X-Message-Number: 2924 Date: 19 Jul 94 22:51:50 EDT From: Mike Darwin <> Subject: SCI.CRYONICS White Case Report Conclusions The following is the final installment of the Jerome B. White Case Cryopreservation Case Report. It contains conclusory and subjective observations. Discussion Agonal Ischemic Injury As can be seen by examining the patient's Agonal Vital Signs and Blood Oxygen Saturation Graphic, the patient sustained a prolonged and profound period of pre-mortem shock and hypoperfusion. Further evidence of this is the marked elevation of the patient's alkaline phosphatase, lactate dehydrogenase (LDH), gamma glutamyl transferase (GGT) and aspartate transaminase (AST) nearly 18 hours before cardiac arrest (see Transport Serum Enzymes Graphic). The sample drawn at 16:50 during Thumper support and immediately prior to going on bypass (78 minutes following cardiac arrest) is indicative of continuing ischemic injury. The LDH has risen from 457 U/L at 23:00 on 02-04-1994 to 3276 U/L. Similarly the AST has increased to 1694 U/L from 66 U/L and the ALT has increased to 479 U/L from 43 U/L. In fact, these increases are greater than they seem when hemodilution by transport medications is taken into account (see Transport Serum Enzymes Corrected for Hemodilution Graphic). If such hemodilution is adjusted for by using the serum total protein value obtained at 23:00 as the baseline, and the values of the serum enzymes obtained at other times are adjusted accordingly, it is clear that serum enzyme levels continue to rise more or less linearly with time, even during the period of bypass and total body washout. Similarly, the disproportionate rise in serum creatinine as compared to serum urea nitrogen from 23:00 to 16:50 is indicative of rhabdomyolisis, probably secondary to hypoperfusion of skeletal muscle in addition to the renal failure of dehydration. Pre-Medication The patient was taking some daily p.o. anti-oxidant vitamins and minerals in the weeks prior to cardiac arrest which are known to be protective against ischemia (1,2,3,4). A precis of these supplements is not available to the author at this time, however they were known to include several grams of vitamin C, 400 IU of alpha tocopherol acetate, 50,000 IU beta carotene, 200 mcg sodium selenite and a 50 mg B-complex tablet. Unfortunately, as is usually the case, the patient's deteriorating mental state and dehydration made continuation of these supplements during the last week or two of life virtually impossible. However, it is probable that there were still modestly protective levels of the fat soluble anti-oxidants which the patient was taking still present at the time cardiac arrest occurred. Where the physician is cooperative and the patient would not be discomforted by it (i.e., is already obtunded or actively requests it) placement of a gastric tube to facilitate continued administration of fat-soluble antioxidants and selected water soluble medications (Hydergeine, phenytonin) until the time of cardiac arrest or the beginning of agonal hypoperfusion/shock would be highly desirable. Need For In-Field Diagnostics Capability It is unfortunate that no labs were drawn during the interval between 23:00 on 02-04-1994 and 16:50 the following day. In particular, it would be of great interest to know what fraction of the increase in serum tissue enzymes and creatinine occurred as a result of agonal hypoperfusion as opposed to post cardiac arrest ischemic injury. Gathering such data and being able to evaluate it in real-time in the field (i.e., hospice, home hospice, nursing home, or hospital) might well prove very valuable in discerning markers or trends which will allow greater precision in predicting when cardiac arrest will occur. This would allow for more cost-effective utilization of resources as well as greatly easing logistics and planning. In this case it would have been of special utility to have been able to evaluate renal function as assessed by serum urea nitrogen and creatinine, and urine specific gravity or osmolality. This would have helped to better quantify the degree of dehydration the patient was experiencing and this in turn might well have lead to a modification of how the post-arrest period of Thumper supported circulation was handled. Improving Post Arrest Cardiopulmonary Support This patient showed a not untypical poor clinical response to Thumper support (5,6) (continuing cyanosis, pupillary unresponsiveness, end-tidal CO2 of 0.5%, etc.) and this poor response was subsequently confirmed when laboratory analysis of the blood sample drawn after 76 minutes of Thumper support disclosed a serum glucose of 11 mg/dl. It might have been of benefit to have immediately performed a cut-down of the external jugular vein and placed a large-bore (14 g) catheter through which large volumes of crystalloid and colloid could have been administered to facilitate more rapid post-arrest rehydration. This might have markedly improved this patient's hemodynamic response to closed-chest cardiac compression and may well have been worth the trade- off of a delay of 10-15 minutes in initiating the start of extracorporeal support. Early, large-bore venous access would also have allowed more rapid administration of high volume, high viscosity transport medications, in particular dextran-40. As it was, administration of dextran-40 was not possible until the start of bypass, over 80 minutes after external cooling had begun. Earlier administration of dextran-40 might have helped reduce the degree of cold-agglutination and failed cryoprotective perfusion observed in the patient's skin (which was in early, direct contact with ice and thus most likely to be affected by cold agglutination). A still better alternative would have been to have had large-bore venous catheter placement (via cutdown) proceed in parallel with preparations for femoral-femoral bypass. To this end, several members of the BPI field team have undergone training in peripheral venous cutdown with more training scheduled for the near future. The use of active compression-decompression CPR (ACD- CPR) might also provide special benefit in patients such as this one who are suffering from dehydration and loss of vascular tone which result in poor refill of the heart with blood during the relaxation phase of the CPR duty cycle. Active decompression of the chest using the Ambu Cardiopump or a mechanical system developed to deliver ACD-CPR might greatly improve cardiac output in all cryopreservation patients (7,8,9). An unusual feature of this patient's extracorporeal support was the high MAP encountered at very low flow rates (see Transport Extracorporeal Perfusion Mean Arterial Pressure Vs. Arterial Flow Graphic): less than 1/4th of resting cardiac output for a man with the patient's surface area. This may have been due to the use of high dose epinephrine or perhaps due to peripheral vasoconstriction during the long period of agonal shock. It is interesting to note that that patient's MAP and arterial flowrate during cryoprotective perfusion (and after a long period of cold ischemia), wherein only the head and chest wall were perfused, was far more physiologic (for the tissue volume perfused): MAP was 60 mmHg at a flow rate of 1100 cc/min. As examination of this patient upon arrival at the cryoprotective perfusion facility showed, the patient sustained additional insult in the form of skeletal muscle rigor during the hours of cold-ischemic ground transportation. The primary reason this patient was not provided with continuous extracorporeal support during the drive from Sunnyvale, CA to Rancho Cucamonga, CA was the unwillingness of the patient to relocate to housing which would have allowed for use of the Mobile Advanced Life Support System (MALSS). As it was, it was not even possible to remove the patient from his condominium where cardiac arrest occurred on a stretcher -- it was necessary to carry the patient out in a body-bag due to the restrictive layout of the home and the steep flight of stairs approaching it. A further complication was the patient's HIV status which would have meant that the bypass circuit would either have had to have been disassembled, removed from the dwelling and reassembled on the MALSS in the confined space of the BPI ambulance, or another circuit/oxygenator would have had to have been set up and femoral-femoral bypass reinstated after the patient was moved into the vehicle. Because of the expense, the extra risk to personnel (particularly in going on bypass in the crowded confines of the ambulance) and the likely added delay in re-establishing extracorporeal support, it was decided to transport the patient without continued perfusion. Yet another limitation to restarting bypass was the psychological and physical state of the staff who would also be required to carry out cryoprotective perfusion after arrival in Southern California. Most of these personnel had been without adequate sleep for days and all of them had been working continually under high pressure to stabilize the patient for over 8 hours. Another alternative would have been to charter an air ambulance to facilitate rapid transportation of the patient and personnel from Sunnyvale to Rancho Cucamonga. It is not clear whether the cost of approximately $5000 is worth the benefit of a decrease in cold ischemic injury and avoidance of rigor. Clearly, the best solution in this case would have been for the patient to have relocated or have been relocated to a more accessible home environment which would have allowed extracorporeal support to have been initiated using the MALSS, or better still to have relocated closer to the cryoprotective perfusion facility. In addition to obtaining more blood samples during the agonal period, it would also have been of tremendous benefit to not only draw lab samples at more frequent intervals during transport, but to be able to at least evaluate such samples for blood glucose. (this was not done at the time owing to limitations of staffing.) It is clear that the patient's transport blood glucose of 11 mg/dg was a result of grossly inadequate perfusion during closed-chest cardiac compression. What is not clear is whether or not administration of glucose to raise blood sugar under such conditions of trickle-flow would be beneficial. It is a very well established fact that administration of excess glucose during reperfusion following ischemia, or the presence of hyperglycemia prior to ischemia is associated with exacerbation of cerebral ischemic injury and a dismal clinical outcome after cardiopulmonary resuscitation (10,11,12). Current transport protocol calls for evaluation of blood glucose and its adjustment during transport (13). This recommendation may need to be re-evaluated in situations such as this one where perfusion during Thumper support is clearly inadequate. Larger Volumes of TBW Solution Needed TBW with 8-liters of Viaspan was not adequate as was indicated by the presence of significant amounts of red cells during open-circuit flush with 5% (v/v) glycerol perfusate at the start of cryoprotective perfusion. While the use of an additional 2-liters of Viaspan would have been helpful, it is apparent that, especially in larger individuals and in patients whose blood is hyperviscous due to disease (Bence Jones) or dehydration, larger volumes of washout solution (20-liters) should be used where feasible. While the cost of Viaspan makes its use in appropriate quantities problematic, if not prohibitive, in many situations it should be possible to prepare perfusate from dry components in the field a day or so prior to use and refrigerate it, or better still, to prepare in-house sterile perfusate which is ready to use and which has a shelf-life (with refrigeration) of 1-2 years or longer. BPI is pursuing both these alternatives. Inhibiting Cold Ischemic Rigor A major limitation of current chill/flush-store organ preservation solutions is their ineffectiveness in preserving muscle (14). Virtually all published studies documenting this lack of effectiveness relate to hypothermic cardiac preservation since skeletal muscle is not normally preserved for clinical use. The author's experience in this case, in addition to his experiences with Alcor Foundation patient's subjected to prolonged cold-ischemia following TBW in both published (15), and unpublished case reports (see for example unpublished case reports A-1165, A-1169, and A-1367) demonstrates clearly that skeletal muscle is also intolerant of prolonged cold-ischemia. A possible solution to this problem which BPI has been actively investigating for nearly 2 -years is the use of an inhibitor of the actin-myosin contractile molecular machinery, 2-3-butane dione monoxime, which has shown promise in facilitating cold-ischemic cardiac preservation for periods of up to 24-hours (16). Summary Overall, it is the author's opinion that this patient received a very high quality transport and cryoprotective perfusion within the limitations imposed by the current legal, medical and financial environment. In particular, this transport was free from any significant problems in terms of failure of equipment, deviation from desired protocol, and/or failure of, or injury to, personnel. The patient (brain) reached a high terminal venous concentration of glycerol, and ischemic injury as indicated by tissue enzyme release was within the range of that experienced during the best of the transports the author has participated in during his tenure with the Alcor Foundation (see unpublished Alcor Case Report on patient A-1049 and case data on patient A-1260). Where the attending physician is cooperative and the patient's condition permits it, pre-medication via feeding tube should be continued at least up until the time the patient becomes frankly agonal. Similarly, the availability of in-field diagnostics capability will probably help to better determine the agonal course and contain costs and facilitate preparedness. Deployment of a more effective premedication protocol should also be a priority. Earlier, more aggressive rehydration and the use of ACD-CPR may facilitate better closed-chest cardiopulmonary support in future patients. Larger volumes of TBW perfusate are clearly desirable, and the use of a washout perfusate containing and inhibitor(s) of rigor may also be desirable. Where possible, continuous extracorporeal support during ground transportation should be used to provide oxygen and substrate to the patient's tissues and in particular to the brain and skeletal and cardiac muscle in whole body patients. References 1) Hara, H, Kato, H, Kogure, K. Protective effects of alpha tocopherol on ischemic damage in the gerbil hippocampus. Brain Res. 1990;2:335-338. 2) Yoshida, S. Brain injury after ischemia and trauma, the role of vitamin E. Ann. N.Y. Acad. Sci. 1989;570:219-236. 3) Poltronieri, R, Cevese, A, Sbarbati, A. Protective effect of selenium in cardiac ischemia and reperfusion. Cardioscience 1992;3:421-429. 4) Kinuta, Y, Kikuchi, H, Ishikawa, M. Lipid peroxidation in focal cerebral ischemia. J. Neuro. Surg. 1989;71:421-429. 5) McDonald, JL. Systolic and mean arterial pressure during manual and mechanical CPR in humans. Annal. Emerg. Med. 1982;11:292-295. 6) Del Guercio, LRM, Feins, NR, Cohn, JD, et al. A comparison of blood flow during external and internal cardiac massage in man. Circulation. 1965;Suppl. 1:171-180. 7) Cohen, TJ, Tucker, KJ, Redberg, RF, et al. Active compression-decompression resuscitation; a novel method of cardiopulmonary resuscitation. Am. Heart J. 1992;124:1145- 1150. 8) Cohen, TJ, Goldner, BG, Maccaro, PC, Ardito, AP, et al. A comparison of active compression-decompression cardiopulmonary resuscitation with standard cardiopulmonary resuscitation for cardiac arrests occurring in the hospital. NEMJ. 1993;329:1918-1921. 9) Lindner, KH, Pfenniger, EG, Lurie, KG, et al. Effects of active compression-decompression resuscitation on myocardial and cerebral blood flow in pigs. Circulation. 1993;88:1254- 1263. 10) Ashwal, S, Schneider, S, Tomasi, L, et al. Prognostic implications of hyperglycemia and reduced cerebral blood flow in childhood near drowning. Neurology. 1990;40:820-823. 11) D'Alecy, LG, Lundy, EF, Barton, KJ, et al. Dextrose contaiining intravenous fluid impairs outcome and increases death after eight minutes of cardiac arrest and resuscitation in the dog. Surgery. 1986;100:505-511. 12) Nakakimura, K, Fleischer, JE, Drummond, JC, et al. Glucose administration before cardiac arrest worses neurologic outcome in cats. Anesthesiology. 1990;72:1005- 1011. 13) Darwin, MG. Level 1 Transport Protocol for Cryopreservation of Humans. 1994, Biopreservation, Rancho Cucamonga California. 14) Stringham, JC, Paulsen, KL, Southard, JH, et al. Improved myocardial preservation by modification of the University of Wisconsin solution with 2,3-butanedione monoxime. Trans. Proc. 1993;25:1625-1626. 15) Darwin, MG, Leaf, JD, Hixon, HL. Case report: neuropreservation of Alcor patient A-1068. Cryonics. 1986;7:17-32. 16) Stringham, JC, Paulsen, KL, Southard, JH, et al. Improved myocardial preservation by modification of the University of Wisconsin solution with 2,3-butanedione monoxime. Trans. Proc. 1993;25:1625-1626. Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=2924