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.


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