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