Date: Sat Jan 04  2:11:24 AM CST 1997
Subject: Premedication of Human Cryopreservation Patients

   Premedication of Human Cryopreservation Patients
                by Michael Darwin

The following is from a series of posts dealing with premedication of
human cryopreservation patients to minimize the effects of ischemia
and hypoxia during the antemortem and post arrest period.

This material is Copyright BioPreservation, Inc, 1997.


Premedication of Human Cryopreservation Patients
by Michael Darwin

"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."

    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 

	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 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.  


	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 in 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 and 
with the knowledge and consent of the patient's personal 
physician and caregivers is considerably greater.

	Use of drugs in category 5 with the 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 

	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 

* 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.

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 

* 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 

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 

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 

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 

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


	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 

	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.


An Exposition of Putative Cerebroprotective Drugs and Their 

	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 

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 

	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.  

	At this time it is recommended that nonesterified d-alpha 
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 about 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 

	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 

	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 vitroAscorbic 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 plain sodium salt or calcium salt (as the 
patient's medical condition dictates) delivered in simple gelatin 
capsules is the preferred form of ascorbic acid for 

	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 

	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  

	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) 100 mg in vitamin E 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  

	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 are used as a source for the  
product it is recommended that the KAL brand be used (30  
mg/capsule in oil). 

	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  
ginkolide 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  

	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  

	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  
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  
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  

	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.  

	Aspirin (acetylsalycilic acid) 30 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 diverse pharmacologic  
actions more of which are uncovered. 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. 

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  

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)- 
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 injury46.  

	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 ischemia48.  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 

	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 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 

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

	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 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 12  
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. 

1) Kalimo H, Garcia JH, Kamijyo Y, et al. The ultrastructure of  
brain death II. Electron microscopy of feline cortex after  
complete ischemia. Virchow's Arch B Cell Path 1977;25:

3) Karlsson U, Schultz RL. Fixation of the central nervous  
system for electron microscopy by aldehyde perfusion. III.  
Structural changes after exsanguination and delayed  
perfusion. J Ultrastruc Res 1966;14:57-63. 

4) Van Nimwegen D, Sheldon, H. Early postmortem changes in  
cerebellar neurons of the rat. J Ultrastruc Res 1966;14:36-46. 

  End of Article 

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