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."
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 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 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
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.
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.
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
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 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
premedication.
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.
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) 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
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 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
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.
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.
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
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 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
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 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:
207-220.
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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