Resuscitation Medicine Research: Quo Vadis

CPR PROCEEDINGS/CONCEPTS

Resuscitation Medicine Research: Quo Vadis From the 5afar Centerfor Resuscitation Research, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Receivedfor publication May 15, 1995. Revision received December 22, 1995. Acceptedfor publicationJanuary 10, 1996. Presented at the Second Chicago Symposium on Advances in CPR Research and Guidelinesfor Laboratory Research, Chicago, October 1994. Parts of this address were adapted from the author's presentations at the International Resuscitation Research Conference, University of Pittsburgh, May 1994. Copyright © by the American College of Emergency Physicians.

Peter Safar, MD, FCCM

Laboratory research should have clinical relevance. Topics should be selected according to need, gaps in knowledge, and opportunities; the investigator's background, expertise, interests, and ambitions; scientific, clinical, and socioeconomic importance; and feasibility of successful performance and conclusion. The current explosion of knowledge and sophistication of methods will require research by multidisciplinary teams. Systematic goal-oriented studies should be conducted in environments that encourage serendipitous discoveries. Mechanism- and outcomeoriented research, in laboratories and on patients, is needed. In cardiac arrest research, hearts and brains "too good to die" offer many challenges. In trauma research, particular challenges include protection-preservation during uncontrolled hemorrhagic shock, suspended animation for delayed resuscitation in exsanguination, and prevention of brain swelling after traumatic brain injury. Emergency physicians have the unique opportunity to initiate clinical resuscitation research in unexplored territory: the prehospital arena. [Safar P: Resuscitation medicine research: Quo vadis. Ann EmergMefl May 1996;27:542-552.] INTRODUCTION Many acute dying processes are poorly understood but are more reversible than previously assumed. About 500,000 people die each year in the United States as a result of emergencies, without lethal disease and before old age. Many more experience emergencies that do not involve cardiac arrest but result in severe permanent disabilities, which are often preventable by improved resuscitation. In October 1995, Dr Lance Becker and Dr Ahamed H Idris invited resuscitation researchers from various base specialties to Chicago to brainstorm on the future. Symposium participants came from both sides of the Atlantic, continuing the "cross-fertilization" of resuscitation research between the United States and Europe that

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began with the discovery of general anesthesia in the mid-1800s in New England. 1 The suggestions for the future of resuscitation research made here are based not only on punished history 1, present clinical guidelines, and practices of modern resuscitation 2-6 but on my personal experience with resuscitation research since the 1950sJ "Quo vadis" could mean "where will it go," which involves predicting the unpredictable; however, for this presentation it will mean "where should it go." Resuscitation research should be influenced by societal needs rather than by demands, r,s The future of this field depends on collaboration among investigators, clinicians, and rescuers; on systematic long-range research programs; and on chance discoveries. Resuscitation research includes laboratory, clinical, education, epidemiologic, and delivery research. Modern resuscitation methods resulted mainly from research in the 1950s. 1 Since then, research has been catalyzed by national r-9 and international 1°-26 conferences. DEFINITIONS

Investigators at all levels should communicate with each other, using the same terminology. Resuscitation medicine is much more than lung inflation and chest compression2; it is based on its science, which Negovsky has named "reanimatology"2r,2s, and aims for increasingly more effective methods} The science of resuscitation mainly concerns the pathophysiology and reversibility of rapid dying, as with shock or asphyxiation (called by Negovsky "terminal states"), and sudden clinical death (potentially reversible cardiac arrest). 29 In 1961, we assembled three phases (basic, advanced, and prolonged life support [BLS, ALS, and PLS, respectively]), with three steps for each phase, into the cardiopulmonary-cerebral resuscitation (CPCR) system 2, also called the "chain of survival." Resuscitation medicine also includes the delivery system for CPCR-namely, life support for all critically ill or injured patients throughout the emergency and critical care medicine (ECCM) continuum, from the scene through transport to the hospital emergency department, operating room, and ICU. 3°,31 Resuscitation medicine should focus on the brain (ie, on survival with human mentation). The addition of cerebral resuscitation to the guidelines is long overdue. 32-35 Resuscitation is a major part of critical (intensive) care medicine. 36-41 For all of these reasons, resuscitation research must be multidisciplinary.

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The results of CPCR studies in animal models and patients have often been contradictory because of different definitions of many variables. 42 First one must differentiate between protection (treatment initiated before the insult), preservation (treatment during the insult), and resuscitation (treatment to reverse the insult and support recovery). One must also distinguish between arrest time (no-flow time) and CPR time (low-flow time). The nebulous term "down time" should be abandoned. Restoration of spontaneous circulation (ROSC) should be defined. Researchers should also differentiate between ischemic, alveolar, and anemic hypoma. Asphyxia is hypoxemia plus hypercapnia. For the brain, one must differentiate between the temporary complete global ischemia of total circulatory arrest (cardiac arrest); exsanguination or asphyxiation, which ultimately ieads to pulselessness; the temporary incomplete ischemia of shock states; permanent incomplete focal ischemia (stroke); and brain trauma with its variable multifocal lesions. The controversy about buffers has revealed the need to differentiate between tissue hypoxia and acidosis versus hypoxemia and acidemia. In considering therapeutic hypothermia, we must differentiate between mild (34°C to 36°C), moderate (28°C to 32°C), deep (10°C to 20°C), profound (5°C to 10°C), and ultraprofound (below 5°C) hypothermia, as well as the site of temperature measurement (eg, cerebral versus core temperature). We must also differentiate between process variables in acute (12 hours or less) and short-term (24 hours or less) experiments and outcome variables in long-term experiments. These outcome variables, for the brain, are valid only after maturing of the postischemic encephalopathy for at least 72 hours after the insult. LEVELS OF RESEARCH

Molecular biology is being increasingly introduced into resuscitation research, opening new opportunities for breakthroughs. However, for some of the most important breakthroughs m therapeutics the molecular mechanisms are still unclear, including anesthesia, cortisone, antibiotics, and insulin. The ultimate importance of changes described at the molecular level still must be determined on the basis of pathophysiologic studies of organ systems and outcome of the whole organism. There can be no vital, life (cell viability)-restoring and life-sustaining chemical reactions without circulation, which delivers oxygen and substrates and removes toxic waste products. Research on the secondary cerebral and myocardial derangements known as the postresuscitation diseaseas or

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syndrome29 is needed. The enormous complexity and multitude of changes at the molecular and cellular levels during death and resuscitation are still only partially understood. 33 These changes call for the design of mechanism-specific multifaceted treatments. 29,33 Increasingly sophisticated and effective methods of studying nuclear DNA damage by ischemia and resuscitation43,4., and the nature of reoxygenation injury45, have recently become available. Is the death of cerebral neurons and cardiac myocytes--days after an ischemic episode, adjacent to surviving cells--primary necrosis, which seems to be the result of mitochondrial failure and membrane destruction? Or is it the result of programmed cell death (apoptosis, "falling off'), which seems to be triggered by nuclear DNA damage by the insult or reoxygenation? The recent discovery of mitochondrial DNA has also opened a new field of research on how cells die. For about two decades, we at the Resuscitation Research Center of Pittsburgh have tried to integrate studies from cells to organs to organisms to communities and even to disasters. Interacting teams have pursued research on cardiac arrest, asphyxia, shock, exsanguination, suspended animation, brain trauma, and mass disasters. Research at the molecular level and brain-trauma research were recently added to this multilevel program. RESEARCH TOPICS Topics and hypotheses (or questions) selected for resuscitation research should be important enough to contribute to improved outcome in human beings. Avoiding unnecessary studies requires knowledge of the history of resuscitation since around 1900.1 Topics should be selected on the basis of importance, need, and opportunities to be

successfully pursued. The selection is inevitably influenced by the investigator's background, expertise, interests, ambitions, and wisdom. The CPCR system 2 has survived 30 years almost unchanged. Regrettably, however, fewer than 10% of prehospital external CPR attempts have resulted in survival. 46 More effective life support techniques are needed. Most important is making BLS more effective in terms of oxygen delivery to the heart and brain. Also essential is reoxygenation of alveoli and at least transiently high reperfusion pressure to heart and brain, which cannot be achieved with external CPR steps A-B-C. Current standard external CPR BLS must be improved. Intermittent abdominal-compression CPR, active compression/decompression CPR, and vest CPR are attempts that have resulted in some improvement in blood flow but not enough to achieve the required high reperfusion pressures. Less effort should be spent on the minutiae of prolonged external CPR steps A-B-C with low flow in healthy dogs, and more effort should be spent on methods for inducing rapid ROSC in patients with sick hearts. For brief witnessed arrests, rapid restoration of the oxygen delivery system by means of CPR BLS-ALS remains the main goal. Once we learn more about how cells die, long after temporary total circulatory arrest and reperfusion, we may realize that for long unwitnessed arrests, a totally different, new approach would be indicated, one in which the brain is preserved during the attempt to resuscitate the heart. Research into ultraadvanced (long-term) "bridging" of life support--to recovery of the heart from stunning or ischemia or to its repair or replacement--is needed. Open-chest CPR is physiologically superior to closed-chest Figure 2.

Figure 1.

Guidelines for large-animal outcome models for CPCR research. Same species, sex, age, weight Reproducible insult in the therapeutic window Controlled reperfusion Randomizedcontrols Standardized life support with long-term control of extracerebral variables that can influence cerebral outcome Accurate control of brain or core temperature Intensive care of at least 72 hours before outcome evaluation, perhaps follow-up over several months Survival of all control animals, with brain damage Deaths from extracerebral causes excluded Final outcome evaluation (blinded)to treatment

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The Brain Resuscitation Clinical Trial, 19 79-1994: Adjunctive information from "milking" of the database. 67-74 01inical prediction of persistent vegetative state 3 days after arrest Adjunctive predictive value of brain cytosolic enzyme analysis in cerebrospinal fluid Quality of survival Occasional reversibility to good cerebra] outcome after arrest (no-flow)times of 6 to 15 minutes 01d age not an independent predictor of poor cerebral outcome Post-ROSC hypertension correlates with good and hypotension with poor cerebral outcome No effect of steroid therapy on proportion of good outcomes Limitation of therapy in prolonged coma Poor and slow ALS in prehospital practice Waiver (deferral) of patient consent

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CPR. 47-49 Portable emergency cardiopulmonary bypass (CPB) provides full control over blood flow, pressure, temperature, and composition 5° and would allow for control of cerebral resuscitation and prolonged life support. 33 At the time the Society of Critical Care Medicine was initiated in the early 1970s 36-3s, resuscitation research topics were ranked according to their scientific, clinical, and socioeconomic importance and to the feasibility of their being successfully pursued. 3r,51 Many of the topics considered important then 3r,51 reappeared in reevaluations of research priorities in the 1980s 14 and 1990s. 15-25 Recurring topics recommended for research have included postischemic-anoxic encephalopathy, with its increasing number of subtopics; microcirculatory failure in vital organs; adult respiratory distress syndrome with emphasis on lung healing; assisted circulation; and bioengineering with servocontrols. Recent additions include how ceils die after temporary ischemic anoxia.32-35,43-45

Of socioeconomic importance is that more effective emergency resuscitation, which is relatively inexpensive, will reduce the need for expensive, prolonged intensive care, which accounts for about 25% of total hospital costs in the United States. 52 Moving clinical research into the prehospital arena requires mobile ICU ambulances, staffed by physicians committed to research. Future research should fill gaps in knowledge. Some gaps can be identified on the basis of current, periodically revised guidelines 2-6. Real-life scenarios should influence laboratory models. Modeling will differ between unexpected and expected cardiac arrest, prehospital and in-hospital treatment, and inside and outside special care units. Finally, the choice of research topics is influenced by the "four Cs': competence, commitment, collegiality, and cash. Figure 3.

Cerebral postresuscitation syndromeY MP loss Ion-pump failure Acidosis Excitotoxicity-calcium loading No-reflow phenomenon, requiring high initial reperfusion pressure Multifocal cerebral delayed protracted hypoperfusien (after transient hyperemia), requiring a combination treatment for CBF promotion, to counteract the oxygen need/delivery mismatching Free radical-triggered chemical cascades with deleterious calcium shifts Extracerebral cardiovascular-pulmonary or microcirculatory failure Extracerebral transient visceral failure causing intoxication Triggering of programmed cell death (apoptesis)

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ANIMAL RESEARCH

Animal models of cardiac arrest have only recently become reproducible in terms of insult, life support, and outcome, and only then in the hands of a few investigators (Figure 1). 33,5°,5>66 Outcome studies in rats have limitations because rats are low on the phylogenetic scale. The rat lung and airway are very sensitive, and the small vessels and blood volume make invasive long-term life support almost impossible. A reliable cardiac arrest outcome model in rats (with asphyxiation) has only recently been achieved. 53 Furthermore, rat models of incomplete forebrain ischemia do not reflect a clinically relevant insult because the brain stem is not damaged, and there is no autointoxication from ischemic extracerebral organs. These models revealed several novel drug treatments that reduce darnage to the rat hippocampus; however, these treatments may prove ineffective in more clinically relevant, reproducible cardiac arrest outcome models in dogs. 54,55 In the 1970s we developed a global brain ischemia outcome model in monkeys using a neck tourniquet. 56 This model was abandoned, in part because actual cardiac arrest is clinically more realistic. Small monkeys and other small animals defibrillate themselves. Resuscitation data from dog models have accumulated over the past 100 years. ~ Dog models of cardiac arrest have been used since the 1950s and have been enhanced with long-term intensive care (3 to 4 days) and outcome evaluation since the 1970s. 5r-65 Dogs remain in (electrically induced) ventricular fibrillation (VF) and react to CPCR efforts much as human beings do. Prolonged VF Figure 4.

Suggestionsfor the Laboratory Resuscitation Researchers Symposia. Agree on key terms and definitions for animal and patient research Recommend requirements for reproducible animal models, particularly outcome models Recommend standard cardiac arrest model for each species so that results from different groups can be compared Consider criteria for taking positive treatment results from rats by way of dogs or pigs to patients Recognize limits of prospective randomized clinical outcome trials Recommend ethical ways to waive prospective consent requirement for resuscitation research in humans Demonstrate to regulating agencies the need for combination treatments Encourage searches for fully reliable measurements for the early prediction of permanent severe brain damage Initiate community-wide resuscitation case registries (for all comatose patients, including cardiac arrest, trauma, stroke, intoxication, etc) Recommend realistic funding mechanisms

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no-flow of 10 to 20 minutes, asphyxia, exsanguination, hyperthermia, hypothermia, drowning, shock, and brain trauma have all been studied in dog models. For cardiac arrest-ROSC studies, standard CPR is used. 5r59,61 For cardiac arrest-cerebral outcome studies, brief (jump-start) CPB is used, for better control of reperfusion, as an experimental tool. 5°,57,6°,52,65 Future resuscitation researchers should make use of these models. 33,5r-65 Reproducible cerebral outcome requires at least 10 features from these models (Figure 1). 32 Which variables should be monitored and controlled and which should simply be observed must be clearly spelled out before the start of any resuscitation study. These variables change according to the hypothesis. Outcome has been measured in terms of overall performance categories, neurologic deficit scores, heart and visceral morphology, and semiquantitative brain histopathologic damage scores in up to 20 brain regions. 33,56-65 Routine necropsies are essential. Morphologic evaluation of vital organs is desirable. The high cost of custom-bred dogs and some public objection to their use for research have stimulated attempts to duplicate cardiac arrest outcome studies from dog models in pigs. 66 Although such attempts are laudable, there has so far been no documented pig model that honors the 10 goals of Figure 1. Arrested hearts in pigs seem to be more difficult to resuscitate, the care of pigs is less aesthetic and more difficult, and there is no database on cerebral outcome. Although they are expensive, I see no substitute for outcome studies in dogs. They are still less expensive than randomized clinical trials. Progress in resuscitation needs continuous long-term funding of a few research ICUs for large animals, with stable, experienced research teams. One such ICU program requires at least $250,000 per year, mostly for custom-bred animals and salaries. With two or three animals simultaneously receiving life support, at least one technician should be continuously present and one physician research fellow experienced in critical care immediately available in the ICU. Improved analgesia and sedation should be developed for outcome studies on animals that are conscious and handicapped after the insult. Clinical realism is important; for cardiac arrest studies, the main unsolved gap in realism is the absence of coronary artery disease in animals. Researchers working at the cellular and molecular levels should appreciate the complexity of interactions among organ systems that determine outcome. Outcome researchers on the other hand, should add mechanismoriented studies, as long as the invasiveness of the mea-

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surement does not influence the outcome. With new imaging techniques, one can noninvasively study tissue edema, blood flow, and chemical changes in vital organs in real time. CLINICAL TRIALS Clinical resuscitation research is much more difficult than, for example, clinical cancer or cardiologic research. Clinical research encompasses concurrent pathophysiologic studies, prospective feasibility and outcome studies, and retrospective case studies. Prospective clinical outcome studies are not as controllable as laboratory studies. On the other hand, recreating human disease such as coronary atherosclerosis in animals is almost impossible. In 1978 we initiated the first Brain Resuscitation Clinical Trial (BRCT), which was supported by the National Institutes of Health until recently. 67-7° These studies have included 20 hospital groups from seven countries. We have learned that such randomized prospective clinical outcome studies have limitations: none of these studies has confirmed statistically, in overall group comparisons, the value of any of the therapies that have been demonstrated to be beneficial in reliable large-animal outcome models of cardiac arrest, although certain subgroups have suggested benefits. °7-7° Uncertainty in clinical study results stems from many uncontrollable factors such as logistic difficulties, deviations in protocol, and difficulty in identifying prospectively those patients who may actually benefit from the experimental therapy, r° Clinical trials have benefits beyond the evaluation of a novel treatment in a randomized, prospective fashion. Much has been learned from the BRCT data about the natural course of the disease, and many therapy-related "dues" have been revealed (Figure 2). Moreover, the BRCT methods formed the basis for ongoing CPCR case registries rl and international guidelines for the evaluation of communitywide CPCR results. 72 The dilemma that results from the inability to obtain prospective informed consent for experimental resuscitation trials in cardiac arrest patients was provoked in 1979 by the BRCT.73,74 After public hearings by the Food and Drug Administration and the National Institutes of Health early in 1995, this legalistic obstacle to clinical resuscitation research is finally being solved rs. HUMAN VOLUNTEERS

We have learned much from human volunteers. In the early 1950s, Archer Gordon studied chest- and back-pressure

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arm-lift methods of artificial ventilation in curarized human volunteers with tracheal tubes. 76 In the late 1950s, stimulated by Elam's studies of rescue breathing by mask 77, I documented steps A7s and B79,s° in curarized human volunteers without tracheal tubes. Use of anesthetized patients would have been unethical. Use of animals or conscious volunteers holding their breath would have been meaningless. Because most animals have a straight upper airway and human beings have a kinked airway that is subject to obstruction in coma, these studies were essential to documentation of backward tilt of the head plus jaw-thrust and the superiority of mouth-to-mouth ventilation over the back-pressure and chest-pressure arm-lift methods 79,s°, which were being taught at the time. We also proved in volunteers and cardiac arrest patients that sternal compressions do not ventilate and determined how steps A-B-C should be combined into BLS.s~ Lessons learned from somewhat risky research on volunteers have been documented on film, which helped convince the world to change the way first aid methods are taught, s2 Although institutional review boards did not exist, these volunteer experiments were peer reviewed and consent was uhrainformed. Similar use of human volunteers for evaluation of new methods for airway control and ventilation might be valuable and feasible in the future. EVERYDAY PATIENT CARE

We can also learn from patients outside randomized clinical trials. For example, CPR step C was developed after the rediscovery of sternal compression in dogs s3 was documented at the Johns Hopkins Hospital in everyday patients, s4 In the late 1950s, before precision vaporizers became available, the new potent anesthetic agent halothane was introduced. During induction of anesthesia, pulselessness occurred not infrequently. A few lung inflations with 100% O x and a few sternal compressions made the pulse return. Other examples of patients as teachers include the Scandinavian epidemics of poliomyelitis s5 and suicidal barbiturate poisoning s6 in the early 1950s and the poliomyelitis epidemic of 1960 in Baltimore. sr,ss These cases taught us about the safety and efficacy of prolonged artificial ventilation and airway care, as well as general intensive care. IMPROVING CPCR METHODS

In many clinical evaluations of novel CPR methods, time factors have not been appropriately considered.

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Optimists quote hospital discharge rates of 20% to 40% after prehospital CPR attempts in communities with welldeveloped EMS systems. .6 Pessimists quote a 10% or lower overall hospital discharge rate and note that 10% to 30% of long-term survivors sustain brain damage. 46,67-71 Realists recognize that since the early 1950s, when most patients with airway obstruction, apnea, or pulselessness outside the operating room were doomed, something previously unthinkable has been achieved.1 Although we cannot always count on bystanders to provide effective CPR BLS, efforts have been made for more than 30 years to give all citizens the capability to provide life-supporting first aid, including CPR BLS. This effort must be continued with increased intensity. Education research should take into consideration the documented superiority of self-training systems, s9,9° With regard to mouth-to-mouth ventilation by bystanders, victims must not be allowed to die because of fear of AIDS and other communicable diseases. A method with an improved pocket-size barrier is needed so that a bystander can oxygenate with zero infection risk. Manual external CPR must be improved to produce blood perfusion pressures of at least 50 mm Hg to support ROSC, ideally 100 mm Hg to overcome the cerebral no-reflow. More than 50% of prehospital CPR attempts fail to restart spontaneous normotension. 46,69 We suspect that many of these cases revolve "hearts too good to die. ''91 Healthy dog hearts arrested because of VE asphyxia, or exsanguination can be restarted after as long as 20 minutes of normothermic no-flow, 92 In defective hearts, loss of up to 40% of myocytes does not prevent heart pumping. 93 When ROSC cannot be accomplished quickly, the current suggestion to give up ALS attempts in the field seems too pessimistic. Getting previously sick hearts restarted, after additional damage from arrest, VF, mechanical or electric injury, or catecholamines, will probably be maximized only through a multifaceted approach. This approach would have to include early automatic countershocks by laypeople9., vigorous immediate bystander CPR95, and earlier and better titrated drug therapy. 96 Aortic approaches are under investigation. Trials of early initiation and possibly prolonged application of ultraadvanced life support methods, which can produce high perfusion pressures, are justified. 50,9r Even many sick hearts would probably be capable of resuming life-sustaining cardiac output if powerful, artificial circulation was maintained over hours or even days. Heart failure from stunning, focal or global ischemia, or arrhythmias can be temporary. One of the possibilities for such life support bridges is open-chest

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CPR. Studies in Belgium have shown that open-chest CPR outside the hospital is feasible and more effective in achieving ROSC than standard external CPR (personal communication, L Come, 1995). Minimally invasive open-chest CPR needs evaluation because it would be more acceptable (personal communication, F Buckman, 1994). Optimized mechanical closed-chest or openchest CPR9r and closed- or open-chest CPB can be performed with a portable pump-oxygenator-heatexchanger apparatus. 5° A novel method for rapid vessel access for CPB is needed. CPB can be continued for hours or days with the use of a heparin-bonded circuit, without the need for full systemic heparinization. This may enable coronary angiography and vascularization; determination of brain death, which may result in organ donation; or determination of permanent heart failure, which would lead to cardiac repair or replacement. Ultraadvanced bridging would be expensive and therefore requires feasibility trials and cost estimates. For "brains too good to die ''2,m, the loss of a few scattered neurons in critical areas prevents human mentation. The results of 20 years of cerebral resuscitation research allows cautious optimism. 14,15 Our cerebral resuscitation research since 1970 has been based on the hypothesis that the multifactorial cerebral postresuscitation syndrome needs mechanism-specific multifaceted therapies to prevent or mitigate at least the 10 known derangements (Figure 3). 7,32 The longest normothermic no-flow (arrest) period that is reversible and is followed by complete cerebral recovery is still believed to be 4 to 5 minutes. The 10-minute response times of mobile ICU ambulance services cannot be shortened. A breakthrough in the reversal of prehospital sudden death seems feasible with more effective methods for ROSC and a cerebral resuscitation method that normalizes cerebral outcome after 10 minutes of normothermic no-flow. Eisenberg estimates this could save an additional 100,000 lives each year in the United States. Drug treatments for the brain have been disappointing SO far. 33 Our cardiac arrest outcome studies in clinically realistic dog models over the past 15 years culminated this year in a study in which 11 minutes of normothermic VF arrest in dogs was followed by complete functional and near-complete histologic cerebral recoveU. This recovery was accomplished with the use of postarrest cerebral blood flow-promoting measures plus mild hypothermia, applied with methods that, with some modifications, should be clinically feasible. 63 This combination treatment was more effective than each treatment alone. A clinical protocol based on this study should be subjected

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to feasibility trials involving in-hospital and out-of-hospital patients. Optimization of brain-oriented prolonged life support should continue in the laboratory to further extend the reversible normothermic no-flow period. Several questions remain to be answered. Does the effective mild postarrest cerebral hypothermia merely delay the inevitable neuronal loss? Could brain healing and functional recovery be improved with gangliosides, nerve growth factors, a more effective fuel for the brain than glucose, or by stimulation? Is triggering of programmed cell death by DNA cleavage, during or after ischemia, the main cause of selective vulnerability of neurons? What could be done about it? How can pharmacologic combination treatments, which make mechanistic sense but have so far been elusive, be tailored in a scientific manner? Myocardial cell culture studies are under way.98 Neuron culture preparations might provide clues before technically difficult rat models of cardiac arrest and the expensive long-term dog models are used. The cell culture approach may be an inexpensive way of untangling and reconstructing multifaceted drug cocktails for myocardial and cerebral resuscitation in terms of relative doses, timing, and drug interactions. In summary, maximizing the reversibility of clinical death has been and will continue to be a great challenge 15,33,99. TRAUMA RESUSCITATION

Secondary derangements after brain trauma are being researched, from the molecular level in rat cortical contusion models l°° to clinically relevant models in large animals. ~ol The latter models allow the study of treatments to prevent or mitigate brain swelling and herniation. Clinical research on brain trauma 2° should start at the scene and should include clarification and treatment of '~impact apnea" and evaluation of early cooling. For uncontrolled hemorrhagic shock 18, new data prove what should be obvious--namely, that injured vessels with higher intravascular pressures bleed more. Under certain circumstances, no fluid resuscitation in the field may be better than vigorous fluid resuscitation 1°2, but the victim must not be allowed to become pulseless. Pulselessness can be prevented with limited (hypotensive) fluid resuscitation 1°3, even better with the addition of moderate hypothermia 1°4 and perhaps also 100% O 2 breathing, lo5,1o6 Optimal fluids, pressures, hematocrit, temperature, oxygenation, and sedation for pharmacologic poikilothermia (hibernation) and preservation of vital

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organs during severe uncontrolled hemorrhagic shock longer than 1 hour, remain to be determined. For temporarily uncontrollable conditions in the field such as penetrating truncal trauma with internal exsanguination, which lead to pulselessness within a few minutes in the field, a totally new resuscitative approach is required. Research into "suspended animation for delayed resuscitation," for transport and repair without pulse, has been recommended for research since 198419; such research was initiated with dog outcome models in 1988.19'l°r'l°s The current limit for profound hypothermic circulatory arrest, induced and reversed with CPB, is 60 minutes, leading to histologically "clean" brains, los The main challenge is normothermic induction of suspended animation by pharmacologic-chemical means, in the field, where CPB is not available. Suspended animation would be of interest not only in the military but in civilian emergency care and select, otherwise unmanageable, cases of elective surgery. Could suspended animation research also be relevant for intractable cardiac arrest? GENERAL SUGGESTIONS

Because of the increasing complexity of the problems and technologies involved, modern experimental or clinical research usually involves teamwork by full-time or mosttime investigators of various disciplines. To move the field forward faster, there must be ongoing open communication and joint planning and--after "internal" peer review by consultants with experience in resuscitation research-collaboration among several groups. ,4,15,3r Such cooperation would decrease the number of cases of submission of disjointed single grant applications, usually peerreviewed by nonreanimatologists. It would also prevent much futility and frustration, arguments about different results with different models, and wasteful duplication of efforts. Laboratory resuscitation research groups should communicate with each other (Figure 4). The "urge for immortality" fosters secrecy to protect priority Fortunately, resuscitation researchers have enjoyed a fair amount of "glasnost." What ultimately counts is that progress has been made, not who gets the credit. Stealing initiatives or not acknowledging others' "firsts" shows a lack of collegiality. Few ideas are truly original. Even more important than publishing a new idea is recognizing an idea's importance and convincing the world of it 1, often by the documentation with research. Advances are made by individuals, not by organizations, unions, or specialties. Discovery requires serendipity. Documentation requires a scientific approach. Promoting

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a new approach requires vision and courage. Developing and implementing a new approach requires tenacity. Once an investigator has selected a broad topic for research, he or she should stay with it as long as important questions remain unanswered. In a long-term systematic research program, the results of each project should influence the direction of the next project. Researchers should avoid pitfalls. They should know something about the history of resuscitation research, at least back to 1900.1 They should be open-minded about new initiatives, should not duplicate what is fashionable at the moment, should not select research topics merely because a new monitoring device has become available, and should not collect massive data without meaning. The researcher should start with a broad goal and clear questions, expressed as hypotheses. Escalating CPCR research in the near future will be expensive, at a time of severe cost-cutting in academic medical centers. 24 A crash program on CPCR research in the last 5 years of this millennium deserves priority funding. Health insurance companies should have social conscience and should return profits to medical research. The National Institutes of Heakh should shift some of the current funding priorities from molecular mechanisms to the support of projects with immediate breakthrough potentials for saving lives. Several resuscitation research centers should create highly productive environments for planned research, with an atmosphere that encourages chance discoveries. CPR researchers should also be engaged in continuing dialogue on issues of biomedical ethics, both those concerning futility and discontinuation of resuscitation efforts and those involving the ethical responsibilities of scientists working with patients and animals. ~o9-1ix Finally, this research- and technology-oriented society should not forget the Third World, where 13 million children die each year of avoidable diseases, including trauma. Sanitation and inexpensive BLS must take priority over expensive advanced and prolonged life support. Emphasis should be placed on research of more effective methods: High technology does not necessarily imply high quality of care, and incorrec t technology is worse than low technology 113 With regard to low technology: increasingly effective austere resuscitation methods must be developed (personal communication, JC Lane, 1995). CONCLUSION

The breakthrough for modern external CPR occurred around 1960. Resuscitation researchers should not make

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the same mistakes in 2000 that our predecessors made around 1900, when they almost had the knowledge necessary for modern external CPR3 By the year 2000, we should know how vital cells die, as well as the limits of the reversibility of permanent heart and brain failure. Beyond 2000, I suspect there will be more challenges for resuscitation researchers in traumatology and brain trauma-related topics, mostly concerning the young and fit. Resuscitation medicine of the future will need not only many skilled, experienced clinicians and dedicated teachers and some focused, experienced scientists, but also a few globally oriented leaders, who are investigators, clinicians, and scholars. Medicine in general and resuscitation medicine in particular impose the value of a single human life over random chance in nature, which protects the species more than the individual. As long as reanimatology is pursued with wisdom, compassion, collaboration, scientific knowledge, experience, historic perspective, and collegiality, it will be a positive force in human evolution.

16. Safar P, Ebmeyer U, Katz L: Future directions for resuscitation research: Introduction. Grit Care Mad 1996;24(suppl):S1-S2. 17. Safar P: On the history of modern resuscitation. Grit Care Med 1996;24(suppl):S3-S11. 18. Shoemaker WC, Peitzman AB, Bellamy R, et al: Resuscitation from severe hemorrhage. Grit Care Med1996;24{suppl):S12-S23. 19. Bellamy R, Safar P, Tisherman S, et ah Suspended animation for delayed resuscitation. Grit Care Mad 1996;24(suppl):S24-S47. 20. Rosomoff HL, Kochanek PM, Clark R, et ah Resuscitation from severe brain trauma. Grit Care Mad 1996;24(supp[):S48-S56. 21. Vaagenes P, Ginsberg M, Ebmeyer U, et ah Cerebral resuscitation from cardiac arrest: Pathophysiologic mechanisms. Grit Care Med 1996;24(suppl):S57-S68. 22. Gisvold SE, Sterz F, Abramson NS, et ah Cerebral resuscitation from cardiac arrest: Treatment potentials. Grit Care Med 1996;24(suppl):S69-S80. 23. Marion DW, Looney Y. Ginsberg M, et ah Resuscitative hypothermia. Grit Care Mad 1996;24(suppl):S81-S89. 24. Thompson WL, Be]lamy B, Cummins RO, et ah Funding resuscitation research. Grit Care Mad 1996;24(suppl):S90-S94. 25. Ebmeyer U, Katz L, Safar P, et ah Concluding comments and suggestions for young resuscitation researchers. Grit Care Mad 1996;24(suppl}:S95-S101. 26. Backer B, Idris AH: Proceedings of the Second Chicago Symposium on advances in CPR research and guidelines for laboratory resuscitation research: Ann EmergMed1996;27:539-541. 27. Negovsky VA: Reanimatology today: Some scientific and philosophic considerations. Grit Care Med 1982;16:130-133. 28. Negavsky VA, Gurvitch AM, Zolotokrylina ES: PostresuscitationDisease.Amsterdam: Elsevier, 1983.

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13, Safar P (ad): Brain resuscitation. Grit Care Mad 1978;6:199- 292. 14. Safar P, Granvik A, Abramson NS, at al (ads): Reversibility of clinical death: Symposium on resuscitation research. Grit Care Mad 1988;t 6:919-1086. 15. Safar P, Ebmeyer U, Katz L (ads): International Resuscitation Research Conference: Intramural publication. Pittsburgh, Pennsylvania: University of Pittsburgh, 1994.

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RESEARCH

43. White BC, DeGarcia DJ, Grassman LI: Brain nuclear DNA survives cardiac arrest and reperfusign. FreeRadBiol Med1991;1g:125-135.

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44. Nitatori T, Sate N, Waguri S, et ah Belayed neuronal death in the CA-1 pyramidal cellulae of the gerbil hippecampus following transient ischemia is apoptosis. J Naurosci1995;15:10011011.

70. Abramson NS, Kelsey SF, Safar P, et ah Simpson's paradox and clinical trials: What you find is not necessarily what you prove. Ann EmergMeg 1992;21:1480-1482.

45. Traystman RJ, Kirsch JR, Koehler RC: Oxygen radical mechanisms of brain injury following ischemia and reperfusion. JAppl Physiol1991;71:1185-1195.

71. Mullie A, Buylaert W, Michen N, et al: Predictive value of Glasgow coma score for awakening after out-of-hospital cardiac arrest. Lancet1988;1:137-140.

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72. Cummins R, Chamberlain D, Abramson NS, et al: Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: The Utstein Style. Circulation1991;84:960975.

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48. DelGuercio LRM, Feins NR, Cohn NO, et ah Comparison of blood flow during external and internal cardiac massage in man. Circulation 1965;31(suppl 1):171-180.

74. Craig MT, Abramson NS, Herzog H, et al: "Deferred consent" experience in a multinational randomized clinical study of cardiac arrest and resuscitation (abstract). Resuscitation 1994;28:$39.

49. Bircher N, Safar P: Manual open-chest cardiopulmonary resuscitation. Ann EmergMad 1984;13:770-778. 50. Safar P, Abramson NS, Angeles M, et ah Emergency cardiopulmonary bypass for resuscitation from prolonged cardiac arrest. Am J EmergMad 1990;8:55-67. 51. Safar P: On the philosophy, physiology, history and future of reanimation (in German). Anaesthesist1974;23:507-519. 52. Lenfant C: Task force on research in cardiopulmonary dysfunction in critical care medicine. Am J RespirCrit CareMeg 1995;151:243-248. 53. Katz L, Ebmeyer U, Safar P, etal: Outcome model of asphyxial cardiac arrest in rats. J Cereb BloodFlow Matab 1995;15:1032- 1039. 54. Sterz F, Leonov Y, Safar P, et al: Effect of excitatory amino acid receptor blocker MK-8Ol on overall, neurologic, and morphologic outcome after prolonged cardiac arrest dogs. Anesthesiology1989;71:907-918. 55. Xiao F, Sire K, Safar P, etal: Beneficial effects on neuron-specific calcium entry blocker SNX111 on cerebral outcome after forebraJn ischemia in rats, but not after ventricular fibrillation (VF) cardiac arrest (CA)in dogs (abstract). Resuscitation1994;28:$36. 56. Nemoto EM, Bleyaert AL, Stezoski SW, et ah Global brain ischemia: A reproducible monkey model. Stroke1977;8:558-564. 57. Safar P, Gisvold SE, Vaagenes P, et ah Long4erm animal models for the study of global brain ischemia, in Wauquier A, et al (eds): Protectionof TissuesAgainstHypoxia.Amsterdam: Elsevier, 1982:147-170. 58. Bircher N, Safar P: Cerebral preservation during cardiopulmonary resuscitation. Crit Care Med 1985;13:185-190. 59. Vaagenes P, Cantadore R, Safar P, et ah Amelioration of brain damage by lidoflazine after prolonged veotricular fibrillation cardiac arrest in dogs. CritCareMeg 1984;12:848-855. 60. Leonov Y, Sterz F, Safar P, et al: Mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs. J CerebBloodFlowMetab 1990;10:57-70. 61. Sterz F, Safar P, Tisherman S, eta[: Mild hypothermic cardiopulmonary resuscitation improves outcome after prolonged cardiac arrest in dogs. CritCareMed1991;19:379-389. 62. Sterz F, Leonov Y, Safar P, et ah Hypertension with or without hemodilution after cardiac arrest in dogs. Stroke1990;21:1178-1184. 63. Safar P, Xiao F, Radovsky A, et ah Improved cerebral resuscitation from cardiac arrest in dogs with mild hypotbermia plus blood flow promotion. Stroke1996;27:105-133. 64. Safar P, Sterz F, Alexander H, et ah Reproducible cardiac arrest-intensive care outcome models in dogs for comparing insults and cerebral resuscitation potentials (abstract). Resuscitation 1994;28:$20. 65. Radovsky A, Safar P, Sterz F, et ah Regional prevalence and distribution of ischemic neurons in dog brains 96 hours after cardiac arrest of 0 to 20 minutes. Stroke1995;26:2127-2134.

75. Biros MH, Lewis RJ, Olson CM, et ah Informed consent in emergency research: Consensus statement from the Coalition Conference of Acute Resuscitation and Critical Care. JAMA 1995;273:1283-1287. 76. Gordon AS, Sadove MS, Raymond F, et al: Critical survey of manual artificial respiration. JAMA 1951;147:1444-1453. 77. Barn JO, Brown ES, Elder JB Jr: Artificial respiration by mouth-to-mask method: A study of the respiratory gas exchange of paralyzed patients ventilated by operator's expired air. N EnglJ Mad 1954;250:749-754. 78. Safar P, Aguto-Escarraga L, Chang F: A study of upper airway obstruction in the unconscious patient. J Appl Physiol1959;14:760-764. 7& Safar P, Escarraga L, Elam J: A comparison of the mouth-to-mouth and mouth-to-airway methods of artificial respiration with the chest-pressure arm-lift methods. N EnglJ Mad 1958;258:071- 677. 80. Safar P: The failure of manual artificial respiration. JAppl Physio11959;4:84-8& 81. Safer P, Brown TC, Holtay WH, at al: Ventilation and circulation with closed chest cardiac massage in man. JAMA 1961;176:574-576. 82. Safar P: Introductionto Respiratoryand CardiacResuscitation:A DocumentaryFilm of Hurnan VolunteerResearch.US Army film PMF5349. Washington DC: Walter Reed Army Institute of Research, 1960. 83. Kouwenhoven WB, Jude JR, Knickerbocker GG: Closed-chest cardiac massage. JAMA 1960:173:1064-1067. 84. Jude JR, Kouwenhoven WB, Knickerbocker GG: Closed arrest: Report of application of external cardiac massage on 118 patients. JAMA 1961;178:1063-1070. 85. Ibsen B: The anaesthetist's viewpoint on treatment of respiratory complications in poliomyelitis during the epidemic in Copenhagen, 1952. ProcR Soc Mad 1954;47:72-74. 86. Nilsson E: On treatment of barbiturate poisoning: A modified clinical aspect. Acta Med Sound1951;253(suppl):1-27. 87. Safar P, Berman B, Diamond E, et ah Cuffed tracheostomy tube vs. tank respirator for prolonged artificial ventilation. Arch PhysMefl Rehabi11962;43:487-493. 88. Safar P: Introductionto ProlongedArtificial Ventilation:A DocumentaryFilm of Patient Research.US Army film PMF534& Washington DC: Walter Reed Army Institute of Research, 1960. 89. Berkebile P, Benson D, Ersoz C, at ah Public education in heart lung resuscitation: Evaluation of three self-training methods in teenagers (abstract). Crit CareMad 1976;4:134. 90. Safar P, Berkebile P, Scott MA, et ah Education research on life supporting first aid (LSFA) and CPR self-training systems (STS). Crit CareMad 1981;9:403-404. 91. Beck CS, Leighninger DS: Death after a clean bill of health. JAMA 1960;174:133-135.

66. Brown CG, Werman HA, Davis EA, et ah Comparative effect of graded doses of epinephrine on regional brain blood flow during CPR in a swine model. Ann EmergMad1986;15:1138-1144.

92. Reich H, Angeles M, Safar P, et al: Cardiac resuscitability with cardiopulmonary bypass after increasing ventricular fibrillation times in dogs. Ann EmergMad 1990;19:877-890.

67. Brain Resuscitation Clinical Trial I Study Group: Randomized clinical study ef thiopental loading in comatose survivors of cardiac arrest. N EnglJ Med 1986;314:397-403.

83. Jennings RB, Reimer KA, Steenbergen C: Complete global myocardial ischemia in dogs. Crit CareMed 1988;16:988-996.

68. Brain Resuscitation Clinical Trial II Study Group: A randomized clinical study of a calciumentry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest. N EnglJ Meg 1991;324:1225-1231.

94. Bossaert L, Koster R: Defibrillation: Methods and strategies. Resuscitation1992;24:211-225.

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95. Wik L, Steen PA, Bircher NG: Quality of bystander cardiopulmonary resuscitation influences outcome after prehospJtal cardiac arrest. Resuscitation1994;28:195-203.

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96. Bircher NG: Cardiopulmoneryresuscitation, in Dentzker DR, Maclntyre NR, Bakow ED (ads): ComprehensiveRespiratoryCare.Philadelphia: Saunders, 1995. 97. Anstadt MP, Bartlett RL, Malone JP, et al: Direct mechanical ventricular actuation far cardiac arrest in humans: clinical feasibility trial. Chest1991;100:86-92.

Reprint no. 47/1/72095 Address for reprints: Peter Safar, MD

98. Vanden Heek TL, BeckerLB, Griem ML, et ah Isolated animal heart cell cultures: A model for cardiac resuscitation (abstract).Ann EmergMed 1992;21:623.

Safar Center for Resuscitation Research

99. Paradis N (ed): CardiacArrest. Baltimore: Williams & Wilkins, 1995.

3434 Fifth Avenue

160. KochanekPM, Clark RSB, Schiding JK, et el: Weight drop model of traumatic brain injury: Assessment of the acute inflammatory responseto cerebral trauma, in Ohnishi ST, Ohnishi T (eds): CentralNervousSystem Trauma:ResearchTechniques.London:CRCPublications, 1995:247-254.

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101. PomeranzS, Safar P, RadovskyA, et al: The effect of resuscitative moderate hypothermia following epidural brain compressionon cerebral damage in a canine outcome model. J Naurosurg1993;79:241-251. 102. Bickell WH, Wall MJ, PepePE, et al: Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating terse injuries. N EnglJ Mad 1994;331:1105-1109. 103. CaponeAC, Safar P, StezoskiW, et al: Improvedoutcome with fluid restriction in treatment of uncontrolled hemorrhagicshock. J Am CoilSurg1995;180:49-56. 104. Kim SH, Stezoski SW, Safar P, et al: Hypothermic(Hth) minimal fluid resuscitation (FR) extends the golden hour of uncontrolled hemorrhagicshock (UHS)in new outcome model in rats (abstract). AcadEmergMed 1995;2:364. 105. Crippen D, Safar P, Porter L, at al: Improvedsurvival of hemorrhagicshock with oxygen and hypothermia in rats. Resuscitation1991;21:271-281. 106. LeenovY, Safar P, Sterz F, et al: Extendingthe golden hour of volume controlled hemorrhagic shock (VHS)in awake rats with oxygen (02) plus moderate hypothermia (Hth)(abstract). Acad EmergMad 1998;2:401. 107. Tisherman SA, Safar P, RadovskyA, et ah Profoundhypothermia (
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