X-Message-Number: 7529
Date: 18 Jan 97 16:38:31 EST
From: Mike Darwin <>
Subject: Anesthesia in Cryopatients

The Following is a BioPreservation, 
Inc (BPI) Technical Brief discussing the 
problem of legally securing anesthesia in 
human cryopreservation patients during the 
period of resuscitation immediately following 
cardiac arrest.

Securing Anesthesia in the Human 
Cryopreservation Patient
by Mike Darwin

Prompt administration of adequate 
cardiopulmonary support (either via CPR or 
cardiopulmonary bypass) immediately (1-4 
minutes) following cardiac arrest and 
pronouncement of legal death is likely to 
result in recovery of consciousness and/or 
spontaneous respiration and cardiac activity 
in some patients being transported for 
cryopreservation.  Recovery of consciousness 
and vital signs raises serious medico-legal 
and ethical issues which are not easy to 
resolve.  Two issues in particular are of 
great concern; return of awareness which 
would subject the patient to the distressing 
and painful procedures (CPR, extra- and 
intra-corporeal cooling, bypass, etc.) of 
transport, and the technical "reversal" of 
the legal and clinical criteria currently 
used for pronouncement of legal death.

Inhibition of the return of spontaneous 
cardiac activity (in monitored cases) can be 
readily and reliably achieved by the 
intravenous administration of potassium 
chloride at the start of cardiopulmonary 
resuscitation.  Similarly, prevention of the 
return of spontaneous respiration can be 
insured by the administration of a long 
acting neuromuscular blocking agent (NMB) 
such as metocurine.

However, preventing the recovery of 
consciousness and depressing cerebral 
metabolism (which is beneficial in the 
context of reduced cardiac output and 
frequently present hypoxia during CPR) has 
previously required the use of barbiturate 
drugs.  Particularly useful has been the fast 
acting, intermediate duration barbiturate 
sodium pentobarbital (Nembutal).

Sodium pentobarbital is still the preferred 
agent for use in cryopatient anesthesia due 
to its minimal hemodynamic effects, reduction 
of cerebral metabolic demand, suppression of 
EEG and relatively long plasma half life. 
Unfortunately, Nembutal and related compounds 
are Schedule II drugs regulated by the United 
States Drug Enforcement Agency (DEA)(1). 
_Possession_ of Nembutal requires a 
triplicate prescription which is all but 
impossible to obtain for post-mortem use in 
cryopatients. Possession of Nembutal without 
a prescription is a felony punishable by 
imprisonment. Additionally, Nembutal is a 
drug of choice for suicide, homicide, and 
active euthanasia and its presence in a 
cryopreservation patient's tissues or body 
fluids can raise serious forensic questions 
(2).

By contrast, the short acting anesthetic 
agent diprivan (Propofol) is unscheduled and 
is an effective induction agent for general 
anesthesia. Propofol is primarily metabolized 
and eliminated via hepatic metabolism to 
inactive metabolites which are excreted via 
the kidney. Propofol has a high metabolic 
clearance and wide volume of distribution (60 
L/kg). Propofol's rapid metabolism to 
inactive gluconorides results in a short 
half-life and due to rapid redistribution 
into body lipids there is an especially short 
half-life for the first doses (until 
saturation of body lipids is achieved). Under 
normal clinical conditions maintenance of 
anesthesia with Propofol requires continuous 
administration of 100-200 micrograms/kg of 
drug.  

Because it must be administered IV and 
because of its short duration of action and 
relatively high cost, Propofol is not a drug 
of abuse, and is unlikely to become one.  
Hence, it not a Scheduled drug and is, in 
fact, the only CNS depressant parenteral 
anesthetic which not Scheduled.

To secure anesthesia in human cryopatients 
Propofol 2 mg/kg IV push is administered. 
Propofol also reduces cerebral metabolic 
activity by about 25% in addition to 
induction of anesthesia.

Propofol is a sterile nonpyrogenic emulsion 
of 2,6 diisopropyl phenol. Diprivan is a 
water insoluble oil at room temperature and 
is made pharmacologically available by being 
dissolved in micelles of soybean oil and egg 
lecithin which are <0.2 microns in size. 
These micelles deliver the drug to the 
membranes of the capillary endothelial cells 
where the drug dissolves into the cell 
membranes and rapidly crosses the blood brain 
barrier (3).  The micelles used to deliver 
Propofol are compatible with micellar system 
used in the cerebral resuscitation protocol 
developed by 21st Century Medicine (21CM) and 
BioPreservation, Inc. (BPI) and which is 
currently used on BPI cryopreservation 
clients.  The compatibility of the micellar 
system in Propofol allows for easy continuous 
administration of the drug during the initial 
phases of drug transport should it be 
necessary.

The micelles and the micellar stabilizing 
agent (glycerol) are both capable of 
supporting rapid bacterial overgrowth. Thus, 
Propofol is a single-dose product and any 
drug which is drawn up should be promptly 
used. Propofol may be refrigerated 
immediately after being drawn up and its 
dispensing life can be extended to 24 hours. 

Understanding the pharmacokinetics of 
Propofol is critical to successful use of the 
agent for induction and maintenance of 
anesthesia in the cryopatient until profound 
hypothermia is induced. In many ways Propofol 
is a non-ideal drug for sustained general 
anesthesia and it is not the drug of choice 
for use in cryopatient transport. 

However, under the conditions of 
cryopreservation patient transport (reduced 
cardiac output, minimal hepatic blood flow) 
it is anticipated that a single dose of 2.0 
mg/kg followed by the administration of 
Soporate and Exiquell and the induction of 
hypothermia will provide sufficiently deep 
anesthesia to prevent return of consciousness 
during the acute resuscitation period. In 
healthy rabbits the simultaneous 
administration of Soporate and Exiquell with 
Propofol in the doses specified here resulted 
in 90 minutes of unconsciousness (Plane III 
anesthesia) with significant respiratory 
depression requiring mechanical ventilation 
(4).

In the event that spontaneous movement, 
facial twitching, agonal respirations, return 
of gag reflex, or other signs of inadequate 
anesthesia occur during transport, bolus 
doses of 25 to 50 mg of Propofol may be given 
to deepen and maintain anesthesia as needed 
or the drug may be continuously infused as 
necessary. 

It is hoped that further research in the 
immediate future will allow the elimination 
of Propofol from the BPI transport protocol 
thus decreasing the protocol's complexity, 
reducing its cost, and eliminating the 
undesirable hemodynamic side effects 
associated with Propofol.  However, in the 
meantime, it is reassuring to know that a 
drug is available which is legal to possess 
and which can be applied to human 
cryopreservation patients in all 50 states 
with the assurance that Plane III anesthesia 
is being achieved.


REFERENCES AVAILABLE UPON REQUEST

BioPreservation, Inc.
10743 Civic Center Drive
Rancho Cucamonga, CA 91730
(909) 987-3883


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