. ALA is available from several supplement manufacturers notably the Life Extension Foundation of Hollywood, FL and Twinlab Company.

Twinlab Daily One Multivitamin capsule p.o. with the evening meal. The ingredients of the Daily One multi-vitamin are reproduced below. Daily One is a good micronutrient supplement which will improve the patient's energy level and sense of well being in wasting disease. Micronutrient deficiency occurs early in terminal illness and is usually acute during the agonal period. Micronutrient deficiency can be expected to exacerbate ischemic injury.

Twinlab Daily-One Multi-vitamin ingredients:

Each hard gelatin capsule supplies:
  • Beta-Carotene (pro-vitamin A) 10,000 I.U.
  • Vitamin D 400 I.U.
  • Vitamin C 150 mg
  • Natural vitamin E (succinate) 100 I.U.
  • Vitamin B-1 (thiamine) 25 mg
  • Vitamin B-2 (riboflavin) 25 mg
  • Vitamin B-6 (pyroxidine) 25 mg
  • Vitamin B-12 (cobalamin conc.) 100 mcg
  • Niacinamide 100 mg
  • Pantothenic acid 50 mg
  • Biotin 300 mcg
  • Folic acid 400 mcg
  • PABA (para-aminobenzoic acid) 25 mg
  • Choline bitartate 25 mg
  • Inositol 25 mg
  • Calcium (from calcium citrate and calcium carbonate) 25 mg
  • Magnesium (from magnesium aspartate and magnesium oxide) 7.2 mg
  • Potassium (from potassium aspartate and potassium citrate) 5 mg
  • Zinc (from zinc picolinate) 15 mg
  • Copper (from copper gluconate) 2 mg
  • Manganese (from manganese gluconate) 5 mg
  • Iodine (from potassium iodide) 150 mcg
  • Selenium (from selenomethionine and selenate - 50/50 mixture) 200 mcg
  • Chromium (GTP) 200 mcg
  • Molybdenum (natural molybdate) 150 mcg

Category 2 Drugs

Naproxen sodium (Naprosyn, Aleve, Anaprox) 125 mg b.i.d. with morning and evening meals. Aleve is an OTC nonsteroidal anti-inflammatory drug which is an inhibitor of cyclooxygenase, arachadonic acid, and leukotrienes. The mechanism of action of naproxen is not fully understood, however much of its anti-inflammatory activity is undoubtedly a result of its activity as a cyclooxygenase inhibitor. Related nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are cerebroprotective in normothermic global ischemia and head injury. Aleve was selected for use in cryopatient premedication because of its long serum half-life (13 hours), its rapid and complete absorption from the GI tract, and its relatively favorable (for NSAIDs) GI side-effect profile.

Despite the fact that naproxen is available as an OTC drug, it must be understood that it has the potential for serious and even life-threatening adverse effects. Like all other NSAIDs, naproxen has hematologic effects including prolonged bleeding and increased risk of GI or other bleeding in terminal illness. Other side effects of the drug as well as drug interactions are reviewed by system (the side effects that are most commonly encountered are italicized).

  • CNS: headache, drowsiness, dizziness, tinnitus, cognitive dysfunction, and aseptic meningitis.
  • CV (Cardiovascular): peripheral edema, palpitations and digital vasculitis.
  • EENT: visual disturbances, tinnitus.
  • GI: epigastric distress, occult blood loss, nausea, peptic ulceration.
  • GU: Increased BUN and creatinine, nephrotoxicity
  • Hematologic: prolonged bleeding time, agranulocytosis, neutropenia.
  • Hepatic: elevated liver enzymes, jaundice
  • Respiratory: dyspnea.
  • Skin: pruritis, rash, urticaria.
  • Metabolic: hyperkalemia.
Drug Interactions:

Naproxen decreases the effectiveness of diuretics and antihypertensives and increases risk of GI bleeding with aspirin, alcohol and corticosteroids. It also increases methotrexate toxicity (a common anticancer drug) and increases toxicity of oral anticoagulants, sulfonylureas, Dilantin, and other drugs that are protein bound.

Patients should take naproxen only with meals and should be advised that naproxen (as is the case with other NSAIDs) can mask signs of infection and gastric perforation. Patients should be carefully instructed on how to determine if they are experiencing silent GI bleeding by cautioning them to examine bowel movements for a tarry black appearance and emesis for coffee grounds appearance or the presence of frank blood.

Naproxen should be used with great caution in patients with renal or liver impairment as naproxen, like all NSAIDs, decreases renal blood flow by inhibiting the formation of renal prostaglandins.

Patients in the final weeks of their illness should have gastric protection in the form of concomitant misoprostol and sucraflate administration as necessary. If continuous administration of naproxen becomes problematic, and it is not otherwise contraindicated, IM or IV ketorlac tromethamine (Toradol) may be given at the start of the agonal phase (see below) and most of the cerebroprotective benefit of NSAIDs administration will result.

NOTE: There is no data indicating naproxen has any antiplatelt activity. Thus it is very important never to use naproxen as a substitute for low-dose aspirin therapy. If a choice must be made between 80mg/day of aspirin or naproxen, aspirin should be the drug of choice because of its profound antiplatent activity and its long duration of action (2-5 days).

Aspirin (acetylsalycilic acid) 80 mg p.o. or by suppository every day or every other day (as tolerated) with the evening meal. Aspirin is an anti-inflammatory prostaglandin synthesis inhibitor and an antiplatelet agent as well as being a centrally acting (hypothalamic) antipyretic. It has surprisingly diverse pharmacologic actions. The mechanism of action as a cerebroprotective in premedication of cryopatients is its antiplatelet activity. The doses of aspirin used for this purpose are sufficiently low that GI and other side effects and drug interactions (including its interaction with naproxen; it decreases Naproxen's effectiveness) will be minimal. Indeed, it is important not to give aspirin in doses greater than 80 mg/day in order to avoid side effects. The sole purpose of aspirin is to acetylate platelets. Aspirin irreversibly acetylates platelets and thus a single dose is effective until a significant percentage of the patient’s circulating platelets are replaced by normal platelet aging, removal and replacement take place (typically 48 hours in the healthy individual). In the typical dying cryopatient platelet turnover is likely to be greatly slowed thus extending the effectiveness of aspirin to as long as 3 to 5 days.

 

Figure 7:1

Possible adverse reactions at this dose are prolonged bleeding, GI distress, peptic ulceration, skin rash and bruising.

A variety of enteric coated low-dose aspirin products are available OTC.

Pepcid (famotidine) 20-40 mg p.o. b.i.d. or p.r.n. for stomach upset or epigastric discomfort or NSAID or agonal GI bleed prophylaxis May be used to decrease risk of GI distress and bleeding with NSAID administration. Famotidine is an H2 receptor blocker which decreases hydrochloric acid secretion by the gastric parietal cells. Onset of action is rapid (30 minutes to 1 hours after p.o. administration) and duration of action is 10-12 hours, greatly simplifying dosing.

Famotidine has no significant drug interactions.

Adverse reactions:

  • CNS: headache, dizziness, hallucinations.
  • GI: diarrhea, constipation, nausea, flatulence.
  • GU: elevated BUN and creatinine.
  • Hematologic: thromobocytopenia (very rare).
  • Skin: acne pruritis, rash.

Famotidine may be given IV as a Category 4 drug during the agonal period to minimize the risk of GI bleed during shock and reperfusion following cardiac arrest.

Category 3 Drugs

Ketorolac tromethamine (Toradol) 60 mg IM or IV may be given when the patient becomes frankly agonal to inhibit cyclooxygenase, prostaglandin A2 and leukotriene production. More than 2 doses of Toradol should not be given due to the risk of GI bleeding. Gastric protection with misoprostol and an H2 blocker such as famotidine or IV cimetidine is recommended. The side effect profile of Toradol is essentially the same as discussed above for naproxen.

Pepcid (famotidine) 20-IM or IV for agonal GI bleed prophylaxis may be used to decrease risk of GI distress and bleeding with parenteral Toradol administration. Famotidine is an H2 receptor blocker which decreases hydrochloric acid secretion by the gastric parietal cells. Onset of action is rapid (30 minutes to 1 hours after p.o. administration) and duration of action is 10-12 hours.

Cytotek (misoprostol) 200 micrograms t.i.d. with meals. Misoprostol is a synthetic prostaglandin E1 analog that replaces endogenous gastric prostaglandins depleted by NSAID administration and the hypoperfusion of agonal shock. Misoprostol also appears to decrease basal hydrochloric acid secretion and increase gastric mucus and bicarbonate production. Unfortunately, misoprostol is not available in a parenteral form, but may be administered to the hemmoroidal plexus by suppository (suppositories of misoprostol may be made by crushing a tablet and mixing it into a regular suppository (such as an APAP suppository).

Adverse Reactions:

  • CNS: headache.
  • GI: nausea, diarrhea, abdominal pain, flatulence, dyspepsia, vomiting and constipation.

Dilantin (phenytoin) 100-300 mg p.o. with the evening meal. Dilantin (use only Parke-Davis Dilantin, do not use generic phenytoin) is discussed here as a cerebroprotective premedication largely because it is cerebroprotective when given before global cerebral ischemia (but not when administered after the insult) and it is a medication that patients dying from malignancies (with brain metastasis or primary brain tumor), HIV or other disease which involves the CNS will frequently already be taking. It is not generally recommended that Dilantin be used a primary cerebroprotective drug except perhaps administered IV during the agonal period because of its unfavorable adverse reaction profile. Adverse reactions are common and in some patients fatal hepatocellular necrosis occurs as a consequence of the administration of the first few doses.

Deferoxamine HCl (Desferal) 2 g, dissolved in 100-200 cc of normal saline given IV or dissolved in 10 ml of sterile water given IM. Desferal can be given during agonal shock to scavenge free iron and reduce ischemia-induced free radical damage. (Note: Higher doses may be needed in patients with high serum ferritins or transferrin: iron overload).

The neurons of the CA1 area of the hippocampus have long been known to be selectively vulnerable to ischemic injury, both global and regional. These neurons are also known to have high endogenous iron levels and low SOD and glutathione peroxidase levels. A large number of studies have shown that these neurons selectively accumulate lipid peroxidation products associated with the iron-driven Fenton reaction.

Desferal is a selective chelator of free iron which has been shown in a wide range of experimental ischemia-reperfusion models to reduce iron-catalyzed biochemistry and to improve electrophysiology and neurological outcome.

Desferal chelates iron by forming a stable non-reactive compound and it is highly effective at chelating free (ferrous) iron but will not combine with iron in cytochromes, transferrin and hemoglobin. It is known that iron is delocalized from cytochromes, erythrocytes (hemoglobin) and perhaps other tissue iron stores during ischemia.

Deferoxamine mesylate (N-[5-{3-[(5-aminopentyl)- hydroxycarbamoyl]propionamido]-pentyl]-3-[[5-(N-hydroxy- acetamido)pentyl]carbamoyl] propionhydroxamic acid methansulfonate (salt) is an off-white powder which is freely soluble in water. It is used clinically to treat iron overload and acute iron intoxication. Desferal has a long plasma half life and its metabolism in the context of cryopreservation transport is not a concern.

Desferal is a sterile lyophilized powder which is reconstituted with water for injection prior to administration.

Methylprednisolone Sodium Succinate (Solu-Medrol), 1 g IM or dissolved in a minimum of 100 cc of normal saline or other appropriate vehicle given by IV administration over a minimum of 30 minutes. Methylprednisolone may be given during agonal shock to provide membrane stabilization, reduce cold agglutination, and protect against cold ischemic injury (46).

Methylprednisolone is a potent synthetic anti-inflammatory steroid which acts to stabilize cell and intracellular (lysosomal) membranes during shock, ischemia, and hypothermia. Methylprednisolone reduces the margination of leukocytes and stabilizes leukocyte membranes. Administered before experimental shock or ischemia it greatly reduces sticking and degranulation of leukocytes in the lungs and heart. Metyhylprednisolone must be administered slowly, over a period of 3 to 5 minutes to avoid hypotension. Solu-Medrol is a white to off-white powder which is extremely soluble in water in sharp contrast to most other steroids. Its onset of action is rapid and its duration of action is 2-4 days after IM or IV administration.

Deprenyl (l-deprenyl) 10 mg p.o. b.i.d. with meals. Deprenyl is an antiparkinsonian agent which is a nonselective inhibitor of MAO at doses great than 5 mg/day. It is known to protect the CNS against toxic, free radical inducing compounds such as 6-hydroxydopamine and it up-regulates the levels of superoxide dismutase and catalase in the selectively vulnerable neurons of the hippocampus and striatum. It is also cerebroprotective in hypoxia and ischemia.

The degree of effectiveness of deprenyl in premedication for cryopatients is very uncertain. Few studies have been documenting its effectiveness in animal models of ischemia, however on theoretical grounds it is an attractive agent. Further, it is well tolerated by most patients and generally results in an improvement in energy level and well being when administered in the context of terminal illness with malnutrition and wasting.

Adverse Reactions:

  • CNS: dizziness, restlessness, behavioral changes, headache, fatigue.
  • CV: orthostatic hypotension, hypertension, arrhythmias, increased anginal pain, peripheral edema, syncope (all uncommon).
  • EENT: blepharospasm.
  • GI: dry mouth, nausea, vomiting, constipation, diarrhea, heartburn, dysphagia.
  • Skin: rash, hair loss.
  • Other: malaise, diaphoresis.

Deprenyl is not recommended as a mainstay of premedication but rather is included here as a drug which may be used at the patient's and physician's discretion. At the doses suggested here it may exert an antidepressant effect which may be of benefit to the patient who is depressed as a result of illness.

Category 4 Drugs

Piracetam (Nootropil) 800 mg p.o. t.i.d. with meals. Piracetam is a nootropic drug used primarily to treat attention deficit disorder in children and adults. It is a stimulant with properties similar to those of caffeine. Piracetam is protective in hypoxia and cerebral ischemia. It is widely available through life extension buyers clubs and is available in Mexico inexpensively as tablets under the brand name Dinagen.

Adverse effects of piracetam are insomnia, restlessness, dyspepsia and skin rash. Adverse reactions are rare and the drug is well tolerated by both healthy and ill patients

NOTE: Since this was written in 1997 Zileuton has been approved for use in the United States and is readily available as a prescription drug for the treatment of asthma. It is marketed under the brand name Zyflo. Zileuton is now a Catergory 3 drug.

Zileuton 400 mg p.o. with any meal of the day. Zileuton is a novel lipoxygenase inhibitor which inhibits 5-lipoxygenase and prevents the release of arachadonic acid and the production of leukotrienes in vivo49. Zileuton also inhibits the production of PAF and inhibits CoA-IT, a major mediator of the early phases of the immune-inflammatory cascade. Zileuton is currently being introduced in Europe as an anti-inflammatory and antiasthmatic compound. It is not known when or if it will be available. Discussion of adverse reactions and other aspects of Zileuton's pharmacology is deferred.

Category 5 Drugs

PBN (N-t-butyl-alpha-phenylnitrone) 10 mg/kg, p.o. with the largest meal of the day. PBN is a spin trapping free radical quencher which is available through buyers clubs and as a reagent chemical. There is no, repeat no pharmaceutical experience with this drug. Its pharmacology and potential adverse reactions are completely unknown.

N-t-butyl-alpha-phenylnitrone (PBN) is a spin trapping agent that combines with a wide range of free radicals to form stable nitroxide radical adducts. In vitro PBN protects neurons against glutamate (NMDA) mediated toxicity. In vivo PBN has proven effective in reducing infarct size in global ischemia, middle cerebral artery occlusion, and a variety of local ischemic insults. The structure of PBN bears some resemblance to melatonin in that both agents posses an electron rich aromatic ring. (See discussion of melatonin below.) PBN and melatonin also have in common free radical buffering through the formation of a nitrogen centered radical intermediate and resonance stabilized mesomery.

PBN is white, granular powder with a faintly pleasant chemical (maraschino cherry) odor. PBN is sparingly soluble in water. To be taken orally PBN is placed in 00 or 000 gelatin capsules using a CapMQuick or similar device.

Category 6 Drugs

WARNING NOTE: Since this was written in 1997 GHB has been reclassified by the Federal Drug Enforcement Agency (DEA) as a Class I prohibited drug. The DEA has effectively declared that GHB has no therapeutic value and is an illegal controlled substance. Possesion of GHB without a special investigational permit is now a Federal criminal offense and is classified as a felony. Further, some states such as California have enacted specific legislation criminalizing the possession of GHB and prescribing harsh mandatory sentence guidelines for those found guilty of its possession or use.

GHB (gamma hydroxy butyric acid, sodium salt) 100 mg/kg IV push to inhibit CNS excitotoxicity and reduce cerebral metabolism.

Gamma hydroxy butyric acid (GHB) is a neurotransmitter associated with sleep and the regulation of cerebral metabolism. It was introduced into anesthesiology in 1960 but was abandoned due to its prolonged and unpredictable action. GHB rapidly crosses the blood brain barrier and produces sedation and Plane II-III anesthesia without respiratory or cardiac depression. GHB acts by binding to sites which actively synthesize, accumulate and release GHB. GHB does not interact significantly with GABA receptors.

GHB causes a profound decrease in cerebral metabolism (roughly comparable to that seen with barbiturates) and is a moderately effective free radical scavenger. GHB is markedly protective in in-house models of murine blunt force head injury and has been demonstrated in in-house studies to inhibit increased spectral edge frequency and other EEG manifestations of excitotoxicity during reperfusion in dogs following 12 minutes of normothermic cardiac arrest. GHB, in conjunction with other cerebroprotective drugs, has allowed for recovery of dogs from 14 minutes of normothermic circulatory arrest without adverse neurological sequelae. GHB has also been used clinically with good results as a sedative in head trauma and it increases neuronal protein synthesis following ischemia. Interestingly, GHB is known to cause absence seizure-like disorders in animals and man, and it may act as an excitatory neurotransmitter for some neurons (auditory hallucinations are reported in some users). Presumably any excitatory/toxic effect GHB may have in the context of this protocol is inhibited by kyneurinine (see above).

GHB was freely available in U.S. health-food stores until 1990, when the FDA restricted its sale, but not its possession (FDA has no power to do the latter). GHB is NOT a federal "controlled substance" (i.e., possession restricted) as of January 1997, but due to the sales restriction, is presently available for human use chiefly as an underground drug and as a street drug. Some GHB has slipped into the country in private pharmaceutical shipments from countries where GHB is a pharmaceutical, and still fully legal. GHB may be used by some cryopatients for sedation and for immunomodulation (as a growth hormone releaser agent) in the treatment of malignant disease. For these reasons this semi-legal substance is included in this text.