Eo mo oy PUBLIC HEALTH LIBRARY ITS EXPANDING ROLE / IN MEDICINE A || Conference Report Sy AUG 21 1975 u.S.8.b Dud ) od. Grr d Ane fhe. / /0 \ } rR sho Belhesaa MA / TF. | ANESTHESIOLOGY: ITS EXPANDING ROLE IN MEDICINE A Research Conference Report Bethesda, Maryland October 10-11, 1974 Sponsored by the National Institute of General Medical Sciences Editors Emilie A. Black, M.D. Deputy Director, Clinical and Physiological Sciences Program Paul A. Deming Office of Research Reports DHEW Publication No. (NIH) 76-918 ¢co145 10 / CONTENTS Tro UBHION wesw oe ein vi EU iY ORs 0 SE HEE FS 4 1 6 1 § 9 0 0 10.31 £ 1 50% 0 1 PortICIPIITES oc vio mv nain vin mam ais 52505 20 00590 Fok 0.00 36 5.0 0.08 08 15 98 6 Rk B0950 906 38 ok 50 9 0 National Health Policies and the Academic Maturation of Anesthesiology ..........ccciiiiiiiiiiiiiiiiiiiii.. John R. Hogness The NIGMS Anesthesiology Program: History and Present Status ......... oo. Emilie A. Black I. PAST ACCOMPLISHMENTS AND STATE OF THE ART Panel Discussion: Current Research .................. oii... Richard J. Kitz, Moderator John W. Severinghaus, Rudolph de Jong, Leonard F. Walts, Nicholas M. Greene, Russell’ A. Van Dyke, Theodore C. Smith, Myron B. Laver, Edmund I. Eger, John J. Bonica, Kenneth L. Casey, Panelists Panel Discussion: Anesthesia Research Centers .................... William K. Hamilton, Moderator John J. Bonica, Henrik H. Bendixen, Nicholas M. Greene, Jerome H. Modell, Panelists Research Training: Past Accomplishments and Present Salus... qn sini mrivisnimasusasi stn hoisssvsmmsss Robert M. Epstein, John E. Steinhaus II. FUTURE DIRECTIONS Views from a Dean’s Office .........ciininiriini iin. James E. Eckenhoff Panel Discussion: Research Objectives ............................. Harry Wollman, Moderator John W. Severinghaus, Ellis N. Cohen, Edmund I. Eger, Raymond B. Fink, Henry Price, Luke M. Kitahata, Shih-hsun Ngai, John J. Bonica, Frederick L. Kerr, Sol M. Shnider, Panelists Panel Discussion: Anesthesiology Links to Other NIGMS Programs ........c.c.uoeeeeenennneennnnneennnneeenns John J. Bonica, Moderator John M. Kinney, Wen H. Ko, Nancy Simpson, David Bruce, Frank J. Standaert, Panelists 07%, iii RD 80 AS4 1974 PUBL Program Prospects: Scientific and Manpower ...................... Robert M. Epstein John E. Steinhaus Henrik H. Bendixen SUMMATY 5 0x vows smsrm sme smpnn snes nad ® 1 EE RaAN ARE AEDT RET HERBERT William K. Hamilton INTRODUCTION For nearly two decades the National Insti- tute of General Medical Sciences and its pre- decessor unit, the NIH Division of General Medical Sciences, has sought to strengthen the scientific base of medical anesthesia. Current- ly, the Institute's research grant program supplies one-third of all Federal funds spent on . anesthesiology research. The program goals are to improve the safety and effectiveness of anesthetic procedures, to relieve pain, and to provide optimal respiratory care in all relevant areas of disease prevention, diagnosis, and treatment. There is compelling justification for this activity. As many as 22 million Americans are anesthetized each year for surgical operations, childbirth, and for other medical procedures. The anesthesia-related death toll alone is esti- mated at 15,000 to 20,000 patients annually. The mortality rate, although not high, rises exponentially in cases of major surgery and in relation to age and the severity of underlying disease or injury. There are grounds to suspect that anesthetic agents may be responsible for the increased childhood incidence of mental re- tardation, brain dysfunction, dyslexia and cerebral palsy. Another factor of considerable concern is the cost of medical care associated with anesthesia-caused morbidity; here the economic loss is estimated to exceed one billion dollars a year. In order to assure wise investments of re- search funds, the NIGMS must continually strive to assess the status of anesthesia knowl- edge, focusing on critical deficiencies. To this end, the Anesthesiology Workshop was con- vened at the NIH on October 10-11, 1974. Among the more than 100 participating scien- tists were those prominent not only in anes- thesiology but in numerous other closely re- lated basic and clinical fields. The sessions were organized to examine the thrusts of cur- rent research, recognize underlying obstacles, and identify those objectives toward which fu- ture efforts might be rewardingly directed. Relevant vital issues including national health and science policies, public expectations, the supply of anesthesia research and teaching manpower, and other factors as they affect the academic research environment similarly were placed in review. The proceedings is published with the be- lief that readers will find the conference delib- erations provocative and useful as a guide to developing new investigations central to exist- ing problems and the broadening of perceived horizons for patient care. Encouragement will be gained in part from the scientific maturation of anesthesiology and its increasingly formida- ble role in interdisciplinary collaboration. The burgeoning pace of fundamental progress, for example, could scarcely be made more clear than by the papers of De Jong, Greene, Eger, and several others. In the same vein, Theodore Smith delineates the course of scientific cross- fertilization in the area of respiratory studies and underscores the implications to patient care. The efforts put forth by the NIGMS anes- thesiology research centers were found to be an important stimulus for interdisciplinary ac- tivity. Nonetheless, the weighing of support strategies against a backdrop of limited avail- able resources, brought forth strong argument for the preservation of individual research grants. Additional perspective is provided in a panel discussion of the relationship of anes- thesiology links to other NIGMS programs in the areas of trauma, bioengineering, genetics, molecular and cellular basis of disease, and in pharmacology and toxicology research and training. The future shopping list of research direc- tions generated by the conferees is lengthy but also reflective of profound promise. For exam- ple, the prospect is good that continuing inves- tigation into effects of anesthetics on central nervous system and cerebral responses may well bring significant advantages to the therapies of stroke and brain injuries. Sub- stantive opportunities also are foreseen for greater understanding and more effective management of chronic pain states that collec- tively cost the American people in remedy up to $50 billion per year. Other conceived poten- tials, to cite but a very few, include the molecu- lar design of far more selective and potent anesthetic drugs, the adjuvant use of such technics as electronarcosis and acupuncture, and major forward strides in the use of auto- orous pursuit of anesthesiological studies and mation for anesthetic induction. knowledge in the public health interest. We believe that the findings of the confer- ence constitute a firm groundwork for the vig- The Editors ii PARTICIPANTS Henrik H. Bendixen, M.D. Professor & Chairman, Department of Anesthesiology College of Physicians & Surgeons Columbia University New York, N.Y. Emilie A. Black, M.D. Deputy Director Clinical & Physiological Sciences Program National Institute of General Medical Sciences, NIH Bethesda, Maryland John J. Bonica, M.D. Professor & Chairman, Department of Anesthesiology University of Washington School of Medicine Seattle, Washington David Bruce, M.D. Associate Professor, Department of Anesthesiology Northwestern University School of Medicine Chicago, Illinois Edward A. Brunner, M.D., Ph.D. Professor & Chairman, Department of Anesthesiology Northwestern University Medical School Chicago, Illinois Kenneth L. Casey, M.D. Associate Professor, Departments of Physiology, Neurology and Neurophysiology University of Michigan Medical School Ann Arbor, Michigan Ellis N. Cohen, M.D. Professor, Department of Anesthesiology Stanford University Medical School Stanford, California iii Rudolph H. de Jong, M.D. Professor, Department of Anesthesiology & Pharmacology University of Washington Seattle, Washington James E. Eckenhoff, M.D. Dean, Northwestern University School of Medicine Chicago, Illinois Edmond I. Eger, M.D. Professor, Department of Anesthesiology University of California Medical School San Francisco, California Robert M. Epstein, M.D. Professor & Chairman, Department of Anesthesiology University of Virginia Medical School Charlottesville, Virginia B. Raymond Fink, M.D. Professor, Department of Anesthesiology University of Washington School of Medicine Seattle, Washington Evan L. Frederickson, M.D. Professor, Department of Anesthesiology Emory University School of Medicine Atlanta, Georgia Nicholas M. Greene, M.D. Professor, Department of Anesthesiology Yale University School of Medicine New Haven, Connecticut William K. Hamilton, M.D. Professor & Chairman, Department of Anesthesiology University of California Medical School San Francisco, California John R. Hogness, M.D. President, University of Washington Seattle, Washington Frederick L. Kerr, M.D. Professor, Departments of Neurosurgery & Neuroanatomy Mayo Graduate School of Medicine University of Minnesota Rochester, Minnesota John M. Kinney, M.D. Professor, Department of Surgery College of Physicians & Surgeons Columbia University New York, N.Y. Ruth L. Kirschstein, M.D. Director, National Institute of General Medical Sciences National Institutes of Health Bethesda, Maryland Luke M. Kitahata, M.D., Ph.D. Professor and Chairman, Department of Anesthesiology Yale University Medical School New Haven, Connecticut Richard J. Kitz, M.D. Henry Isaiah Dorr Professor Harvard Medical School Boston, Massachusetts Wen H. Ko, Ph.D. Director, Engineering Design Center Case Western Reserve School of Medicine Cleveland, Ohio C. Philip Larson, Jr., M.D. Professor & Chairman, Department of Anesthesiology Stanford University Medical Center Stanford, California Myron B. Laver, M.D. Professor, Department of Anesthesiology Harvard Medical School Boston, Massachusetts iv Bryan E. Marshall, M.D. Professor, Department of Anesthesiology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Jerome H. Modell, M.D. Professor & Chairman, Department of Anesthesiology University of Florida Medical School Gainesville, Florida Shih-hsun Ngai, M.D. Professor, Department of Anesthesiology College of Physicians & Surgeons Columbia University New York, N.Y. Henry Price, M.D. Chairman, Department of Anesthesiology Hahnemann Medical College and Hospital 230 N. Broad Street Philadelphia, Pennsylvania John W. Severinghaus, M.D. Professor, Department of Anesthesiology University of California San Francisco, California Sol M. Shnider, M.D. Associate Professor & Chief of Obstetrics Anesthesia University of California San Francisco Medical Center San Francisco, California Nancy Simpson, Ph.D. Associate Professor, Departments of Pediatrics & Biology Queens University Kingston, Ontario, Canada Norman Ty Smith, M.D. Associate Professor of Anesthesia, Veterans Administration Hospital San Diego, California Theodore C. Smith, M.D. Professor, Department of Anesthesiology University of Pennsylvania Medical School Philadelphia, Pennsylvania Frank J. Standaert, Ph.D. Professor & Chairman, Department of Pharmacology Georgetown University Medical School Washington, D.C. John E. Steinhaus, M.D. Chairman, Anesthesia Service Emory University School of Medicine Atlanta, Georgia Russell A. Van Dyke, Ph.D. Consultant-in-Anesthesia Mayo Clinic & Foundation Rochester, Minnesota Leroy D. Vandam, M.D. Secretary, Executive Committee, Department of Anesthesiology Peter Bent Brigham Hospital Boston, Massachusetts Leo H. von Euler, M.D. Deputy Director, National Institute of General Medical Sciences National Institutes of Health Bethesda, Maryland Leonard F. Walts, M.D. Associate Professor, Department of Anesthesiology The Center for Health Sciences University of California Los Angeles, California Harry Wollman, M.D. Professor & Chairman, Department of Anesthesiology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania NATIONAL HEALTH POLICIES AND THE ACADEMIC MATURATION OF ANESTHESIOLOGY JOHN R. HOGNESS I intend to divide my remarks today into two parts. First, I want to talk about some of the current issues in health policy, as I see them, both in the research area and in areas relating to manpower and health care, to pro- vide a backdrop, if you will, for your discussion over the next two days. Second, I will turn to a relatively brief discussion of developments in the field of anesthesiology and needs for the fu- ture, as seen by an outsider to the field, but one who has long been interested in it. Health Policy Issues I talk, with some trepidation these days, about health policy because I've been some- what removed from Health's center stage for over six months, and important things in this area seem to have a way of happening at an ever accelerating pace. I'm here today not only in testimony of my high regard and friendship for John Bonica, but because I believe that my time in Washington, D.C., developing the new Institute of Medicine of the National Academy of Sciences gave me some insights and perspectives on health policies and policy- making that might prove of interest to you as you proceed with your deliberations. I propose to share with you some of the lessons I have learned over the past three or four years of intensive exposure to national health policy matters. It does not take a sophisticated observer to realize that the bar- rage of powerful Federal initiatives in the health field in the past few years will only be- come more intense and more sweeping in scope in the years ahead. The fact that the health portion of our budget is so large assures us of continued searching attention by Washington policy-makers. From the perspective of the medical academic, these pressures emanate from a poorly understood part of the world and may help to produce feelings of uncertainty, confu- sion and anxiety. Certainly, I was (and remain) frustrated by the bizarre array of forces, fac- tors and pieces that go into the health policy puzzle. When the pieces are in place, they do not define a recognizable figure or entity. There is no unified national health strategy for the next decade or beyond, and the newcomer is often too quick to assume that political stupidity and or cupidity are the root causes for this state of affairs. Four general points deserve emphasis be- fore proceeding into specific areas of concern. First: By and large, the people in the gov- ernment (both Legislative and Executive branches) who are thinking about health poli- cy, form a highly competent, sophisticated and effective group. Not too many people in the academic community realize, for example, that the Carnegie Corporation and the Johnson Foundation have supported a project over the past few years which aims at educating appro- priate health-related legislative and executive staff to the major health issues. Speakers, con- ferences, and site visits are all part of a care- fully orchestrated program called “Health Staff Seminars” which is under the very com- petent direction of Judith Mills and which, many of us believe, has successfully decreased appreciably the ignorance and naivete in these people. It is no longer possible to say that the powerful voices of outside experts can direct health staffers solely because of their prestige; no longer are the staffers blank blackboards on which to write; rather they are critical, thoughtful and informed participants in the policy making and legislative processes. The concerned professional is less often successful these days by simply proclaiming his position and convictions, excathedra; rather his pro- posals gain credence when the facts, analyses, and arguments are compelling. In this sense, health policy making is a new ballgame, a far different contest than that of five or ten years ago. Second: As a society in general, and in the health sector particularly, we are aware that we have begun to reach the limits of our re- sources. The American people are realizing that expenditures in the health area cannot continue to increase at the rate they have in the past. Therefore, choices must be made and priorities set, either by design or default. People will not pay for care that isn’t effective, or for research that will not ultimately add to humanity’s well-being. Third: There is a growing awareness that doctors and medical care are not the major con- tributors to improve health status in the soci- ety as a whole. More and more people are say- ing, as though it is a most striking insight, that improved economic conditions, housing and an enhanced quality to urban and rural life are far more important contributors to improved societal health status than is classical medical care. The distressing aspect is the large number of people who feel let down by this consideration. Fourth: Health policy issues are inextric- ably interrelated. For example, one cannot re- ally solve the manpower problems we face without giving due attention to the financing and organizational questions as well. And one cannot talk about new modes of clinical prac- tice without anticipating future research policies and results. Now, to some specific issues. The Insti- tute of Medicine found the broad issues of sci- ence policy to be the most difficult to address effectively. How much of our overall health budget should be invested in research in the natural and social sciences basic to health? How much of that budget should go to the so- cial and behavioral sciences? What proportion should go to basic, untargeted research? How much will be needed for practical, clinical ap- plications? It is no secret that it has been ex- ceedingly difficult in recent years for the scien- tific establishment to frame its arguments and budget justifications such that they continue to compete as successfully as in the past for the Federal dollar with other claims on the budget. In the end, it may simply be a question of human values: how much we, as a society, are willing to invest for the development of new knowledge, often for the benefit of future gen- erations. If so, then it behooves those of us who value research highly to increase our ef- fort to reach individual legislators, for it is at the committee table and on the House and Se- nate floors that votes are cast which reflect our priorities and values. Beyond these broad considerations in sci- ence policy, I see pressures building which may have major influence upon the distribution of dollars under the “Research” rubric. Archie Cochrane, the author of the influential little book, “Effectiveness and Efficiency,” and a world famous proponent of the randomized clinical trial, has been saying for 40 years in England that the government should pay for all care that has been proven effective. Like most challenging and stimulating people, Ar- chie has a way of speaking in hyperbole which, at a certain level, leads one not to take him very seriously. But now I believe the stage is set for just such a situation as his words imply. Allow me some poetic license to spin out a pos- sible scenario for you. The PSRO’s are likely to be in place in every state on a voluntary basis before January 1, 1976, the date set by law for the implementation by the Secretary of HEW. Despite the damaging cutback in PSRO fund- ing now in the legislative works, there is no reason to doubt that some “machinery” will be in place everywhere in the United States within a year or so. National Health Insurance will go through—perhaps by degrees—and of- fers eventually to provide comprehensive care for all segments of our population. It is quite clear that budgetary restraints will be estab- lished so that, in fact, the government simply will not have the money to pay for all the care that is rendered. Who will decide what is worth paying for and what is not? On what grounds will a decision be made that a new op- eration has been proven effective enough to warrant payment by the National Health In- surance Program? Taking these thoughts one step further, questions of efficiency and cost- effectiveness will also be asked. For example, will society find it worthwhile to outfit every hospital with the latest and most advanced anesthetic technology without knowing quite precisely how much of an advantage in morbid- ity and mortality the new technology will bring? The “discovery” by our culture of acupuncture and its practice in a strange and exotic foreign land has been characterized first by great enthusiasm for its benefits and now, more gradually, a highlighting of its deficien- cies and drawbacks. The result is that studies are underway to make an assessment as to whether its effectiveness in specific situations is sufficient to warrant inclusion in our health care armamentarium. Surely, if there were no tradition of manipulative therapy in the west- ern world, and if chiropractic were an ancient Chinese art, then I suspect that we would be treated to the same process as regards chiro- practic. In fact, isn’t it true that inevitably such studies of manipulative forms of therapy will be called for and probably warranted? We might even learn something! What I am implying in all this is that studies of effectiveness and efficiency, whether they be randomized clinical trials or not, will need to be greatly expanded, de- veloped and refined. The entire area of health services research will need to grow and the other elements within the research budget will inevitably be feeling the subsequent squeeze. My own fervent hope is that such develop- ments do not lead to a sort of internecine com- petition among elements of the academic com- munity, each belittling the activities of others. Rather, I would hope that we can all work to- gether towards the allocation of enough money to meet all our legitimate needs. I would like now to turn to some health manpower issues. As many of you will know, the Congress has asked the Institute of Medicine, NAS, to carry out a huge study on teaching hospital funding of postgraduate edu- cation programs in the United States. This $4.3 million dollar study, to be completed by March 1976, is referred to at the IOM as the “Social Security Study.” The study arose out of the turbulence created by the Social Security Administration when it established a new guideline, that teaching physicians would be paid for service rendered to patients financed by Medicare or Medicaid. This new guideline is temporarily being placed aside pending the re- sults of the IOM study. Thus, this SSA study is widely believed within the academic commu- nity to be aimed at determining how teaching physicians are to be paid; but the agenda for that study is far more comprehensive than that. When the study idea first developed within the Senate Finance Committee, I un- derstand that the House Committee on Ways and Means, thinking in the terms of a com- prehensive National Health Insurance plan, got interested in how the financing mechanism might be used to influence the production and geographical distribution of specialists. Also, there is an explicit provision dealing with foreign medical graduates, who filter into the United States system through the teaching hospital. Thus, the law in effect asks that the study determine whether the use of SSA funds contributes to the maldistribution of physi- cians by total numbers and by geography, how they are used to support the education of FMGs, and how distribution of such funds might be used to modify these matters. In the proposed current manpower legisla- tion, there is now an additional study calling for the IOM to develop manpower projections by specialty needs for the years 1980, 1985, and 1990. The implications of these studies are obvious, and objective professional input is badly needed. For example, simplistic all or none solutions to the FMG “problem” may not prove to be in our own best interests. Some specialty areas, and perhaps anesthesiology is among them, are underserved by American graduates, and may therefore have a genuine need for competent FMGs. If this is true, then these kinds of judgments must get into the policy-making process. One last point on the manpower and health care organization issues relates to the distribu- tion of manpower resources. There are several proposals at various stages of development aimed at getting doctors into underserved areas. One is, of course, the establishment of the National Health Service Corps. Another relates to indentured service for all physicians: a kind of domestic, peacetime draft for doctors only. Still another alternative calls for financial inducements such as educational loan forgive- ness. This latter proposal would, in effect, mean that well-to-do students would escape all participation in efforts to solve these prob- lems. All of these ideas involve, I believe, seri- ous ethical, legal and human value concerns and should make for a lively national debate, in which professional participation would be very much in order. It should be noted here, in passing, that policy makers in the United States are paying increased attention to how Canadians have handled some of the problems we are just be- ginning to address. Dr. John Evans of Toronto, in a major address on manpower issues at the IOM last spring, laid great emphasis on the apparent success of the Canadians in filling the underserved areas. Two initiatives he thought most effective were: 1) the establishment of local health councils which must give their ap- proval before a physician can open an office in a given locale (thus presumably preventing an over-concentration of physician services); and 2) the identification of underserved locales and the provision of “seed” money to help a new physician establish a practice there. Suffice it to say, influential policy-makers in the United States are well aware of these Canadian initiatives. The legislation concern- ing regional health councils in the United States is a beginning step in this direction. Again, informed professional opinion, particu- larly if proposed from the public interest perspective, is badly needed and will be most useful and welcome. I am reasonably certain that in the relatively near future we will see the establishment, not only of regional health councils, but of a national health council as well. Development of Clinical Anesthesiology Now let us turn to consideration of anes- thesiology as a particular clinical specialty, to point out its importance and its needs as one of the many areas of medicine placing demands on finite dollars and manpower resources. In ad- dition to the preceding comments, we need as background a brief overview of the develop- ment and current status of this specialty. Al- though this is well known to most of you, I and some of the audience, as well as the Congress and the public at large, need this information as a framework for the discussion of current problems and future needs. The introduction of surgical anesthesia in the 1840's is considered one of the milestones in the annals of medicine and the first and most important factor in the early development of surgery. Although numerous surgical opera- tions had been conceived decades and even centuries earlier, only a few urgent life-saving procedures were done. Most operations had not been attempted because the shock of surgi- cal pain was responsible for a 20% mortality rate. Despite the obvious importance of the new discovery, which Osler later described as “medicine’s greatest single gift to suffering humanity,” and the admonition of John Snow and other pioneers that these potent agents should be administered only by trained per- sonnel, for half a century this task was rele- gated to untrained people—an orderly, nurse or medical student. Consequently, improperly administered anesthesia was a major cause of death or complications among surgical and obstetrical patients. It was not until the turn of the century that nurses and a very few physi- cians began training and specializing in this field. During the ensuing four decades the in- crease in the number of physician-specialists in anesthesia was disappointingly small, totalling less than 1,000 in 1940. This period was marked by many scientific and technical ad- vances made by physiologists, phar- macologists, and a few surgeons and anes- thesiologists; but unfortunately, because of a lack of competent personnel, many of them were not widely applied to improve anesthetic care in the United States. World War II gave anesthesiology its first real impetus to rapid growth. The disastrous results with anesthesia administered by un- trained personnel during the early part of the war prompted activation of intensive training programs in military and civilian hospitals. Following the war, many physicians whose interest in anesthesia had been stimulated by their military experience sought formal train- ing. Consequently, during the past three dec- ades the number of anesthesiologists in the United States has increased over twelve-fold. Even more impressive than the growth in numbers has been the increase in breadth and scope of the specialty. Initially, the task of the anesthesiologist was limited to the administra- tion of anesthesia, but, as surgeons came to appreciate the specialized knowledge and unique skills of the anesthesiologist in main- taining ventilation, circulation, and other vital functions, they began to relegate more and more responsibility. This trend first took place in the operating room and then was extended to the preoperative and postoperative man- agement of patients. This type of total anesthetic care had a major impact on surgical practice, for it has been critical to the success of open heart surgery, lung and brain opera- tions, organ transplantations, radical opera- tions for cancer, and surgery on the critically ill, the very old patients, and very small in- fants. It followed logically that the same knowl- edge and skills could be used to great advan- tage in the management of patients with acute or chronic respiratory disease or those who are critically ill and require support of vital functions with artificial ventilation and so forth. Anesthesiologists have provided lead- ership in the development of modern intensive care units, in managing patients with pain of cancer and other chronic pain states, and in providing better and safer care during childbirth. Today, the role of the anes- thesiologist extends far beyond the operating area. Development of Academic Anesthesiology Despite impressive gains, it became ap- parent by the early 1960's that the long sought goal of providing optimal anesthetic care for the American people would not be achieved without rectifying a number of major deficien- cies. Of these, two interrelated problems were particularly important: decline in recruitment of American physicians into the specialty, and a great lag in the development and growth of academic anesthesia in the United States. Dur- ing the period of most rapid growth in the number of clinical anesthetists, anesthesiology in most universities remained grossly under- staffed and its activities were limited to clinical services. In 1960 there were fewer than 200 full-time academic anesthesiologists, and of these less than 10% had research training. Ex- cept for programs in a few medical schools, sci- entific research by anesthesiologists was non- existent; teaching programs for medical stu- dents and anesthesia residents were also in- adequate; and even clinical services not in- frequently were inferior to those given in pri- vate hospitals. All of these factors diminished anes- thesiology’s attractiveness to medical students and physicians who might consider it a field for specialization. In retrospect, this was not sur- prising because a medical specialty that is not backed by vigorous research and teaching ef- forts of its own has serious trouble in the fierce competition for bright medical graduates in this science-conscious era. At a time when many other clinical disciplines were developing strong research teaching programs in most universities, anesthesiology failed to gain sci- entific maturity and respect. Thus, academic anesthesiology remained a scientifically de- prived discipline, which led to what Dr. Henry Beecher termed “a parasitic existence,” de- pending on basic scientists to obtain critically needed information and to give research train- ing to a few interested individuals. The Crisis in Anesthesiology Although the shortcomings of academic anesthesiology were apparent during the 1950's, they became progressively more prom- inent during the early 1960’s. During this period the number of American graduates who went into anesthesiology declined. This lag in recruitment during a period of rapid popula- tion growth, the ever-expanding horizons of surgery, the progressively longer and more radical operations along with the non-surgical activities, widened the gap between the need for, and the supply of, anesthesiologists. Moreover, because of the severe shortage of academic anesthesiologists, the acquisition and rapid application of new knowledge essential to diminish mortality and morbidity also lagged in a very disappointing fashion. By the mid- 1960's these deficiencies progressed to such proportions that medical leaders were promp- ted to declare a “crisis in anesthesiology.” This crisis spawned the development of several programs intended to help rectify the situation. Besides major programs mounted by the American Society of Anesthesiologists, the most important corrective measure was the expansion of support for research and training initiated by the National Institute of General Medical Sciences in 1966. Dr. Emilie Black, our conference chairman, will soon describe this program in detail. Therefore, I will simply say that the evidence suggests it has been very productive. Indeed, output of the expanded training program now constitutes a new gen- eration of anesthesiologists providing vigorous leadership in research, teaching, and the appli- cation of scientific knowledge to patient care. NIH research support has also played a very important role in the recent development of academic anesthesiology in a number of uni- versity medical centers. Research centers supported by the NIGMS have been especially effective. Though barely eight years old, these centers have transformed academic anes- thesiology in their institutions from a purely service discipline to one that is contributing significantly to fundamental science and pro- viding badly needed information for better anesthetic care. Equally important, the re- search centers have markedly improved the capability of their departments to attract more physicians and to train them as anes- thesiologists. This impact is easily illustrated by the ef- fects on our own anesthesiology program at the University of Washington. The NIH program has directly supported the research training of 13 of our faculty and the research career de- velopment of three more. It also enabled the training of 18 others who are now members of other medical centers. And by helping to im- prove the academic environment, the program has helped us attract other well-trained academic anesthesiologists and basic scien- tists. Thus, our research center has greatly enhanced interaction and active collaboration among some 20 basic scientists, 25 anes- thesiologists, and a dozen clinicians from other various disciplines. Furthermore, increased NIH support and consequent improvement in various aspects of our program prompted a comparable increase in support by the School of Medicine and the University. In short, our Department’s increased scientific capability has helped improve teaching programs for stu- dents and anesthesia residents which, in turn, has increased the program’s ability to attract more bright young physicians to the specialty. I've been told that four other NIGMS-aided anethesiology research centers have had simi- lar experiences. What do these programs in anesthesiology mean in terms of health care for the American people? Anesthetic care in this country has im- proved in both quality and quantity as a result. Availability of a larger faculty permits the training of more and better anesthesiologists. Again using our own program as an example, it has trained nearly 40% of the anesthesiologists practicing in the state of Washington, plus many others in the Northwest and other parts of the United States. Consequently, hospitals which 15 years ago had no anesthetic services currently have an ample number of anes- thesiologists who provide surgical, obstetric, and medical patients with expert care. Current Status These are impressive gains indeed, but un- fortunately they are insufficient to achieve the ultimate goal of safe anesthesia for all the American people. Although accurate statistics are not available, it is estimated that 15,000 to 20,000 deaths related to anesthesia still occur annually among surgical and obstetric pa- tients. Some of these are due to the radical and complex nature of the operation, but even here anesthesiologists, through their expanded role in the operating room, should help decrease them. Most anesthesia-related deaths are due to improper administration or other errors and are therefore preventable. Improperly ad- ministered anesthesia remains the fourth most common cause of maternal mortality and prob- ably plays a role in newborn mortality and mor- bidity contributing to cerebral palsy and men- tal retardation. Why do these serious deficiencies exist and detract from the overall achievements? The reasons are several and interrelated. For one thing, in many instances the knowledge cur- rently available, both old and new, is not prop- erly applied. This, in turn, is due to insufficient numbers of well-trained anesthesiologists and nurse anesthetists, inadequate equipment and technology for monitoring, and inadequate training of anesthesia residents and nurse anesthetists in all too many teaching pro- grams. Currently, anesthesiologists adminis- ter only about 40% of the surgical anesthetics and less than 20% of the obstetric anesthetics, while nurse anesthetists administer 35 and 30%, respectively. This means that 25% of sur- gical anesthetics and one-half of obstetric anesthetics are administered by people not trained in anesthesiology. Another significant factor is that we still have an inadequate number of academic anes- thesiologists who are able to do high quality anesthesia research. Despite impressive ad- vances in the last 20 years, anesthesiologists themselves have played a relatively secondary part in the scientific productivity of their spe- cialty. Chemists, pharmacologists, engineers, and other scientists were generally the creators; anesthesiologists, in the main, only applied the new knowledge. This is, of course, a natural and proper function of clinical anes- thesiologists, but it means that the pace of ad- vance has been dictated principally by dis- coveries in other areas. It seems to me that such a state of affairs is not satisfactory, that it has retarded and continues to retard progress, because work done in a sister science is too sel- dom directed at anesthesiologic problems as such. Anesthesia laboratories ought to be ca- pable of undertaking their own research design and development. Another intimately related reason for the deficiencies in anesthetic care is that in many areas there are critical voids in knowledge. Presumably, these will be defined during to- morrow’s session. Future Needs Obviously, to correct the deficiencies it is essential to increase the number of well- trained academic anesthesiologists who devote their efforts to teaching scientific anesthetic care and to doing individual and collaborative research. While gains made by the country’s five research centers are impressive, these are not enough. Using the collective experience of these centers as models, we must develop simi- lar research centers in several other univer- sities and nurture research and training pro- grams in still others which do not have them. Only through such improvements will it be possible to recruit the better American graduate into anesthesiology and to achieve a more widespread improvement of anesthesia training in the United States. Equally impor- tant, an increase in academic anesthesiology programs will facilitate the more rapid trans- fer of new scientific information and technol- ogy from the laboratory to the care of patients. These types of expanded programs in re- search and teaching will require adequate funding by the National Institutes of Health and other research agencies and ample re- sources by universities. As one of the least academically developed clinical specialties, anesthesiology should receive sufficient sup- port and be permitted to achieve academic maturity and its full potential in research, teaching, and patient care. Because the needs of anesthesiology must be considered within the framework of the broad societal need in health care, the participants of this workshop have the onerous task of defining these needs in specific and quantitative terms. I wish you success. THE NIGMS ANESTHESIOLOGY PROGRAM—HISTORY AND PRESENT STATUS EMILIE A. BLACK In October 1962, Congress authorized the establishment of the National Institute of Gen- eral Medical Sciences to conduct and support research and research training in basic medical and related applied sciences, which would con- tain research of interest to two or more categorical institutes or would be outside the general areas of responsibility of another insti- tute. Until new programs could be organized, the Institute continued to support many of the program areas funded by its predecessor, the Division of General Medical Sciences. These programs included anesthesiology, general surgery, pharmacology, and biomedical en- gineering. The anesthesiology program at that time consisted of eight research grants and two program projects with funding at the level of approximately $350,000 per year. Under the aegis of the new Institute, the program ex- panded, and by 1965 anesthesiology research was supported at a level of $1.2 million, includ- ing three program projects. In 1966, as part of the Heart Disease, Cancer, and Stroke Act, the Congress pro- vided $4.5 million in supplementary funds to the Institute for support in areas where new knowledge and technology were urgently needed. Anesthesiology was one of these areas. Following this Congressional mandate, the Institute held a meeting of the Nation's leading anesthesiologists to identify major problem areas in this field. These recommen- dations ensued: 1) Identify and study the sites of anesthet- ic action; 2) Study anesthetic action at the molecu- lar level; 3) Develop better anesthetic application methods; 4) Improve conduct of anesthesia involv- ing refinement of equipment to incorpo- rate fail-safe design, to permit better control of important variables, and to achieve maintenance-free operation; 5) Improve anesthetic agents; 6) Investigate pulmonary function and re- lated problems; 7) Develop improved nerve impulse blockers; 8) Observe visceral functions in anes- thesia. To begin implementing these recommen- dations and step up its anesthesiology pro- gram, the Institute appointed Dr. Emmanual Papper as a consultant-in-residence for six months. Attention was given to mechanisms for stimulating applications for research, train- ing, and fellowships in anesthesiology. Concept for Centers The Institute sought to intensify this re- search by establishing centers to carry on the work. It was decided that from a practical viewpoint only a few of these research centers, probably not more than four or five, would be established. The following set of criteria was used in planning the center research program: e The center should be a university-based research activity with free access to clin- ical material appropriate to its research and training roles. e The multidisciplinary research pro- grams proposed in the application should be those probably of long-term duration and of central importance to anes- thesiology. e Opportunities should be provided for multidisciplinary, collaborative pro- grams of research and training involving basic sciences and clinical disciplines. e The center director and staff should provide scientific leadership of the high- est quality. e The senior scientific personnel should be able to commit a significant fraction of their time to the activities of the re- search center, and should have univer- sity appointments in departments re- lated to their primary discipline. Simi- larly, appointments to the research cen- ter should be open to qualified univer- sity faculty wishing to collaborate in the research programs of the center. Quoting the Anesthesiology Advisory Committee’s Report: “The main thrust of the center's activities should be one of problem- solving. The research and research training aims of the program undertaken at these cen- ters would be of such nature, breadth, and scope in anesthesiology as to best satisfy the public health needs of the nation and serve as a focal point for such activities in the region in which the research center is situated. While these grants would not provide for construction, they should promote collabora- tive programs of research and training involv- ing other universities, government agencies, and independent research institutes in the area.” In 1967, the first anesthesia research cen- ter was awarded to the University of Pennsyl- vania under the direction of Dr. Robert Dripps. This was an outgrowth of a program project which had been supported by NIH funds for five years. Three anesthesia research centers were established in 1968, at Harvard, University of Washington, and Columbia University College of Physicians and Surgeons. A program project at the University of California’s San Francisco Medical Center was designated a research cen- ter in 1973. These research centers have continued to be supported, have closely followed the criteria set down by the Institute, and have become major resources for training and re- search in the field of anesthesiology. All have been reviewed for a second granting period. Also, the Institute currently supports 16 proj- ect grants. Many accomplishments in anes- thesiology have sprung from these research centers and projects. Complex operations such as open heart surgery are possible only be- cause new anesthesiology techniques enable a patient’s vital functions, breathing and blood flow, to be controlled for hours. New anesthet- ics have virtually eliminated the period of ex- treme nausea, intense headache, and weakness which patients formerly suffered following most anesthesia. Muscle relaxants, which do not depress the functions of the rest of the body, have become essential surgical aids. 10 Anesthesia equipment has progressed to the point where the anesthesiologist regulates the exact amounts of several anesthetics being administered to the patient. Monitoring in- struments enable him to closely observe the patient’s condition and to vary the depth of anesthesia or assist the patient’s breathing. A fail-safe method of administering anesthetic agents prevents toxic overdoses. The skills and techniques plus the equipment of the mod- ern anesthesiologist enable him to expand his role beyond operating rooms and intensive care units to the care of patients suffering res- piratory failure from accidents, poisoning, as- phyxia in the newborn, and other causes. Critical Gaps in Knowledge Despite the impressive development in clinical practice, anesthesiology research has not kept pace and still is modest in scope, due largely to the fact that the field has not in- terested many scientists. As a result, there are still critical gaps in the knowledge of anes- thesiology. The mode of action of many single anesthetics is not completely clear. There is a continued need to evaluate the use of anesthet- ics from the standpoint of dosage, toxicity, and patient recovery. New and improved anesthe- tics are being developed and tested, and there is a need for further testing of some anesthe- tics already in use. The design of new devices could enable the anesthesiologist to extend his services to the care of more patients. Present day operating room equipment could be im- proved, permitting better data processing and retrieval. A Fiscal Year 1974 assessment of the NIGMS anesthesiology program revealed little opportunity for the Institute to nurture new research. This was due in part to a paucity of new applications, and also to a tendency for the research to be categorized into disease areas and thus fall within the purview of other insti- tutes. Also in FY ’74, the status of the anes- thesiology program reflected the necessary budget reductions which occurred in all pro- grams. During the past few years, the Institute concentrated on several areas related to anes- thesiology: Pain and Acupuncture. An NIH sponsored international pain symposium was held on May 16-21, 1973, at the University of Washington School of Medicine. The sym- posium brought together 60 international au- thorities who were doing important scientific research on pain. Following this meeting, a few applications were received by NIH in the areas of neurophysiology, psychology, and the emotional aspects of pain. With regard to acupuncture research, the Institute was assigned by the Director, NIH, the task of evaluating its merits and, if jus- tified, coordinating a research program. A two-day acupuncture meeting was held at NTH July 17-18, 1972. The guidelines set forth were that NIH should support acupuncture research in the areas of surgical anesthesia and chronic pain, make a comprehensive survey of the lit- erature, and hold a workshop to discuss the current state of the art. On February 28 and March 1, 1973, the NIH held its first acupuncture research conference. The results of this meeting have been published. To date 39 applications on acupuncture have been sub- mitted. Of these, eight have been approved and are or shortly will be funded. In addition, there is continued interest by the Institute in the pharmacokinetics of 11 anesthetic agents, in new instrumentation for inducing and monitoring anesthesia, obstetri- cal and neonatal anesthesia, metabolic effects of anesthetics, and the relationship of projects on anesthesiology to trauma research. Also, tentative plans for the NIGMS include in- creased emphasis on needed areas of anes- thesia research such as: pain control with em- phasis on regional anesthesia, neurophysiolog- ical studies of the molecular basis of general anesthesia, bioengineering approaches to anesthetic administration, drug interactions, the influence of anesthetics and various drugs on organ systems, and acupuncture. The purpose of the workshop is to provide the institute with a complete national picture of the present state of the art in anesthesiology and a set of recommendations for future re- search priorities. Future programming activ- ity, with your help, will be devoted to improv- ing the quality and quantity of research for a safer method of anesthetic administration. Armed with such knowledge, clinicians will hopefully be better equipped to cope with the many challenges which they will be en- countering in the years ahead. I. PAST ACCOMPLISHMENTS AND STATE OF THE ART IN ANESTHESIOLOGY RESEARCH PANEL DISCUSSION: CURRENT RESEARCH Central Nervous System, Local Anesthesia, Neuromuscular Research, Metabolism, Drug Disposition, Respiratory Studies, Cardiovascular System, Mechanisms of Anesthesia, Pain Research, Acupuncture Analgesia RICHARD J. KITZ, Moderator John W. Severinghaus, Rudolph de Jong, Leonard F. Walts, Nicholas Greene, Russell A. Van Dyke, Theodore C. Smith, Myron B. Laver, Edmund I. Eger, John J. Bonica, Kenneth L. Casey, Panelists DR. KITZ: Today's discussion addresses itself to Past Accomplishments and Current State of the Art. The use of the word ‘Art’ in conjunction with what we assume is a scientific discipline initially struck me as rather unfortu- nate. But indeed, in its beginnings the practice of anesthesiology was more artful than scien- tific and virtually all of the fundamentally im- portant discoveries in our field were made by pharmacologists and physiologists—the anes- thetist was only concerned with their applica- tion to clinical situations. When did the specialty begin to assume responsibility for developing its science? It’s hard to say but perhaps the primary change was levied in 1950 by Dr. William T. Salter, Professor of Pharmacology at Yale. He wrote an editorial in Anesthesiology titled “The Leaven of the Profession,” holding that no pro- fessional science could maintain itself on serv- ice alone. There has been a tendency, he noted, to “pass the buck” to the professors of physiol- ogy and pharmacology in the vain hope that the answer could be learned from monkeys and mice. “The applied pharmacologist must do this—one familiar with the everyday practice of anesthesia. To this end, there must be de- veloped a group of so-called anesthesiologists with special training and the license to address the basic concepts of an applied science.” Fortunately for our specialty, the chal- lenge was accepted by vigorous men in univer- sity centers: Waters at Wisconsin, Cullen at Iowa, Dripps at Pennsylvania, Papper at Co- 13 lumbia, Rovenstein at New York, and Beecher and Vandam at Harvard. The beginnings of science in our specialty, then, are of relatively recent vintage, starting in these universities and now spreading to many more. With only a few exceptions, this panel will deal with our past contributions and current research ef- forts. CENTRAL NERVOUS SYSTEM DR. SEVERINGHAUS: The territorial borders in research land are unguarded be- tween anesthesiologists and physiologists in- vestigating respiration, circulation and the central nervous system. In practice, what interests anesthesiologists we call anesthesia research. I will review five CNS fields of in- vestigation invaded and perhaps dominated by our profession, other than the central regula- tion of respiration and circulation. I am almost delighted to avoid respiration, a current battleground between high altitude physiologists and anesthesiologists, some of the former assaulting the bastion of controlled spinal fluid pH as the unique stimulus of Mitchell's chemoreceptors. Instead, I have selected cerebral circulation, EEG, elec- tronarcosis, psychologic studies and anesthetic protection against stroke for review. For a decade, cerebral circulation investi- gation has centered around a Scandanavian- based organization whose members have come to be called the Cerebral Blood Flowers. Many of them sprouted in anesthesia departments here and abroad. The last meeting, co-hosted by the Anesthesia and Neurology Departments of Pennsylvania and published in Stroke, showed the impact of a decade of interchange of ideas between disciplines. Discussions at former meetings led to the concept that high PCO2 might do more harm than good in provid- ing blood flow to ischemic brain (i.e., the pos- tulated Intracerebral Steal of blood by healthy tissue from damaged, fully dilated but poorly perfused regions; and from this to the Robin Hood Syndrome, at first only a theory but now translated into data, showing that deliberate reduction of PCO2 below normal can safely re- duce flow to normal areas, lower intracranial and venous pressures, and offer more perfu- sion to the still acidotic, dilated, damaged “poor” brain regions). One result was a revolu- tion in management of anesthesia during carotid endarterectomy. The “stump” pressure in the internal carotid artery distal to the oc- clusion is higher with hypocapnia than with hypercapnia. Direct measures of flow in is- chemic areas have not always been able to show these effects, possibly because regional flow analysis depends on washout of radioac- tive indicator which poorly labels such areas, making them almost invisible. The effects of various anesthetic agents on cerebral blood flow and its regulation is of im- portance in managing surgical anesthesia. Smith has shown that halothane, ethrane and forane, in spite of their different effects on CBF, all increase venous and presumably tis- sue PCO2 in direct proportion to the depth of anesthesia (MAC), suggesting first that a mechanism exists for regulating tissue PCO2 and, second, that when this mechanism is de- pressed by anesthesia, PCO2 rises; that is, its usual operation is to hold tissue PCO2 down. He and others found that autoregulation of CBF is not impaired by anesthesia, revealing that CBF is independent of blood pressure over a wide range. Smith then showed that a step rise in arterial halothane concentration produced a gradual rise of CBF which closely paralleled sagittal sinus blood rather than arterial blood halothane concentration, suggesting that the vasodilation depends more on the tissue than the arteriolar smooth muscle concentration. Arteriolar ECF pH has come to 14 be recognized during the last decade as the prime regulator of CBF, this being the pre- sumed link between metabolism and local flow. These results and other evidence point to another possible O2-dependent control. For example, high arterial pPO2 may impede sur- vival of devascularized brain, perhaps by con- stricting anastomotic vessels. Ketamine greatly increased CBF while slightly reducing brain metabolic rate. Only the barbiturates permit flow to fall in proportion to metabolism, such that tissue PO2 is constant or slightly reduced. This implies a better preserved link- age of local flow to metabolism, and may be the key to barbiturate protection of ischemic brain. Acute tolerance to thiopental develops within hours. with both flow and metabolism returning more than half-way to normal at con- stant blood thiopental levels. Stroke Therapy The old concept that three minutes of is- chemia or anoxia killed brain has given way to evidence that survival depends on a complex series of subsequent events in the microcircu- lation, and that post-insult therapy can save tissue. After ischemia, reperfusion of brain is non-uniform. Factors include potassium in- duced spasm, edema which increases local tis- sue pressure and collapses some capillaries, in- travascular clotting, and total vasodilatation, such that the limited inflow can only perfuse a small fraction of capillaries. Both barbiturate anesthesia and hypocapnia have been shown to promote survival of brain after anoxia or cere- bral arterial occlusion. Efforts to exploit such therapeutic possibilities in various brain in- juries are under way in many laboratories at present. However, the implications are not clear cut since hyperventilation did not protect rhesus monkeys when it was begun an hour after vessel ligation; it also exacerbated brain lactacidosis and ATP depletion two hours after arterial occlusion in squirrel monkeys. And while deep pentobarbital anesthesia virtually prevented infraction after vessel ligation (mid- dle cerebral artery) in dogs, it did not in ba- boons. Nor do barbiturates or inhalation anesthetics slow metabolic depletion of ATP during total (decapitation) anoxia, while hypothermia does. Other factors which may be therapeutic are hypothermia, osmotic and adrenal corticoid reduction of edema, elevation of arterial pres- sure, epinephrine administration (to promote reperfusion by blocking potassium induced vasospasm) and decompression. Anes- thesiologists have pioneered most of these studies both to improve their management of surgical patients, and because stroke therapy, if proved useful, will demand cardiorespiratory management skills like those employed in surgery and intensive care. Thus they have de- termined the effects on CBF and cerebral metabolism of virtually all the anesthetics, ad- juvant drugs and procedures. However, little is known about how these factors interact, especially in abnormal states, and how they af- fect long-term tissue survival and function. EEG and Anesthesia Early efforts to use human surface elec- troencephalogram as a measure of anesthetic depth have given way to analysis of the nature of anesthetic effects on various brain strue- tures, the sequence in which actions occur, and the responses evoked by stimuli. These have been facilitated on the one hand by the avail- ability of patients with chronically implanted electrodes (for seizure localization), and on the other by computer technology permitting the computing of average transients (CAT) in the period following some regular electrical stimulus (cutaneous, auditory or visual). This has permitted visualization of cortical and other very weak responses, normally swamped by EEG activity, and has demonstrated differ- ences in the nature of effect of various anesthetic agents. The investment of time in these researches has been vast: Clark and Rosner cite 295 studies in their review of Neurophysiology of General Anesthetics, omitting ketamine and noting that data are far from complete except for barbiturates and ether. Perhaps the most important insight gained is a recognition of relationship between chemi- cal structure and “Increasing CNS Irritabil- ity,” derived both from EEG and evoked re- sponse studies. The relationship permits pre- diction of the anesthetic characteristics of other agents. Two agents now in common use regularly induce epileptiform activity in elec- trical recordings, usually without manifesting motor phenomena. They are enflurane and ketamine. Both enhanced evoked responses while most agents suppress them. Barbitu- rates suppress the non-specific, later-evoked responses, but not the early specific responses. The depth electrode recordings of ketamine effects show seizures in neocortex and hip- pocampus, and other signs of stimulation, lead- ing Kayama and Iwama to suggest that it ob- tunds consciousness in a manner analogous to petit mal seizures. Although isoflurane (Forane) is almost as irritating as enflurane in Clark and Rosner’s tabulation, it does not in- duce electrical seizures. Evoked responses seen with the more irritant agents suggest that the anesthetic state is not so much “anesthe- sia” as interference with memory and motor response. Perhaps EEG studies will eventually help us understand just how much information processing does occur during anesthesia, but it will surely remain for psychologists to discover to what extent such information is deposited in memory which ultimately may impact itself upon unconscious behavior. Psychologic Effects Psychologic and psychiatric investigations on the impact of anesthesia on patients must be regarded as inadequate. The use of ketamine has stimulated interest, and has led to the search for agents which “cover” the hallucina- tions during emergence. Similar problems occur during emergence and perhaps induction with halogenated hydrocarbons, but only fragmentary findings have been reported. The highly traumatic experience of open drop ether induction in children is well-known to leave a life long terror-recall at the smell or even thought of ether; surely this is a far more significant trauma than pain. Induction ex- citement is reported to involve a death experi- ence, with massive activation of autonomic phenomena, and the imprinting of a fear re- sponse that later can occur over and over again. The occasional recall by a patient of traumatic comments (more than pain) during anesthesia (even without relaxants) suggest that cerebration continues sometimes deeper than MAC, and that anesthesia may be more an inhibitor of recall than of experience. Objective measures of performance and subject studies of the impact of anesthesia 15 alone (cyclopropane in volunteers) suggest that a three-day post anesthetic period of some impairment occurs. The more lipid soluble agents may be presumed to linger longer. Kornfeld’s review of psychiatric aspects of anesthesia deals primarily with the environ- mental and personal rather than pharmacologic factors which traumatize patients. Perhaps more attention is due to the nightmares and anxieties which may persist in some patients during subsequent months or years after a de- lerious induction or emergence. Electronarcosis A subcommittee of the National Research Council is currently reviewing some 500 refer- ences, mostly Russian, on electrically- facilitated sleep and anesthesia, respecting the licensing of apparatus for commercial use in the United States. Evidence is sufficient that passage of certain forms of pulse trains through the scalp of animals and man can con- tribute to the anesthetic state safely. It has not been possible to induce surgical anesthesia in man using electrical stimulus alone, without either pain or convulsions, and for this reason there is little present interest in this field. I regard this as unfortunate, since it seems probable that electronarcosis could be a safe supplement to nitrous oxide after conventional pharmacologic induction and might have some advantages over halogenated hydrocarbons used so routinely. Like N20, electrical current in a safe (non-convulsive) range provides less than the normal anesthetic requirement (MAC) in man. A large variety of currents have been used, the most common now being 1 msec pulses at about 100Hz, and average currents up to 40 ma, often with a DC bias. Phar- macologic intervention appears needed to avoid cardiac slowing or arrest, hypertension, and increased muscle tone. Electrodes are placed either front and back or side to side on the head. Recovery after discontinuance of current appears to occur in seconds. The evi- dence leads me to believe that more research in man is warranted. LOCAL ANESTHESIA DR. De JONG: To bring some order to a diffuse topic, I have arranged the local anes- 16 thesia material into broad categories. While focusing on current status, progress and new directions, some introductory material seems essential to link past, present and future. Pharmacology The local anesthetic properties of cocaine were demonstrated less than a century ago. With cocaine’s chemical structure elucidated, synthesis of less toxic derivatives became pos- sible, culminating in the introduction of pro- caine at the start of this century. Subsequent development of literally hundreds of new com- pounds has yielded increasingly better drugs, with lidocaine another landmark at mid- century. Currently, the classic anes- thesiophoric structure seems to have been largely mined out; few earthshaking break- throughs are in prospect. To render the local anesthetic base more stable and water-soluble, a salt (commonly the hydrochloride) is marketed. In aqueous solu- tion, the salt dissociates into uncharged bases and positively charged quarternary amine ca- tions. A key feature of local anesthetics, estab- lished by recent research, is that only the charged cationic species is neurally active. However, the uncharged lipid soluble base is equally essential as this is the mode in which the drug is moved from site of injection to site of action. Dissociation is governed by the drug’s unique pK, which, together with am- bient pH, determines the cation to base ratio. One intriguing departure from presently- used formulations is the synthesis by Swedish investigators of a tertiary amine that, through structural rearrangement, forms a positively charged cyclic cation within a nerve fiber. The cation, by virtue of its charge, cannot diffuse outward and remains trapped intra-axonally, so providing long-lasting blockade. This par- ticular chemical approach may have important ramifications for long-lasting pain relief. Local anethetics are readily leached from their contact site, being lightly held by ionic and hydrogen bonds, and other lesser-known electrochemical attractions. Pending new de- velopments in membrane chemistry, the anesthetic receptor configuration remains un- certain. Local anesthetic blockage is reversi- ble, as distinct from the permanent block by destructive agents such as phenol. Clinically and physiologically, local anesthetics leave the nerve no worse for the experience, and normal conduction is resumed without evident func- tional defect. Even nerves kept in contact with local anesthetic for weeks on end recover quickly once the drug is removed. More subtle changes in membrane and neural structure can be demonstrated with anesthetic concentrations exceeding the minimum blocking concentration. Electron microscopic changes are reported from time to time, and rapid axonal transport is slowed, and even halted, for the duration of the block. Further, local anesthetics can interfere with the normal immunologic and phagocytic func- tions of scavenger tissue elements. While local anesthetics predominantly af- fect sodium permeability, they also, though to a lesser extent, limit potassium conductance. A marine toxin such as tetrodotoxin (TTX) is unique not only in that it attaches to the exter- nal membrane surface, but also in blocking sodium channels exclusively. The bond is tenacious, requiring only minute quantities of the drug; TTX is one of the most potent toxins known. One obvious new research direction is development of local anesthetics based on ma- rine toxins so as to provide much longer- lasting blockade than currently attainable. Presently these toxins are much too deadly for clinical use, and their derivatives thus far have proven to be inactive. Nevertheless, suitable chemical manipulation could conceivably yield a promising new crop of anesthetics. Physiology Recognition of the fundamental mode of action of local anesthetics has been an impor- tant triumph for fundamental research. In resting nerve, the membrane essentially is im- permeable to sodium ions. The resting trans- membrane potential thus is largely attributable to the potassium battery. The nerve’s action po- tential is generated by a brief voltage-dependent membrane reorientation that permits an inward deluge of sodium ions. Whether this is a physical process of widening of sodium pores, an opening of channel shutters, a facilitation of sodium car- rier mechanisms or all of these remains to be unraveled. Calcium ion is intimately tied to the process too, but its precise role needs to be worked out. 17 Basic agreement exists that the local anesthetic cation binds to oppositely charged membrane “receptors.” The role of calcium in anesthetic blockage remains speculative, lack- ing a complete picture of this ion’s function in the excitation cycle. Competition between cal- cium and local anesthetics for receptor sites can be demonstrated. The site of local anesthetic action has come under increasing scrutiny. Studies with local anesthetics have been instrumental in advanc- ing our knowledge of ionic fluxes through the membrane, and the factors that control them. Thus, two groups of sodium-channel blocking agents now can be distinguished. One group, comprising TTX and related marine toxins, blocks the channel from the external side, while local anesthetics block the channel at the internal pore. Local anesthetics presumably reach their target on the axoplasmic mem- brane side by diffusing as the uncharged base through the membrane; egress from the axon appears to be rapid too, as they can be easily washed out. The significance of membrane swelling upon exposure to local anesthetics remains obscure. Whether the swelling physically pinches shut ion transport channels or whether it is merely an incidental observation, deserves further investigation. If it is indeed functional, pressure reversal of block may be feasible, opening up intriguing new therapeutic spectres. Regrettably, studies to date have been confined to inexcitable structures, such as red blood cells. Future work, to be meaningful, could well be extended to excitable membranes. Intrigu- ing and promising in this regard are the artifi- cial membranes that generate resting and even action potentials. The sodium-blocking property of local anesthetics precludes generation of an action potential. The passage of impulses is blocked and analgesia of the innervated area results. Nerve fibers are not blocked equally by local anesthetics. Among the myelinated axons found in mixed peripheral nerve, thin ones (delta group) are blocked at about half the local anesthetic concentration that blocks large diameter (alpha group) motor fibers. A differ- ential block that provides analgesia, but spares motor function, thus is fairly common after nerve block. Why thick fibers should be less reactive than thin ones has been a long- standing puzzle. A clever study indicates that all mylinated fibers, regardless of size, are blocked. The greater sensitivity to local anesthetics of thin fibers is caused by their shorter internodal distance. As myelin is a pharmacological as well as an electrical in- sulator, drugs can reach the membrane only at the node of Ranvier. To block impulse conduc- tion, at least two or three adjacent nodes must be rendered inexcitable. Since the internodal distance is greater the thicker the axon, fewer nodes of a thick axon are reached than of a thin one, hence block of the former often is incom- plete unless more drug molecules are deliv- ered. Still to be explained is the relatively great resistance of thin unmyelinated C-fibers to local anesthetics. Lacking myelin, these fibers should by all accounts be the most readily blocked. Yet they are not; in fact their minimum blocking concentration is on the order of that of small myelinated (delta group) A-fibers. Long suspected on clinical grounds, but only recently demonstrated experimen- tally, is that myelinated preganglionic au- tonomic axons (B-fibers) are the most sensitive to local anesthetics of mammalian nerves. In fact they are some three times more readily blocked than C-fibers. The reason may again be a physical one, as C-fibers are packed into so-called Remak bundles. A notable observation—frequently, though unsuccessfully, challenged—is that local anesthetic block is dissociated from the metabolic furnaces. One indication is the lack of effect of these agents on the resting mem- brane potential, ongoing metabolic activity evidently continues unimpeded. Not so when metabolic poisons are applied. The latter block impulse generation too, but not without first leveling the resting potential. It is only when their normal blocking concentration is ex- ceeded by one or two orders of magnitude that local anesthetics begin to alter metabolic fac- tors. Subtle metabolic actions might well exist at normal blocking concentrations, but simply cannot be demonstrated with currently avail- able tools. Clinical Applications Regional Anesthesia: The major clinical application of local anesthetics is provision of 18 surgical, dental and obstetric anesthesia. Con- duction block of peripheral nerve trunks pro- vides analgesia and motor block. Closer to the neuraxis, spinal conduction blocks provide au- tonomic nerve interruption as well, rendering large portions of the body totally denervated. In obstetrics, local and regional anesthesia have largely supplanted general anesthesia, as they cause less fetal depression. While local anesthetics have been implied in fetal distress states, no convincing proof exists. Quite to the contrary, the fetus in utero can tolerate as- tounding quantities of local anesthetic—up to 10 ug/ml lidocaine for instance—without seri- ous cardiovascular effect. Prilocaine produces less fetal depression than either lidocaine or mepivacaine, so seems useful in paracervical block for delivery. Whether reduction in ma- ternal oxygen-carrying capacity by methemo- globin (see later) would offset this advantage remains to be studied. The (weak) immunosuppressive properties of local anesthetics may make regional anes- thesia a choice for cancer surgery. Their inter- ference with normal phagocytosis, on the other hand, could preclude local anesthetic use dur- ing surgery in patients with lower resistance to infection. These crucial considerations are just now beginning to receive belated atten- tion. It behooves anesthesiologists to look carefully into the possibility that their drugs may profoundly alter body systems other than heart, lung and brain. In the past decade Bonica’s group has added much to our knowledge of the physiology of major conduction block. One unexpected outcome of this research was the demonstra- tion that absorbed local anesthetic exerts posi- tive inotropic actions that compensate to some extent for the increased vascular capacitance brought about by vasomotor paralysis. That these compensatory drives are finely balanced is illustrated by the detrimental effects of re- duced blood volume. An important conclusion from these and related studies is that analgesic block extend- ing to the fourth and fifth thoracic dermotome has remarkably little effect on circulation and respiration. Evidently, sparing of the sympa- thetics to upper body and heart mobilizes major homeostatic compensatory reserves. And, with the phrenic nerve intact, the diap- hragm can adequately fill in for the blocked in- tercostal motor supply. Interestingly, epinephrine commonly added to solutions to retard local anesthetic absorption is itself absorbed. Epinephrine’s beta stimulant properties interact with the ef- fects of autonomic denervation and the cir- culating local anesthetic to form a complex mosaic of factors that are slowly yielding to the scientific approach. Judicious selection of block procedure of drug and of vasoconstrictor will go far towards tailoring regional anesthesia to patient status as well as to surgical require- ment. Some clinical studies have attempted to examine the relative advantages and disadvan- tages of regional versus inhalation anesthesia. Regrettably, valid conclusions are difficult to draw for lack of suitably matched pairs. This is one further area where more conclusive studies would be of immediate practical benefit to the practitioner trying to pick the “best” anesthetic for his patient. Pain: Local anesthetics provide pain relief—albeit of a temporary nature—by block- ing the innervating structures. Common appli- cations are post-operative analgesia and treatment of acute traumatic conditions such as rib fractures. Local anesthetics have been used also for relief in chronic pain states. Here they have been applied both as diagnostic tools to delineate the innervation and demonstrate the consequences of surgical neurectomy, as well as therapeutic agents. Intravenous infu- sion of procaine and lidocaine, so popular in the 1950's for treating ills ranging from pruritis to pancreatitis, has largely fallen by the wayside. Whether nerve blocks for chronic pain states are merely one form of Western acupuncture may give pause for reflection. With the estab- lishment of pain centers, long-term effects of nerve block therapy can profitably be studied on a large patient group with extensive follow-up. Therapy Uses: Local anesthetics, espe- cially lidocaine, have found additional uses. Of these, cardiac therapy has become so impor- tant as to warrant separate description. Rather remarkably, in view of its propensity to induce convulsions, lower doses of lidocaine exert anticonvulsant effects. While this appli- cation has not caught on in North America, it has been utilized in Scandinavia, where lidocaine’s titratability is considered an impor- 19 tant advantage in managing status epilepticus. In Eastern Europe procaine has been touted as a rejuvenating agent, and claims for providing the Fountain of Youth have been made. Re- juvenation clinics have flourished in Switzer- land. Antiarrhythmic Actions A large and growing application of local anesthetics is in the treatment of ventricular tachy-arrhythmias. Anesthesiologists in the 1950's, long familiar with the antiarrhythmic effects of procaine, began to switch to systemi- cally less depressing lidocaine to treat ar- rhythmias during cardiac surgery. Car- diologists treating these patients postopera- tively soon adopted this practice; nowadays lidocaine has grown into the most popular drug in the coronary care unit. Neurophysiologic techniques of intracellu- lar potential recording and voltage clamping have been extended to cardiac muscle prepara- tions such as Purkinge fibers. But the results, as they pertain to local anesthetic as least, still are no match for those obtained on neural tis- sue. Even as fundamental a mechanism as sodium permeability seems to be largely ap- proached indirectly. Further, earlier studies have been carried out in tissue baths contain- ing half the normal extra-cellular potassium concentration. As a result the muscle is hyper- polarized and erroneous conclusions (e.g., lidocaine facilitating instead of suppressing sodium conductance) became rooted in the lit- erature. Potassium permeability is said to be enhanced by lidocaine, a finding that con- tradicts the case in nerve. This controversy deserves in-depth study, as it ties directly to therapeutic actions such as repolarization. The cardiac actions of local anesthetics clearly are of enormous clinical interest and opportunities for clinical study are legion. A great need for a long-acting lidocaine-type anesthetic is evident from the current practice of infusing the drug. An approach like that of Mark and colleagues at Columbia who intro- duced procainamide is hoped for. Current long-acting agents such as bupivacaine have an antiarrhythmic effect that is as fleeting as that of lidocaine. Pharmacokinetics: A fresh impetus for detailed kinetic studies derived from labora- tory and clinical evidence that the car- diotherapeutic properties of lidocaine corre- lated nicely with the drug’s blood level. Drug level, in turn, is determined by drug distribu- tion into various compartments. Dilution by a large initial compartment will yield lower blood levels than when the initial distribution volume is small. This was demonstrated in pa- tients with reduced cardiac output where a “standard” dose of lidocaine produced a blood level that was some 50% higher than attained in control subjects. The fragile cardiac patient thus needs less lidocaine for a given therapeu- tic level than his healthy counterpart. Pharmacokinetic studies have also shown that orally ingested lidocaine, though well ab- sorbed from the GI-tract, is intercepted by the liver so that only one-half to two-thirds of an ingested dose eventually is bioavailable. To ob- tain therapeutic blood levels, large quantities of lidocaine need to be ingested, with corres- pondingly high metabolite levels approaching the toxic range. Intramuscular administration, on the other hand, provides therapeutic anesthetic blood levels for one to two hours. Even so, higher than wanted blood levels are registered in a substantial portion of the popu- lation. A simple yet efficient means of provid- ing rapidly active therapeutic drug levels is important where a patient with a fresh infarct is to be transported to a medical center. The first few hours after infarction are critical due to the generation of ectopic ventricular foci, that easily progress to ventricular tachycardia and death. Not fully settled yet is whether man’s lidocaine disposition is modeled best by a two- or a three-compartment representation. The question is of some importance in that therapeutic regimens aimed at a sustained plasma drug level are decidedly influenced by the disposition model. Now that the impor- tance of sampling arterial rather than venous blood levels (and of early sample collections) are being more widely practiced, improved models may be expected. The theoretical foundations of phar- macokinetics have advanced considerably, with computers making light work of tedious curve fittings. But practical application and experimental design have lagged till recently. Analytical developments are such that tissue level of lidocaine can be measured reliably. The time thus is at hand where drug flow to and 20 from the heart and brain can be quantitated di- rectly. The therapeutic implications of these advances in terms of improved antiarrhythmic therapy and reduced central toxicity alone seem worth the research investment. Biodegradation The metamorphosis of local anesthetic to more soluble and (presumably) less toxic frag- ments is important in several respects. The more resistant a drug to breakdown, the longer it will persist. Further, the decomposi- tion products themselves may have biological actions that differ from the parent drug’s. Prilocaine is a case in point; orthotoluidine, one of its byproducts, binds to hemoglobin. The methemoglobin bond displaces oxygen and, if enough is formed, cyanosis appears. When a drug such as lidocaine is infused for extended periods, detailed knowledge of the pharmacology, distribution and excretion of metabolites is crucial to patient welfare. The secondary amine metabolites of lidocaine, for instance, retain about one-half the parent compound’s depressant effect on heart and cir- culation, and are CNS-toxic as well. Only sub- sequent hydrolysis to primary amine and basic building blocks seems to yield compounds with little demonstrable pharmacologic action. Nonetheless, residual metabolites conceivably could compete with the parent drug for recep- tors. Little is known about this latter possibil- ity. The linkage between the straight chain nitrogen-bearing portion of the local anesthetic molecule and the aromatic ring is the keystone to the route of degradation. In the ester-linked local anesthetics, simple hydrolysis prevails. While the rate of hydrolysis may vary from one agent to the next, the mechanism still remains the same. The amide-linked local anesthetics generally resist hydrolysis in the tertiary amine form, and must first be de-alkylated to the secondary amine before any hydrolysis of consequence can take place. Both secondary and primary amines thus are found, as well as the final hydrolysis products. Species-linked variations, including hydroxylation of the aromatic ring, are frequent. That the linkage importantly regulates metabolism is exemplified by procainamide. This drug is one of the classic showcases for inductive pharmacologic reasoning. Procaine’s antiarrhythmic properties were long known, but its fleeting action made use inconvenient. By changing the procaine structure from an ester- to an amide-linkage, a substance was synthesized in the 1950’s which proved to be singularly resistant to hydrolysis. Soon there- after, procainamide became a staple in treat- ment of cardiac ailments, to be supplanted only by lidocaine—another local anesthetic. Toxicity One factor limiting wider application of regional anesthesia is the systematic toxicity of local anesthetics. The target organ toxicity of local anesthetics is itself negligible, and hypersensitivity to the amide-linked anesthet- ics likewise is vanishingly small. It is their sys- temic toxicity, expecially that on the central nervous system (CNS), that is the limiting fac- tor. In the past, cardiovascular toxicity was considered an equally important consideration. However, the huge quantities of lidocaine being pumped nowadays into the veins of some very sick patients make one realize that car- diovascular collapse is less likely than previ- ously thought. Management of CNS toxicity may be ap- proached from two directions. One would be to synthesize local anesthetics having fewer cen- tral effects. As for the present crop of local anesthetics, the response pattern to a rising drug level is essentially similar for all. A spec- trum of minor CNS signs is observed first, in- cluding drowsiness, excitation, tinnitus, ete. As the blood level rises, muscle twitches and fibrillations make their appearance, eventually culminating in grand mal convulsions. An alternate attack, then, is to accept the available local anesthetics for what they are, but reduce the reactivity of the brain to them. Impetus for this approach was provided by the discovery of a circumscribed seizure focus in the limbic portion of the brain. Rather than tackling the problem with general CNS de- pressants, precise therapeutic avenues were opened. Benzodiazepenes, for instance, exert a specific quieting effect on the limbic brain. And current research has turned to these drugs in providing profound protection from local anesthetic-induced convulsions. Diazepam (Valium) appears to have a clear therapeutic edge over previously used nonspecific CNS 21 depressants in preventing, as well as arrest- ing, local anesthetic-induced convulsions. An expanding body of knowledge from several laboratories attests to the safety and efficacy of diazepam prophylaxis and therapy. Consequently, considerably larger than nor- mally used doses of local anesthetics can be administered, so making extensive blocking procedures or long-term therapy feasible. An added advantage of diazepam prophylaxis, particularly in cardiac therapy, is that the drug potentiates lidocaine’s antiarrhythmic actions and produces minimal vascular depression. Also having considerable therapeutic po- tential is the COz-dependence of the brain's seizure threshold. The greater the hypercap- nia, the more rapidly is the brain triggered into convulsions. Conversely, hypocapnia has a protective effect so that much larger than usually tolerated quantities of local anesthetics can be administered. These modes of treat- ment, diazepam and hyperventilation, gradu- ally are finding their way into the clinician’s armamentarium. In summary, local anesthetics are a homogenous class of drugs that reversibly block sodium permeability, so rendering nerve inexcitable. The positively charged cation species is the membrane-active dissociation product, whereas the uncharged base is the form by which the drug is transported from depot to site of action. Distribution and biodegradation studies have placed intrave- nous lidocaine therapy on a sound scientific basis that is a model for clinical pharmacologic investigation of other drugs. The long-term ef- fects of local anesthetics and their byproducts, however, remain to be examined intensively in man. Major regional conduction blocks (as well as intravenous therapy) tend to push the anesthetic blood level towards the toxic range. Local anesthetics can be made safer by faster removal, greater specific affinity for the target tissue, or by slowing their absorption from a depot. Alternately, the reactivity of the brain can be reduced by appropriate therapy, as with benzodiazepenes, barbiturates, or hyperventi- lation. Major developmental requirement is for a long-acting anesthetic providing one-shot pain relief for several days. Two new direc- tions in drug evolution, one deriving from ma- rine toxins, the other from molecular cycliza- tion, may prove rewarding. Local anesthesia research has shown a healthy admixture of fundamental and clinical research, with dem- onstrable patient benefits the spinoff. NEUROMUSCULAR RESEARCH DR. WALTS: I wish to discuss progress over the past decade in the area of muscle re- laxants and suggest avenues for future re- search. To broaden the scope of my presenta- tion I sought advice from many anes- thesiologists active in the field. Their opinions, understandably, differed as to where emphasis should be placed, based mainly on whether basic research should be awarded a higher priority than clinical research. Thus, with little choice but to reflect my personal views, I shall emphasize work directly applicable to anes- thesiology practice. One significant advance has been popu- larization of the nerve stimulator to monitor neuromuscular blockade. Although use of the stimulator might be considered an investiga- tive by-product, its significance in terms of pa- tient care may be greater than the investiga- tions carried out with its use. Nonetheless, popularization is by no means universal. Con- ceivably, it will require yet another decade be- fore anesthesiologists monitor the effects of muscle relaxants on neuromuscular transmis- sion as routinely as they now monitor the ef- fects of general anesthetics on the cardiovascu- lar system. Another significant advance has been rec- ognition and elucidation of some of the dangers of neuromuscular blocking drugs. Of primary consideration is the discovery that circulatory collapse in burn patients following succinyl- choline was due to potassium release from in- jured muscles. Identification of similar hyper- kalemia problems in patients with massive trauma and neurologic disorders soon fol- lowed. While this information has shed no light upon the basic mechanisms of neuromuscular conduction, it too has been responsible for the safer practice of anesthesia. Another danger area that has received attention concerns drug interactions. Both quinidine and magnesium have been added to the list of drugs that in- cludes many antibiotics which may result in prolonged weakness following concurrent use with nondepolarizing relaxants. 22 The introduction of pancuronium must be considered one of the advancements of the past decade. The specialty has always been seeking neuromuscular blocking drugs that lack side effects. The hypotension associated with d-tubocurarine has made its use less than ideal. While pancuronium itself has not been proven free of cardiovascular effects, hypoten- sion is no longer a major problem. Other notable areas of research include drug durations, side effects, and phar- macologic antagonisms. Additionally, some in- vestigators have turned their attention to pharmacokinetics, utilizing the principles of radioactive tagging. The most exciting current research seems to be the synthesis of a new series of non-depolarizing neuromuscular blocking drugs, which, by nature of their structure, are intended to have a short dura- tion of action. One such compound is currently receiving clinical trials in anesthetized pa- tients. Radioimmunoassay techniques to measure d-tubocurarine blood concentration may prove useful for the clinical study of neuromuscular blocking drugs. It has advantages over previ- ous methods of analysis in that it can be used in humans and is more sensitive than spec- trophotometric analysis. This measurement may help us gain a clearer understanding of re- laxant redistribution and elimination and to understand the processes involved in drug an- tagonisms. My thoughts about the direction of future research are predicated by my belief that the ultimate goal for anesthesia investigation should be better patient care. This can be ob- tained through the prevention of side actions of neuromuscular blocking drugs. Carrying this view one step more, better patient care may best come about through the development of newer agents that are not associated with ob- jectionable side actions. Current work to de- velop a short acting non-depolarizing neuromuscular blocking drug has already been mentioned. Studies must continue until a drug can be found that will replace the depolarizing relaxants which are so fraught with hazard. Besides developing better neuromuscular blocking drugs, efforts should be directed to- ward finding drugs that will produce relaxa- tion by acting at sites other than the myoneural junction. One site potentially useful in creating a reversible neuromuscular block is the nerve terminal. We have substances such as local anesthetic drugs, magnesium, and botulinus toxin which act by inhibiting acetyl- choline release. Unfortunately, these drugs are not useful to produce reversible neuromus- cular blockade. Acceptable agents should be sought. We should further explore the central nervous system in an attempt to produce a safer muscle relaxant. Again, drugs are al- ready available that produce excellent relaxa- tion through action at synaptic sites in the cen- tral nervous system. Good examples are diethyl ether, enflurane and methoxyflurane. However, because of other characteristics, these drugs are not ideal relaxants. Knowing that various general anesthetic agents have a spectrum of effects in producing relaxation, there is reason to believe that other drugs as yet undiscovered may be potent relaxants and have none of the undesirable characteristics. Such a general anesthetic would allow us to eliminate the need for a special adjuvant drug to produce only muscle relaxation. Concerning general anesthetics, thought should be given to drugs that produce abdomi- nal muscle relaxation while sparing the mus- cles of ventilation. Biethyl ether has been shown to produce excellent abdominal muscle relaxation while the diaphragm remains ac- tive. Newer drugs should be synthesized to capitalize on this effect. The muscle membrane is yet another site amenable to block in order to produce muscle relaxation. General anesthetic drugs partially exert their effect at this site. A search must be made for other drugs that do so in a readily re- versible manner. At the same time that investigators are looking for drugs that produce muscle relaxa- tion, efforts should also be made to find better antagonists to drugs already in use.In the past decade we have seen that germine monoace- tate and diacetate have limited capability of reversing d-tubocurarine and succinylocholine block without producing cholinergic side ef- fects. Recently, I observed incomplete an- tagonism of pancuronium following an in- travenous injection of azathioprine. The effect was noted after a minimal latent period and was not accompaned by muscurinic side ef- fects. Neither germine acetate nor azathiop- rine are clinically useful antagonists but the finding does suggest that alternate methods of drug antagonism are available. Finally, we need to have a better under- standing of the fundamental process of neuromuscular transmission. DISCUSSION DR. KITZ: It seems that, relative to cardiopulmonary research. CNS research in anesthesia developed late. Would John Severinghaus please comment? DR. SEVERINGHAUS: First, I think the anesthetic state, as long as it served a surgical purpose, solved that problem, in that the trou- bles we got into were cardiovascular troubles. Second, the resurgence in clinical physiology which occurred after World War II was primarily cardiovascular physiology. DR. BONICA: It is a fact that these car- diovascular respiratory effects are due to di- rect action on the central nervous system. In retrospect, I think we should have mobilized more of our efforts to look at these sites and try to see how we could minimize or eliminate them. DR. KITAHATA: These effects of anesthetics on heart and lungs which we con- sider as side effects are more easy to study than effects on the central nervous system, per se. Although I agree with John Bonica, that they effect the central nervous system, they also have effect on peripheral organs. I think the difficulty of attacking this problem, in terms of studying side effects in the central nervous system, has been the principal obsta- cle. DR. de JONG: I think it is a matter of priority. We have not been able to look as deeply into CNS research until quite recently. We simply couldn’t afford the luxury, really, of looking into the mechanism of action of anesthetics, for instance, until the really im- portant clinical problems of patient care had been, if not solved, advanced towards solving, both as to respiratory and circulatory effects. DR. SEVERINGHAUS: Another simplis- tic answer is that we were able to overcome the central nervous system’s effects on respiration and circulation with peripheral means, rather than altering the agents. 23 DR. KITAHATA: I enjoyed the presenta- tion by John Severinghaus, especially the last comment on electronarcosis. Since we do not know what is really happening in the central nervous sytem as a whole, and since we do know the more precise mechanism of a nerve transmission in the peripheral nerves, the ap- plication of electronarcosis might be more applicable in Rudy de Jong’s area of local anesthetics. This may be related further to acupuncture and its mechanisms. I would just have one question of John. Has any study been done on the electronarcosis effect, on the psychological after-effect? DR. SEVERINGHAUS: The studies are inadequate, but there are some. Nobody has come up with any evidence that there are psychological effects other than the fact that sometimes, if it is used without pharmacologi- cal induction, there is memory of the pain—of the surgery, or the pain of induction. But the electrical anesthetic effect, if there is one, does not seem to have any other psychological ef- fects. DR. KITZ: In both the presentations rela- tive to drugs the word “receptor” was not men- tioned. Yet in the literature, that is an impor- tant area. Why don’t we have research on re- ceptors in anesthesia? DR. de JONG: We have the concept of re- ceptors for local anesthetics, but we don’t call them receptors. We can be much more specific. I think the term “receptors” is a catch word that one uses when one does not know where the drug acts and what it does. It is very con- venient, and one can come up with a great deal of mathematical manipulation. But we can be much more specific, and pretty accurately pin- point at least the side effects of local anesthet- ics, except perhaps not the exact anatomic structure of where the anesthetic binds. But we have a good idea of the overall configura- tion. The word receptor just is not used very much in membrane physiology. DR. KITZ: There is such a thing called a cholinergic receptor. Frank Standaert, do you want to comment on receptor research? DR. STANDAERT: There is a tremen- dous amount of research on the cholinergic re- ceptor. Many people think they either have or just about have the answer. This work is going on mainly in neurophysiology, biochemistry, pharmacology, and anatomy. If it is the recep- 24 tor, how one gets from that to another group of agents is not really being contemplated, as far as I know, because presumably one would have to know the receptor, identify the chemical structure, the stereo-configuration, and then begin to define drugs that would go into this area. So it is a very hot area of research, but a long way from practical application. DR. MILLER: Away from receptors, in the clinical area, I would ask about research on the causes of patient morbidity. In general, it appears from the literature that about 75% of the clinical studies on neuromuscular blockers is concerned with what happens with the first dose, and roughly 10% with the second and third dose, while only about 10% is concerned with antagonisms. Yet, in terms of the case re- ports on morbidity, complications or problems in antagonizing the neuromuscular block are the principal causes. So why is only a very small fraction of research in this area de- voted to antagonisms? DR. WALTS: In answer, the major prob- lem to the patient may not necessarily be that we do not have the antagonist, but that we are unable to recognize that the patient is still paralyzed. Use of the nerve stimulator to monitor neuromuscular blockade thus poten- tially may be the best area for improved pa- tient care; that is, if you recognize that a pa- tient is probably paralyzed, you can treat him recognizing the cause of paralysis. In short, I think that recognition and avoidance of these problems is properly emphasized at this time. METABOLISM DR. GREENE: Little had been done prior to the mid-1960s in the field of anesthesia metabolic research. And this research more often than not was superficial, naive, and far below current standards of quality in metabolic studies. Today, this has changed. Not only is more anesthesia metabolic research being done, but much of it now is at a level of sophis- tication and expertise equal to that seen in any field. This happy situation is partly a manifes- tation of the growth and maturity academic anesthesiology has enjoyed in the last decade and a half. It is also, and more specifically, due to the appearance of biochemically qualified researchers in anesthesiology. These are men and women who have trained, often for periods of years, in laboratories of biochemists and other basic scientists before going into anes- thesia research. They are competent, expert, and respected biochemists in their own right. They have replaced the semi-trained anes- thesiologist of the past who knew what ques- tions needed to be asked, but who did not know how to go about providing the answers. They have also replaced the skilled biochemist of the past who knew how to study biochemical as- pects of anesthesia but did now know what were the important questions. General Objectives This upsurge of interest and productivity in anesthesia research on metabolism has en- compassed two major areas. One, the metabolism of xenobiotics, which will be dis- cussed by Dr. Van Dyke. The other, research into normal human biochemistry and metabolism as affected by anesthetic drugs and procedures, has had four general objectives: 1) knowledge for the sake of knowledge; 2) anesthetic toxicity; 3) clinical management of patients undergoing anesthesia and surgery; and 4) the relationship between metabolic changes and alterations in cell or organ func- tion. The first of these objectives, derivation of knowledge for itself, with no apparent practi- cal application, has been especially fruitful at cellular and sub-cellular levels. Particularly noteworthy have been investigations directed to the effects of anesthetics on mitochondrial metabolism, microsomal metabolism, and the metabolic processes by which the integrity and function of cell membranes are maintained. This type of research is often—and easily— criticized: who cares about a toad’s bladder, firefly’s luminescence, or a rat’s hepatic mitochondria? How do these studies help the clinical anesthesiologist. They don’t—yet. But they will. Basic research lacking in any appar- ent clinical application is essential to under- standing the process of anesthesia and, indeed, the very nature of cell irritability. It is the type of research which must continue to be carried on. It is encouraging to note the number of qualified investigators active in the field. It is an aspect of anesthesia metabolic re- search which is in a remarkably healthy state, despite its complexities and despite its lack of popular appeal. A second objective of anesthesia metabolic research addresses itself to the problem of anesthetic toxicity. Three toxicologic problems in anesthesia have enjoyed the lion’s share of attention (in addition to those attempting to re- late drug metabolism and toxicity). These three problems are: malignant pyrexia; hepatic toxicity of halogenated anesthetics; and metabolic effects of anesthetics on dividing cells. The greatest progress has been made in understanding the metabolic basis of malig- nant pyrexia. We may be approaching the point where future productivity in this field may start to decline. We seem to have gone about as far as one can go in metabolic research in malignant pyrexia. Perhaps it is time to give equal emphasis to other aspects of this impor- tant problem. Research into the possible metabolic basis of hepatotoxicity of halogenated anesthetics is providing important and very fundamental in- formation. It is a field which deserves to be even more actively studied, but which would benefit by being more circumspect and more tempered in its generalizations regarding clini- cal significance of research data. Effects on Dividing Cells The metabolic effects of anesthetics on di- viding cells has received added clinical signifi- cance with demonstration of the teratogenetic effects of chronic exposure to trace concentra- tions of anesthetics. Teratogenicity of this type may well have a metabolic basis. The mag- nitude of this problem in terms of the number of individuals involved and the clear and pres- ent danger to which they are exposed em- phasizes the importance of this aspect of metabolic research. Research on the metabolic effects of anesthetics and how they may affect the clini- cal management of patients has been disap- pointing in the past and continues to be disap- pointing. It is a field rich in theory but with a paucity of objective data. For example, how are the diabetic patient, the patient with hyperthyroidism, the patient being treated with metabolically active drugs who needs anesthesia, or the patient in shock being bene- fited by anesthesia metabolic research? They aren’t, right now, but they should be. At the present time, for example, we do not even know the answers to questions as fundamental 25 as whether or how anesthetics affect insulin production, insulin release, or insulin activity. Until we know the answers to such questions, the anesthetic management of hundreds of thousands of diabetics anesthetized each year is based purely and simply on intuition, clinical impression, and/or specious biochemical reasoning. The same can also be said for the present state of our knowledge as to how the metabolic effects of anesthetics can and should affect anesthetic management of other patients suffering from concurrent disease at the time they need anesthesia. Additional laboratory research and its application to clinical situa- tions under controlled conditions are sorely needed in this area. The fourth objective, how anesthetics may alter cell or organ function through metabolic means, has received attention particularly in- sofar as the cardiovascular and the central nervous systems are concerned. A consider- able amount of good work, for example, has gone into attempting to explain the negative ionotropism of anesthetics on a metabolic basis. The implications of these studies remain uncertain, but they have great potential. At- tempts to relate metabolic changes in nerve tissue to the anesthetic properties of drugs continue to be pursued today, as in the past. These studies are valuable insofar as obtaining knowledge for the sake of knowledge is con- cerned. As a basis for explaining anesthetic ac- tion, however, this type of research has lim- itations all too finite. Present evidence over- whelmingly suggests that metabolic changes in nerve tissue exposed to anesthetics are a re- sult and not a cause of the state of anesthesia. A major advance in the study of the metabolic effect of anesthesia has been the de- velopment in recent years of technics which permit organ perfusion for prolonged periods under conditions normal enough to maintain cellular viability. The old problems of inter- preting the significance of in vitro data ob- tained from tissue slices or homogenates are well on their way to being solved by in vitro perfusion of whole organs with anesthetic solu- tions. These perfusion technics already have been applied with notable success to the liver, the pancreas and the heart. Of equal impor- tance has been development of tissue culture technics and their adaptation to the study of the metabolic effects of anesthetics. Organ perfu- sion and tissue culture are still in the process of being exploited in metabolic studies, but the in- formation already obtained represents a major advance over that previously obtained from less normal preparations. Their continued use and development will undoubtedly provide us with insight into the metabolic consequences of anesthetics, hithertofore denied those working in this field. DRUG DISPOSITION DR. VAN DYKE: I would turn your at- tention to the subject of drug metabolism and the contributions made. The anesthetic agents for several reasons have proven to be excellent models with which to study drug metabolism. First, the anesthetic agents, at least the vol- atile agents, were considered to be inert biochemically, that is, not metabolized. Thus, discovery in 1963 that these anesthetic agents could be metabolized by mammalian enzyme systems opened the eyes of many investigators to the fact that metabolism of xenobiotics may play a larger role in disposition of the com- pounds than previously considered. Model Substrates Second, anesthetic agents, particularly the volatile agents, are chemically unique drugs, being highly halogenated compounds and/or ethers. Study of the metabolism of these compounds is, accordingly, a study of dehalogenation and ether cleavage, informa- tion which can be used in the study of other types of drugs containing similar structures. Third, we have found the anesthetics useful in studying the drug metabolizing enzyme sys- tem. This system is membrane bound and al- though difficult to isolate, we have been able to separate component parts and determine many of its characteristics by using these agents as substrates, work which supports the findings of others using other types of substrates. A fourth reason is that more insight has been gained into the cause of untoward side ef- fects of drugs seen unpredictably in some pa- tients. Many of these effects can be traced di- rectly to an intermediate metabolite which in high concentrations results in adverse effects. In this case, the anesthetic agents have proven extremely useful as model substrates and can emphasize certain principals of drug 26 metabolism. For example, methoxyflurane metabolism results in the production of inor- ganic fluoride which has a toxic effect on the kidneys, producing polyuria, a problem first noted in humans. When studies were under- taken in experimental animals, no polyuria was observed until it was found that a certain strain of rats (Fischer 344) mimic the fluoride- induced polyuria seen in humans. Now this anesthetic agent is proving invaluable in de- termining the basis for strain differences. Still to be determined: does this strain difference result from a difference in sensitivity of the various strains to inorganic fluoride, does the route of metabolism vary, or does the extent of metabolism differ? It would appear from the data that a variation in the extent or route of metabolism between strains can be ruled out; therefore it must be that the kidneys of Fischer 344 rats respond differently to the in- organic fluoride. Another example is the species variation found with fluroxene. But we don’t know, as yet, whether fluroxene is metabolized to a toxic product in certain species or where the route of metabolism varies. Nevertheless, the fact remains that certain species such as the cat, rabbit and dog are much more susceptible to fluroxene hepatotoxicity than are other species such as humans. Halothane has also proven to be a valuable tool in the study of toxic side effects of drugs. We are all aware that halothane is thought to produce hepatitis in certain humans, but the suspicion is not confirmed. One of the inves- tigative problems is the inability to consist- ently produce this response in experimental animals exposed to halothane; however, some recent reports have indicated that induced rats are susceptible to the hepatotoxic effects. In a similar vein, there is progress in studying what may be some of the initial steps leading to these effects in rats. It’s been found that under certain adverse physiological circumstances halothane is metabolized to a highly reactive intermediate which then binds to cellular con- stituents, initiating events leading to hepatotoxicity. Perhaps the adverse physiolog- ical conditions are important in developing halothane-induced hepatitis in an animal mod- el. This research is being actively pursued be- cause the whole study of covalent binding of drugs or intermediate metabolites of drugs to 27 cellular constituents is much more widespread than previously believed and halothane is a particularly useful model for examining the phenomenon. Nitrous oxide has not been studied as ex- tensively as many of the other agents, mainly because it cannot be synthesized with a radioactive isotope as can the other agents. This makes it necessary to trace the nitrous oxide by very expensive procedures and equipment. However, with the recent sugges- tion that there may be a problem associated with long-term exposure to operating room atmospheres, this agent, because of its almost universal presence in the O.R., certainly should be studied in greater depth. If nitrous oxide does cause problems in persons exposed to long-term subclinical levels everyone will agree some transformation must take place, making this an important area of research. Enflurane and isoflurane have been studied and found to undergo some bio- transformation, with enflurane being more ex- tensively biotransformed than isoflurane. However, many studies remain to be made on these two agents since they should be sub- jected to the same scrutiny that the other agents have had. Exogenous Factors Recent studies have been concerned with the role that endogenous factors play in the control of drug metabolism. Here again, the volatile anesthetics are proving to be very use- ful tools. Apart from the already noted species and strain differences, such things as diet, steroids, enzyme induction, sex, age, and a va- riety of other factors are being studied with respect to the metabolism of volatile anesthetic agents. And while much remains to be done in this regard, some studies have been initiated. Another research area gaining impetus is the study of drug metabolism in extrahepatic tissue. Most of the metabolism is carried out in the liver but is not confined to this organ, rais- ing the possibility that differences in types of metabolism may exist between organs. We have initiated a study of the isolated, perfused lung and are tracing the disposition of anesthetics in this organ. Our study encompas- ses not only the volatile agents but also several other general agents. In addition to the need to continue and ex- pand our base of knowledge in all of these areas, we need to apply the already available information on drug metabolism to patient care. We must begin to ask such questions as: can control of drug metabolism through en- zyme induction or inhibition be used therapeu- tically, or is there a way to determine the status of an individual in terms of drug metabolizing activity? DISCUSSION DR. KITZ: Is the quality and level of re- search on the theory of metabolism by anes- thesiologists in their laboratories less than, equal to, or better than research in the distin- guished metabolic laboratories? DR. GREENE: I think the quality of metabolic research in anesthesia now is equal to the quality of metabolic research being done by other disciplines which have a clinical base including, for example, cardiology and various aspects of internal medicine. DR. VAN DYKE: I think the research coming from a laboratory in an Anesthesia De- partment can be as good as that for any other biochemistry laboratory; generally, because there is a mix of anesthesiologists and basic biochemists or pharmacologists working in these labs. It is important that such a mix exists. DR. COHEN: I would like to support the last remark: the strength lies in a team ap- proach. It is very difficult to expect an anes- thesiologist to be a clinician, a biochemist, a chemist, and all the other disciplines it takes to do the work. Certainly, the anesthesiologist is aware of the problems. If he can bring together and stimulate a group of basic scientists, be they pharmacologists, physiologists, or biochemists, and learn to speak their language, then the contribution that the anesthetist makes to this overall picture is at the most ef- fective level. It is very difficult for anyone trained in two specialties to practice those specialties to the same depth and with the same expertise as one devoting full time to this area. It is the coordination of these groups that provides the best opportunities. DR. NGAI: The important thing is that since these people are dealing with anesthetic 28 agents, they are more interested in what hap- pens to them in patients or in animals. It is still mission-directed research. You are using the drug itself. You want to know what happens to it. Can you convince a genetic biochemist to work with metabolism? That’s the basic prob- lem. DR. FINK: The function of the anes- thesiologist is a very significant one, to give guidance and concept, to formulate the pro- gram and understand what is pertinent. To un- derstand what can be done requires special training in addition to his own competence. DR. VAN DYKE: Speaking as a bio- chemist and not as an anesthesiologist, we need the guidance of an anesthesiologist to tell us what the problems are. As Dr. Fink pointed out, that guidance is essential to our work. DR. BRUNNER: I think there’s no doubt that we do not measure up to the standard of neurochemistry, for instance. As a matter of fact, in reviewing Dr. Severinghaus’ talk on the central nervous system and Dr. Greene's on metabolism, there is almost a complete lack of reference to neurochemistry. There is a time lag that is built into the system as we have it now, and two directions are left open to us. We must recruit trainees for our laboratories as you have done from Dr. Krebs’ lab, for exam- ple, or we must identify men and women with that type of interest and send them into such labs to gain expertise. RESPIRATORY STUDIES DR. THEODORE SMITH: As one follows the progress of physiological concepts, it is easy to identify areas that are of specific im- portance and interest to anesthesiology. Within these areas one can easily discern that anesthesiologists have proposed problems worthy of study and also have contributed to the solution of many of these problems. Res- piratory physiology is a good example. In the last 30 years, I see three levels of knowledge and sophistication in respiratory physiology and in anesthesiology. I will indi- cate the interrelationship as they progressed from one to another level, and also suggest the stimuli and other disciplines which contribute to that progress. The thought is schematically suggested in the illustration, where time and progress are generally conceived to flow up and to the right. Intensive Care Level Ill 1965 pS et i snl Level Il 1955-65 Ka swt i) Level | 1945-55 = Surgery | 4 i | oi treme se ete), ed areas indicate a discipline. Dashed Boxes suggest an area of stimulating problems. ows suggest the flow of time and scientific progress. The intent is to suggest only a few of ing relations and interrelations of respiratory topics in the various areas Only a small part of the interacting areas can be suggested. I tend to think of it as a pyramidal structure where each layer of masonry used in the construction of the pyramid reflects a particular level of knowl- edge and degree of sophisticated thought. Each additional block added to the structure is supported by the several blocks beneath it— representing the support of the historical background for a particular discipline as well as the contributions from other allied disci- plines. Level I in respiratory physiology was rep- resented by the state of the art at the end of the second World War. This level of knowledge could be characterized as the study of the whole lung. A major effort was to understand the components, establish normal values and assign gross significance to departure from normal. One wanted to know something about lung volumes, not only the spirometric lung volumes but the total lung capacity, and how they varied with age, sex, size and position. One wanted to know something about the total ventilation and its breakdown into components of alveolar ventilation and dead space ventila- tion. Different results from different methods for the latter were responsible for the intro- duction of increasingly complex models of the lung’s organization. One also wanted to know about the mechanics of breathing, the resistance of the airways and the total system, the compliance of the lung and of the thorax, and how these affected not only quiet breathing but more par- ticularly maximumly forced breathing pat- terns. The function tests of the lung began now to introduce stresses to evaluate the reserve. Gross problems of the distribution of ventila- 29 tion, of gas exchange in the lung through diffu- sion as well as convective distribution, affected by the equivalent or physiological shunt, were detailed areas of interest that were just begin- ning to be considered as important and attack- able problems. And finally, people were interested in ven- tilatory control, identifying the major stimuli to respiration and suggesting some of the neural integrative and reflex control mechanisms. In retrospect, there appeared to be a missing area, as there was not much inter- est in the pulmonary circulation and its dis- tribution at this time. In the decade following World War II, the standard pulmonary func- tion tests were largely established: spiromet- ry, total lung capacity by body plethysmog- raphy or inert gas dilution, airway resistance, compliance of the lung and thorax, forced ex- piratory volume and maximum voluntary ven- tilation (known in those days by the names of timed vital capacity and maximum breathing capacity), the single breath nitrogen test and helium dilution curves for ventilation distribu- tion, the diffusing capacity of the lung for CO, application of the mixing equation to give dead space and physiologic shunt, and the ventila- tory response to CO2. These tests were de- scribed, standardized and applied in a wide va- riety of circumstances. Much of the stimulus for this work came from the needs of physi- cians treating tuberculosis. Pulmonary Physiology The role of the anesthesiologist in physiol- ogy at this time was largely that of a student. Anesthesiology was rapidly becoming a recog- nized clinical specialty and establishing its roots in pharmacology as well as in physiology. Many anesthetists spent periods of time in pulmonary physiology laboratories as part of their training. For example, Dripps had worked with Comroe at the University of Pennsylvania and this culminated in the invita- tion to write the first scholarly review of gen- eral anesthesia and respiration, published by R.D. Dripps and J.W. Severinghaus in Physiological Reviews, 35: T41-T77, 1955. However, the major relationship of anes- thetists to physiologists was that of an eager, willing and receptive audience to a brilliant and vital new show. Level II is the period of the second decade after the second World War and in my view was characterized by two steps. The lung was examined in progressively smaller regional areas instead of in its entirety, and the interre- lation between the factors involved in lung function was considered in more detail. For example, the airway resistance was found to vary with changes of lung volume, and the compliance of the lung with lung volume and frequency of breathing. The pressure volume and the flow volume diagrams were interre- lated. It was recognized that ventilation and perfusion of the lung were interdependent, and critically so, as regards their matching. Thus one began to deal with models involving two, three, four and finally many compartments. The three major abnormalities of gas exchange were recognized: diffusion block, anatomic shunt and maldistribution. Gravity was recog- nized to be an important part of the distribu- tion of the pulmonary circulation. Ventilatory stimuli were not only detailed but considered in their interaction with other ventilatory stimuli. Much of the stimulus for this respiratory physiology came from increasing concern on the part of clinicians dealing with chronic obstructive lung disease. Debate on the rela- tionship between bronchitis, asthma and em- physema was stimulated by trans-Atlantic dif- ferences in syndromes. Anesthetists continued to contribute to this physiological development by providing a continuing flow of young men through the physiological laboratories for research ex- perience and instruction. Increasingly, these people contributed importantly not only to physiology but particularly to anesthesiology. Foremost on the list would be John W. Severinghaus whose development of the car- bon dioxide electrode alone would earn him a place in history. Raymond Fink made the im- portant contributions to respiratory control in the area of effects of wakefulness. Bendixen, Laver, Hedley-Whyte and Pontoppidan be- came interested in the pathology of oxygen ex- change, developing the methodology to a height not hitherto achieved. Several groups, particularly Edmund I. Eger and his col- leagues at the University of California and my colleagues at the University of Pennsylvania, began studying the effects of drugs on ven- tilatory control. In this period, anes- thesiologists were proud to lose some of their members to full time research such as David Lieth to the Harvard School for Public Health, and Jim Dixon to the Hyperbaric Facility at the University of Pennsylvania. They contrib- uted to the understanding and design of breathing circuits, for example, the useful non-rebreathing valves of Frumin and Fink. The spectacular success of the American ex- pedition to conquer Mt. Everest was due in some part to the redesign of oxygen breathing devices by Tom Horbein, a member of that ex- pedition and of the list of academic anes- thesiologists. Ultrastructure and Function As respiratory physiology advanced to Level II, it could be characterized by detailed understanding of regional interactions and an interest in submicroscopic structure and func- tion. Important research involved the small airways, their support and their function, kinetic studies of hemoglobin function, oxygen, and CO2 transport modified by 2, 3-diphosphoglycerate, the concept of continu- ous distribution of ratios and ventilation and perfusion in the lung, and the stratification of dead space producing regional inhomogeneity with both parallel and serial dead space con- tributions. Neural control of respiration, re- flex integration of stimuli, and a variety of non-respiratory functions of the lung represent other segments of this level. The major clinical stimuli to this work comes from the group of adult respiratory distress syndromes appear- ing in ever-increasing numbers in respiratory and medical intensive care units staffed in part or whole by anesthesiologists. Anesthesiologists working in Level III contributed and are contributing in major fash- ion to the care of babies with acute respiratory distress; from Gregory in California to Downes in Pennsylvania, the whole country has had a renaissance of interest in perinatology. The ef- fects of drowning and near-drowning on lung function have been studied in ever-increasing detail by the group under Modell in Florida. Neurosurgical problems, particularly brain trauma, were found to be a fertile field for both application of respiratory knowledge and the advancement of the state of the art regarding pulmonary edema and respiratory control. 30 Clinical physiology is practically a recognized sub-specialty with the advent of various inten- sive care units. Anesthesiologists have fed this lusty child in many ways, including the al- phabet soup with ingredients IPPB, CPAPN, PEEP, IMV, etc., and have demonstrated for example, the value of dead space to tidal vol- ume, shunt to cardiac output, the alveolar to arterial difference for oxygen, and the central venous pressure as clinical measurements in the care of patients. In addition to the clinical application of physiologic function tests to medical problems, anesthesiologists have also been paramount in the application of physiological function tests as pharmacological tools. Noteworthy are studies of the interaction of various drugs on ventilatory control, and the alterations in gas exchange caused by both hyperinflation and decreased FRC below closing volume. They have been diligent and useful in their applica- tion of what were previously called purely re- search methods such as dilution cardiac out- put, arterial blood gas analysis and on-line cardio-respiratory monitoring. The clinically important topics of oxygen toxicity, hyper- baric therapy, respiratory physiotherapy and cardio-pulmonary resuscitation are clearly areas where the training of anesthesiologists in respiratory physiology have been responsible for major clinical advances. Thus, it is clear to me that anes- thesiologists have carved out an area that is deserving and properly considered an inde- pendent discipline with important roots in the contributions from physiology, biochemistry, pathology, pharmacology and clinical care. The growth of these areas need a continuing input of people who are conversant with the lan- guage of the contributory disciplines, skilled in the management of the ill, and foresighted enough to see the rewards of the future. I conclude with a few thoughts as to where we are now and to what our current major def- icits are. It seems to me in many areas we have two kinds of data: we have a good bit of careful, detailed physiologic understanding for the healthy, young and often non-operated volun- teer, before, during, and after anesthesia. Secondly, we have anecdotal accounts in the elderly and the ill undergoing surgical attack. We are mounting rational attacks on the de- 31 ficits in this second area, with tools as sophisti- cated and current as in any basic science. CARDIOVASCULAR SYSTEM DR. LAVER: The Anesthesiology Center that I participate in includes most but unfortu- nately not all Harvard hospitals, and will soon reach its seventh anniversary. By contrast, my association with cardiac surgery at the Mas- sachusetts General Hospital is nearly 15 years old. I therefore assume that the decision to re- cruit my services as a discussor of clinical rele- vance in current cardiovascular research was prompted by the thought that such tenacity would not have been tolerated unless there had been evidence for some ultimate benefit to the patient. However, I am allowing this exposure to the patient with operable heart disease to in- fluence the nature of my remarks, but not with- out apologies to other members of the Harvard hospitals whose contributions to cardiovascular research have been of equal or greater im- portance. The explosive growth of surgery for coro- nary artery disease and the long-standing as- sociation between cardiac anesthesia and surgery, combined with the financial support of NIGMS, has provided a classical setting for relevant clinical research. Heart Disease Patients Accurate figures are not available, but an educated guess might place the number of yearly operations for coronary artery disease well in excess of 50,000. The present rate of growth appears limited only by the willingness of payors to allow for the initiation of new pro- grams in open-heart surgery. I will not comment upon the controversy regarding the effect of the surgery on the natural history of the disease. Rather, I want to use this recent interest to emphasize the enormous knowledge gained in our under- standing of the relationship between myocar- dial ischemia and myocardial function, a knowledge that has helped immeasurably in safe intra- and post-operative management whenever patients with coronary artery dis- ease require other operations. Experimental data accumulated over two decades have provided important information on the effects of anesthetic drugs on myocar- dial function using a variety of models from cat papillary muscle to the instrumented normal adult volunteer. However, were it not for the recent need to anesthetize the patient with life threatening myocardial ischemia, it is likely that the test of clinical relevancy would have been delayed with significant consequences to the well-being of all patients. Several years ago the anesthetist was told that a history of myocardial infarction a few weeks before operation was associated with a forbiddingly high risk of repeat postoperative infarction. Will this continue to be true as we learn to sail the troubled waters of general anesthesia in the patient with crescendo an- gina, left ventricular dyskenesia and failure secondary to diffuse coronary artery disease, or with an intra-aortic balloon pump assist for cardiogenic shock? I doubt it, and time alone is a factor until appropriate statistics will sup- port these impressions. Forced by circumstances, we have mod- ified our anesthetic techniques, extended our indications for what and when to monitor and, in essence, taken the laboratory to the operat- ing room. But to move the clinical experience out of the realm of the anecdotal has required careful planning of study protocols and close working relationships with other clinical specialties. I have chosen three examples of innova- tions first introduced clinically that have grown to find use outside open-heart surgery. First, the need for improved anesthetic techniques prompted the use of large doses of intravenous morphine as a principal anesthetic drug for patients with acquired heart valve disease. Initial results were promising and it eventually became apparent that morphine in large doses (2mg/kg intravenously) provided nearly ideal operating conditions because the patient’s autonomic response to the surgical stimulus remained intact, thereby allowing for a smooth hemodynamic course. Parenthetical- ly, these results engendered a veritable “mor- phine olympics” and several investigators have vied for the honor of having used the highest quantities in history. Fortunately this ill- chosen approach appears to be losing its fol- lowers. Although the drug possesses advantages for the child and adult with congenital or ac- quired heart valve disease, its use in the pa- tient with myocardial ischemia has proved to be a mixed blessing, and search for the ideal anesthetic technique for this disease must con- tinue. Nevertheless, clinical studies have firmly established the hymodynamic advan- tages of morphine used in large quantities, and the drug has found broad use in critically ill pa- tients. A second innovation relates to our under- standing of the relationship between au- tonomic activity and myocardial performance in the sick heart. A considerable body of data has been accumulating describing the desira- bility of decrease in sympathetic activity to counteract the depressant effect of most anesthetic drugs on myocardial contractility. Unfortunately, this argument is not univer- sally applicable to the patient with angina pec- toris. A pharmacological blockade of myocar- dial B-receptors is essential whenever diseased coronary vessels cannot provide the flow re- quired to meet oxygen demand. It is also evi- dent that intraoperative stimuli, such as tachycardia and an elevated blood pressure can have lethal consequences, if unchecked. Since the product of systolic pressure times heart rate is an excellent index of adequate myocar- dial blood flow, careful monitoring of ST- segment changes by multiple lead ECGs is mandatory and appropriate therapy must be instituted forthwith, if catastrophy is to be avoided. Both these guides are approximate and better methodology must be developed, but the examples serve to emphasize how the clinical experiment leads to better patient care. Contrasted with our earlier attitude, it would appear that continued, controlled “myocardial depression” is advantageous in the patient whose collateral coronary circula- tion is not sufficiently developed to prevent angina during a common handshake. For example, Lowenstein and Bland have studied the potentially protective effect of anesthesia with halothane on brief coronary occlusion in the experimental animal. Using the technique originally described by Maroko et al (1971), they have shown that the sum of the peri- infarct ST-segment changes was substantially reduced if the ischemic episode occurred dur- ing halothane anesthesia. This suggests that anesthetic drugs with B-blocking type proper- 32 ties are desirable. Furthermore, according to Lappas et al (1973) the addition of 50% nitrous oxide to the inspired air in patients anes- thetized with morphine markedly reduced myocardial contractility when measured shortly after extracorporeal bypass. Since the patient with coronary artery disease was also shown by Lappas et al (in press), to respond to morphine like the pa- tient free of congestive heart failure or heart valve disease, then the reduction in contractil- ity elicited with nitrous oxide may prove to be of benefit. Projecting into the future, one might pre- dict that governmental support of increased ef- fort toward outpatient surgery will sharpen the need for accurate non-invasive monitoring. To be acceptable, such devices must first be tested in the critically ill patient where inva- sive techniques are now routine. Failure to support such efforts will delay the inception of a health care delivery system intended to reach a large population without the risk of fiscal bankruptcy. Lessening Blood Requirements A final example of the type of evidence that runs contrary to established dogma re- lates to the clinical use of hemodilution during extracorporeal circulation. The technique which we have developed in the experimental animal was first used clinically in 1971 in a five-year-old child, a member of Jehovah's Witness sect, who required repair of a tetral- ogy of Fallot. Since blood and blood products could not be used during operation, blood was temporarily removed into a bag containing ACD solution. Contact of the blood with the patient’s circulation was maintained and the blood volume replenished with Ringer’s Lac- tate. Following cessation of extracorporeal cir- culation, all of the blood was reinfused. The technique used subsequently in other children, also Jehovah's Witnesses, with equal success, was a unique combination of laboratory exper- iment in clinical trial first initiated by the need to save a life when blood transfusion was im- possible. On first blush one might conclude that the experiment represents a clinical oddity un- likely to have importance for the population at large. I would consider it a hasty and unjus- 33 tified conclusion. The lessons learned have re- sulted in the intra-operative harvesting of the patient’s blood and blood products. Hallowell et al (1972) have shown that this technique in adults during open heart surgery can reduce blood requirements by as much as 25%. Since the method is gradually gaining acceptance for both cardiac and non-cardiac surgery, the ul- timate saving of blood and blood products, as well as the attendant reduced morbidity from transfusion, will exceed in cost that expended to support a single anesthesia center. Finally, the popularity of hemodilution does justify a careful evaluation of its effect on the ischemic myocardium. Yoshikawa et al (1973), have demonstrated that the return of ST-segments to baseline following temporary occlusion of the left anterior descending coronary artery in the dog was more prompt in animals exposed to extreme hemodilution as compared with a re- duction in O2 content produced by arterial hypoxemia. These data suggest that the qual- ity of collateral blood flow is of greater impor- tance than hemoglobin concentration which we consider so glibly under the concept of oxygen transport. Many examples, too numerous to mention, of ongoing work from other centers support the concept that the wedding of laboratory sci- ence to clinical practice can grow into a suc- cessful marriage. Like all marriages this one also has major problems. Given wisdom from the supporting bodies and realization that a close and effective relationship is difficult to build but easy to tear apart, anesthesia will continue to make itself felt as a specialty with a singular talent for steering the critically ill pa- tient through his moments of greatest danger. DISCUSSION DR. KITZ: Have we reached a level of suf- ficient facilities, personnel, and skills that we need no longer add to the level of funding in the area of cardiopulmonary research? Can we shunt future funding to other more needed areas? DR. SMITH: Let’s take the devil's advo- cacy position. Research on oxygenation is a matter of no concern, because you don’t have to breathe at all to maintain adequate oxygena- tion of blood. However, inspiration of 100% oxygen and then cessation of any respiratory efforts would obviate any problems of diffusion block. You don’t have to ventilate at all. The mechanics of breathing are obviated. You are left only with a very small fraction, what true shunt there might be, and it is still argued as to whether there are any truly shunting vessels. An accountant could clearly demonstrate that any research into oxygen transport is clearly unnecessary on the basis of the small problem that exists. I don’t know how to scale the various problems until they've been applied. One of the ways to scale problems is by the difficulty in applying them. We have a tremendous diversity of competence in apply- ing knowledge about oxygenation in various training centers, not to mention what is going on in private hospitals some distance away from the training centers. DR. LAVER: As I see it, the major prob- lem is how to coincide top level decisions on the direction of research and our desire to bolster segments of anesthesia in need of more funds. For example, dedication of substantial funds to the study of heart disease resulted in the for- mation of several centers for study and surgi- cal treatment of coronary ischemia. We as anesthetists cannot ignore this effort since we are called upon to participate in the care of these patients. Thus our everyday problems grow commensurate with the magnitude of the thrust into goal-oriented research. Although I agree that we must use our resources wisely, given the present interest in coronary artery disease and the overall limitations on funding, I find the enthusiasm for study of problems re- lated to heart disease easy to understand. Un- fortunately, as the system is presently struc- tured, the choices are made for us. DR. SEVERINGHAUS: During Ted’s talk, I listed eight areas of respiration research in which anesthesiologists are the leading in- vestigators, and in which more work is needed. I would like to list them, because I think it il- lustrates, in answer to your question, that we still have much to do. First of all, the effects of drugs on the regulation of respiration has been primarily our field. There is no doubt that anesthesiologists have done much more than anyone else to document the way in which drugs affect the control of breathing. Second, the central chemoreceptors have been charac- 34 terized as CSF pH receptors. Much of that work’ has been done in anesthesia depart- ments, but it is not yet known what structures are receptors, and how they are connected. Third, anesthesiologists have described and studied the wakeful stimulus of respiration, which prevents apnea with low CO2. This poorly understood physiologic effect needs more study. Fourth, the peripheral chemoreceptors and their responses to hypoxia are of considerable importance because about 10% of the population lacks this response. We need tests to detect which of our patients lack these responses. Fifth, the depressant effects of combinations of agents is beginning to be studied. Some drugs, such as narcotics and barbituates, have synergistic effects on respir- ation. Sixth, the methods of study of respira- tory control have fallen into our hands. We are the ones equipped with the apparatus, and have designed the methods. Seventh, the methods of measuring blood PO2, and PCOze, have come into widespread general use and are in the hands of anesthesiologists, in intensive care units and in the recovery and operating rooms. There is a need for more dependable blood gas instrumentation. Finally, in the in- tensive care unit, the respiration of patients chronically on respirators needs much more work. MECHANISM OF ANESTHESIA General Anesthesia DR. EGER: Most theories of how general anesthetics act are of rather recent origin. The development of these theories required some understanding of nervous transmission, par- ticularly at the synapse, and such an under- standing has only recently come forth. Several of the earlier theories now are discarded or have undergone substantial revision. Ver- worn’s theory that anesthetics act by produc- ing hypoxia proved untenable although in the past year Krnjevic noted that there are signifi- cant parallels between the action of anesthetics and the effect of hypoxia. The biochemical theories, that anesthetics act by inhibiting carbohydrate metabolism or by inhibiting the formation of high energy phosphate bonds (by the uncoupling of oxydative phosphorylation), no longer are seriously considered. The latter suggestion was demolished by the finding that anesthetics simply do not diminish cerebral stores of high energy phosphate. The hydrate theory advocated by Pauling and Miller has fallen for want of supporting evidence. Support for the hydrate theory con- sisted principally of the correlation between anesthetic potency and the anesthetic pressure required to form a hydrate (the hydrate dis- sociation pressure). That correlation turned out to be poor for agents such as sulfur hexafluoride, halothane or chloroform. Finally, the theory of Allison and Nunn that anesthe- tics act by the reversible dissolution of mi- .crotubules was discarded when they discov- ered that ether failed to cause microtubular dissolution. The Search for the Site of Anesthetic Ac- tion: As the old theories have fallen, new theories have arisen. I propose first to examine the anatomic basis for these. For some time, anesthetists and neurophar- macologists have searched for the major gross anatomic site of anesthetic action within the central nervous system. Their rationale was that, once localized, the basic properties of that site and the interaction with anesthetics could be defined and explained. The search was rewarded with an unwanted abundance. Anesthetics were found to act everywhere: the cerebral cortex, the reticular activating sys- tem, the spinal cord, and perhaps even the peripheral nervous system. On a microscopic level the search has been somewhat more satisfying. Some time ago, Larrabee and Posternak demonstrated that anesthetics more effectively blocked synaptic as opposed to axonal transmission. Several investigators have corroborated these findings. However, a recent report by Barker suggested that the greater synaptic inhibition might depend on the relative hydrophilicity of the anesthetic: alcohols with a high hy- drophilicity may be equally effective in block- ing axonal and synaptic transmission. On a molecular level, the correlation of lipid solubility and anesthetic potency de- scribed by Meyer et al has survived (in a mod- ified form) as the best of all correlations of physical properties with potency. The implica- tion of this finding is that anesthetics act at a 35 hydrophobic site which might be one of the cell membranes (including vesicle membranes) or a hydrophobic portion of a protein. The general applicability of the lipid correlation has been challenged by Mullins and more recently by Nahrwold who note exceptions to the correla- tion. These exceptions always take the same form: some substances (e.g., normal decane) have high lipid solubility yet are not anesthet- ic. The reverse (anesthesia in the absence of lipid solubility) has not been demonstrated. Mullins has explained these exceptions by postulating that the anesthetic site of action is limited in capacity and that molecules beyond a certain size cannot be accommodated. His ex- planation leads to a “critical volume hypothesis” which postulates that anesthesia is achieved when the anesthetic site of action has been expanded by a critical amount. Support for this concept has come from the finding that application of very high pressures (tens to hundreds of atmospheres) antagonizes the ef- fect of anesthesia (“pressure reversal”). K.W. Miller has calculated that the compression of a lipid phase produced by such pressures roughly equals the expansion produced by the additional anesthetic which must be applied to achieve anesthesia at high pressures. Several investigators have examined what anesthetics do to model lipid or lipoprotein membranes. All agree that anesthetics in- crease the fluidity of such a membrane and in- crease the surface pressure within the mem- brane. Trudell has demonstrated that this in- crease in fluidity is opposed by the application of high pressure. Normal Synaptic Transmission: Let us return to the synapse and examine where and how anesthetics might act on the conductive process. Synaptic transmission may be sum- marized as follows: The nerve action potential depolarizes the nerve terminal by opening sodium channels. Calcium ions then enter the nerve terminal and act both to facilitate vesicle release and to open potassium channels. The opened potassium channels are essential to re- polarization and to the hyperpolarization that transiently follows depolarization. The calcium is removed by mitochondria and the potassium channels close. The preceding vesicle release of neurotransmitter into the synaptic cleft re- sults in depolarization of the subsynaptic membrane by opening relatively large chan- nels that permit the passage of both sodium and potassium ions. If the subsynaptic de- polarization is sufficient to cause the adjacent postsynaptic membrane to reach threshold, then a regenerative pulse appears and synaptic transmission is successful. Anesthetic Effects on the Nerve Terminal: There is conflicting evidence as to the impor- tance of the nerve terminal as a primary site of anesthetic action. There is little evidence for blockade of sodium channels. However, Krnjevic and R.N. Miller have suggested that anesthesia may cause hyperpolarization by sustaining a high potassium conductance. The sustained conductance may be produced by the failure of mitochondria to absorb calcium. This may be mediated by the build-up of cyclic AMP. All anesthetics tested (including halothane, isoflurane, methoxyflurane, fluroxene, ketamine, and morphine) by Biebuyck and Seager increase cyclic AMP in brain cells. In conflict with this theory is the finding by Cohn that injection of cyclic AMP into rat cerebral ventricles antagonizes anes- thesia from halothane, alcohol, ketamine, diazepam, or chloral hydrate. How might anesthetics inhibit the release of vesicle content into the synaptic cleft? Anesthetics may alter the nerve terminal membrane, either making the vesicle attach- ment to the membrane more difficult or making the rupture of the vesicle membrane less prob- able. Vesicular rupture must precede release of neurotransmitter. The work of Seemans’ group suggests that anesthetics protect against rupture of red blood cells induced by immersion in hypotonic solutions. The protec- tion is proportional to anesthetic potency. By analogy, anesthetics might strengthen the ves- icle membrane and prevent its rupture. The difficulty with either this or the preceding thought, that anesthetics may cause hyper- polarization, is that many anesthetics do not decrease but rather increase neurotransmitter release (Quastel). Subsynaptic and Postsynaptic Anesthetic Effects: There is general agreement that most if not all anesthetics inhibit subsynaptic or postsynaptic transmission. There appears to be a decreased sensitivity to excitatory neurotransmitters (which actually could be a postsynaptic effect). Three subsynaptic areas might be affected. First, by distorting the un- derlying lipid or protein phase, anesthetics might modify the acetylcholine (or other neurotransmitter) receptor. There is little di- rect proof for this thesis although it is known that anesthetics can alter the tertiary struec- ture of protein. Second, anesthetics might hinder the mechanism which opens the sub- synaptic channels. In neuroblastoma cells, Hinkley found that 0.75% halothane inhibits formation of microspikes containing microfila- ments and causes regression of microspikes al- ready formed. Microfilaments contain actin which may be similar to the protein involved in the contractile process responsible for opening subsynaptic channels. Third, anesthetics may obstruct the channels. Mullins originally pro- posed that anesthetic molecules might lodge in the channel like a plug in a hole. The hydrophilic nature of the channel would make this seem un- likely. Alternatively, by dissolving in, and ex- panding the cell membrane, anesthetics may compress the channels. As noted earlier, anesthetics increase lipoprotein film surface pressures and do so in proportion to their po- tency. The pressure reversal effect also would seem to be supportive. However, Roth has noted that high pressures increase the anesthetic effect of TEMPO on axonal conduec- tion and Kendig similarly has found that high pressures increase the depressant effect of halothane on synaptic transmission. Finally, anesthetics might make depolari- zation of the postsynaptic membrane more dif- ficult. The possible mechanisms are identical to those involved earlier for depolarization of the nerve terminal. Most likely is the possibility that slight hyperpolarization occurs. The effect of cyclic AMP on calcium re-uptake by mitochondria may be crucial to this hyper- polarization. I hope I have conveyed my feeling that we are tantalizingly close to knowing how anesthetics act. Local Anesthesia The investigation of how local anesthetics act is simplified by the specificity of the site of action. It is obvious that in some way axonal conduction is blocked. We now know that this is achieved by preventing the increase in 36 sodium conductance required for regeneration of the nerve action potential. The trans- membrane potential is stabilized and gives no indication that hyperpolarization (opening of potassium channels) contributes to blockade. Nor is there an increase in chloride conduc- tance which also could cause stabilization of the transpotential. The Effect of Ionized vs. Non-ionized Local Anesthetic Molecules: By separately perfusing the inside and outside of axons with quaternary derivatives (i.e., highly ionized) of local anesthetics, several workers have dem- onstrated that the site of action of the ionized species is on the inside of the nerve. That is, blockade of sodium current occurs far more readily when local anesthetics are applied within as opposed to outside the axon. Strichartz suggests that the ionized species acts about halfway down the electrical gra- dient (at the gate?) through the sodium chan- nel. Furthermore, he and Hille find that the application of prior depolarizing pulses in- creases the blockade of sodium currents, perhaps by increasing the access of the anesthetic to its site of action within the chan- nel. These experiments suggest the impor- tance of the ionized species. However, two facts suggest that the non-ionized species may be equally and sometimes more important. First, in desheathed nerves, the minimum blocking concentration of procaine decreases as pH is raised from 7.2 to 9.2 (Ritchie and Ritchie): such a reduction in hydrogen ion must increase the fraction of non-ionized procaine. It should be noted that an opposite effect is seen for lidocaine and dibucaine. Second, ben- zocaine readily produces local anesthesia al- though its pKa of 2.8 would preclude signifi- cant ionization at a normal pH. Varying pH from 7.2 to 9.2 does not affect benzocaine po- tency. Thus, we must conclude that both the ionized and non-ionized species have local anesthetic effects. This also implies that two sites of mechanisms of action may exist. Effect of Sodium and Calcium: Sodium and calcium ions influence the effect of local anesthetics. A reduction of the sodium con- centration bathing a nerve increases the po- tency of a local anesthetic (Condouris). An in- 37 crease in calcium ion augments local anesthetic potency and it appears that calcium and local anesthetics act at the same site of action (Frankenhauser and Hodgkin). Both may form part of the “latch” which holds the gate to the sodium channel in place. Theories of Local Anesthetic Action: None of my previous comments describe a specific mechanism which would explain the decrease in sodium conductance that produces axonal blockade. Let us examine some possibilities. Local anesthetics all increase the lateral pressure of lipoprotein films in proportion to their potency (Clements and Wilson). Perhaps such an increase in pressure occurs in the lipoprotein axon membrane and is sufficient to impair conductance by compressing the sodium channel. Levy suggested a similar explanation for an effect at the nodes of Ranvier: the solu- tion of local anesthetic into myelin sheath might expand the sheath sufficiently to cover the node and thereby exclude sodium from the external surface. In effect, this would lower the external sodium concentration and thereby reduce the polarizing pulse. The lateral pres- sure induced within the axon membrane also may impede the protein rearrangement re- quired to open the channel. An increase in membrane fluidity might have the same effect. The above comments on mechanism apply chiefly to the non-ionized species. The ionized species probably acts in the same fashion as calcium to hold the sodium gate in place. The local anesthetic may be more effective than calcium because, even in the ionized state, a portion of the local anesthetic molecule re- mains hydrophobic. This hydrophobicity may secure the local anesthetic to the nerve mem- brane and prevent its dislodgement by an on- coming nerve action potential. How the local anesthetic specifically keeps the gate from opening probably will remain unknown until the molecular process involved in normal func- tion becomes more clearly defined. PAIN RESEARCH DR. BONICA: During the past two de- cades the field of pain research and theory, which lay conceptually stagnant for almost a century, has suddenly become alive—full of new controversy and renewed fascination. Consequently, a vast amount of new informa- tion has become available which clearly dem- onstrates that pain is a much more complex phenomenon than the simple straight-through system implicit in the traditional theory. The pain experience provoked by injury or disease is the net effect of any interacting physiologic and psychologic mechanisms which involve ac- tivity of most parts of the nervous system con- cerned with sensory, motivational, cognitive, and psychodynamic processes. I shall give a quick overview of a few of the new facts per- taining to peripheral systems, ascending sys- tems, descending systems, and psychologic factors with mention of some research done by anesthesiologists. A comprehensive review of many of these studies appears in the Proceed- ings of the International Symposium on Pain, published as Volume 4 of Advaices in Neurol- ogy by Raven Press, 1974. Peripheral Systems Many recent electrophysiologic studies have shown an impressive degree of specializa- tion among receptor-afferent fiber units which transmit information from various parts of the body to the neuraxis. Several types of recep- tors have been identified: mechanoreceptors, thermoreceptors, and nocireceptors or pain re- ceptors. Nociceptors are characterized by high threshold, small receptor fields, persistent discharge for a suprathreshold stimulus, and are terminals for small A delta and C afferent fibers. They are activated by very strong mechanical stimulation, extreme cold (less than 15° C), or high temperatures (above 50° C) and are thus known as mechanonociceptors and thermonociceptors, respectively. New data from single and multiple fiber studies in animals and man support earlier ob- servations that A delta and C fibers are essen- tial for pain sensation. Studies by Perl, Iggo, and others show that about 25% of A delta fib- ers and 50% of C fibers respond only to mechanical or thermal stimuli which are either potentially or frankly tissue damaging. Some high threshold fibers are polymodal, respond- ing to both thermal and mechanical noxious stimulation. Nociceptor-afferent fibers supply not only the skin and subcutaneous tissue but 38 also viscera, muscle, and other deep struc- tures. Anesthesiologists and neurophysiologists have used nerve blocks of peripheral nerves as a tool for pain research. A block with very low concentration of local anesthetics, which af- fects only the C fibers, combined with pressure block, which affects large fibers first, has been used to define the role of small fibers in pain sensation and in preliminary studies of pain mechanisms of herniated disc and postamputa- tion pain. We have used discrete paravertebral and segmental epidural blocks to study the pathways of the uterine contraction pain and the sensory (pain) nerve supply of the cervix. Central Mechanisms It is now clear that the pain mechanisms involve an incredible degree of modulation all along the course of transmission by local, seg- mental, and suprasegmental influences, achieved through the phenomena of excitation (facilitation), inhibition, convergence, summa- tion, and divergence among others. Dorsal Horn: Recent studies have shown that the dorsal horn, which was traditionally considered as a simply relay station, is a highly complex structure containing many varieties of neurons and synaptic arrangements. There are not only contacts between dorsal route fibers and dorsal horn cells, but among dorsal horn cells by axonal contacts and by contact with cells descending from the brain and higher parts of the nervous system. These permit not only reception and transmission, but a high de- gree of sensory processing, including local abstraction, integration, selection, and divi- sion. This is achieved through complex interac- tion of excitatory and inhibitory influences coming from the periphery, adjacent neurons, the brain, and from various other parts of the central nervous system. Numerous studies have defined some of the anatomical and functional characteristics of cells in the six laminae of the dorsal horn. Imput from the periphery is roughly distrib- uted according to fiber size. The large myeli- nated fibers give a collateral that sweeps vent- rally, enters the dorsal horn, and makes synap- tic contact with cells in various laminae, while the small diameter myelinated and non- myelinated fibers enter more directly to make contacts with cells in various layers. Cells in laminae I and V are especially important be- cause many of them respond to peripheral nox- ious stimulation. Cells of lamina I receive dorsal root input exclusively from A delta and C fibers and have connections with the cells in the substantia gelatinosa of the same neighboring segments, and their axons project to the ipsilateral and contralateral cord and in some of these ascend cephalad. Cells of lamina V receive contacts from other dorsal horn cells and directly from some dorsal root afferents which supply the skin, subcutaneous tissue, muscle, viscera, and other deep structures. Some lamina V cells send axons to the dorsolateral and to the ven- trolateral white matter of the spinal cord both ipsilaterally and contralaterally. Lamina V cells also respond to noxious chemical stimuli, such as peripherally applied bradykinin, a property not found in other dorsal horn cells. Moreover, all of the lamina V cells which re- spond to visceral high threshold afferents also respond to low threshold cutaneous afferents from an area of skin supplied by the same spi- nal cord segments. Thus, these lamina V cells, with convergence of somatic and visceral fib- ers, provide a basis for the phenomenon of re- ferred pain seen with visceral and deep somatic disorders. Anesthesiologists have contributed to our knowledge of physiology and pharmacology of the dorsal horn and the homologous cells of the trigeminal system. Contrary to the old concept that spinal cord function is depressed only by deep general anesthesia, De Jong, Heavner and collaborators and Kitahata and coworkers have shown that analgesic and anesthetic con- centration of intravenous and inhalation anesthetic agents depress the spontaneous and evoked activity of dorsal horn neurons, espe- cially those of laminae I and V by direct intras- pinal action. De Jong and Heavner showed that nitrous oxide depressed spontaneous firing and firing response to innocuous stimulation con- siderably less than the response to noxious stimulation, suggesting that the dorsal horn ef- fects of anesthetics relate better to analgesia than unconsciousness. Heavner and De Jong studied the effects of halothane, thiopental, and ether in decerebrate or decerebrate plus low spinal cats. That halothane had the same 39 effect in both preparations indicates anesthetic-induced changes are due to direct intraspinal drug action. Fifty percent depres- sion of evoked and spontaneous activity corre- lated roughly with light surgical anesthesia in intact cats. Neurons responding to innocuous and noxious stimuli were similarly affected, but overall units in lamina V were depressed more consistently than units in other laminae. Ongoing studies by Heavner and De Jong show that ketamine has little effect on the response of dorsal horn neurons to peripheral stimula- tion. Very recently they have shown by ionotophoretic studies that halothane depre- sses spinal cord throughout by interfering with the postsynaptic effect of the excitatory trans- mitter glutamate, but has no effect on post- synaptic action of the inhibitory transmitter glycine. Kitahata et al noted that 75% N20 and hyperventilation selectively and profoundly suppressed spontaneous activity of lamina V cells, leaving laminae I, IV and VI essentially unchanged. They also found that intravenous ketamine suppressed single-unit and evoked activities of lamina I and lamina V by 23 to 43% and 44 to 64%, respectively, but did not affect spontaneous activity of laminae IV and VI. Subsequently, they found that morphine sup- pressed single-unit activities, both spontane- ously and when evoked by noxious stimulation, but did not affect them spontaneously in laminae IV and VI. Ascending Systems: Although the lateral spinothalamic tract traditionally has been con- sidered as the specific pain pathway, there is now much evidence that it is also involved with other sensory information and, conversely, other sensory pathways play a role in pain. Moreover, recent anatomic and physiologic evidence suggests that spinothalamic system is composed of two divisions: 1) The phylogenetically more recent neospinothalamic tract, located more laterally and composed of long fibers which make direct connection to the ven- trolateral (VPL) and posterior thalamus (PO), where they synapse with a third relay of fibers that project to the primary somatosensory cortex. This system shows discrete somatotopical organization and has the capacity to process discriminative information regarding the location of peripheral stimulation in space and time and along an intensity continuum. This function is influenced by the dorsal column-lemniscal system which also proj- ects to the ventrobasal thalamus and thence to the somatosensory cortex. 2) The older paleospinothalamic tract, located more medially and composed of short fibers that project to the reticular formation of the spinal cord, medulla (par- ticularly nucleus gigantocellularis (NGC), the lateral pons, and midbrain (limbic midbrain area), and then to the medial in- tralaminar thalamic nuclei (MIT). These spinoreticular, spinomesencephalic, and paleospinothalamic fibers, which Melzack and Casey called the paramedial ascending system, then make contact with nerve fib- ers that connect with the hypothalamus and limbic forebrain structures and also with diffuse projections to many other dif- ferent parts of the brain. This older sys- tem is not organized to provide discrete in- formation, but is involved in supraseg- mental reflex responses concerned with ventilation, circulation, and endocrine function, and also in provoking the power- ful motivational drive and unpleasant af- fect that triggers the organism into action. The Dorsal Coliwmn System: Composed of the central branch of large myelinated spinal nerves and long-known to transfer touch and proprioception, is now considered by Melzack, Wall, and others to play some role in pain mechanisms. Increase in dorsal column fiber activity inhibits dorsal horn transmission either directly or, more likely, indirectly through propriospinal fibers. In addition, the fast-conducting dorsal column and dorsolateral projection pathways, together known as the lemniscal system, may also function as a “cen- tral control trigger” or a “feed forward” path- way which triggers the activity of brain sys- tems involved in the spatial and temporal analysis of input ascending through other pathways. The very rapid transmission makes it possible for the brain to identify, localize and selectively modulate, through corticofugal im- pulses, the sensory input before the action sys- tem is activated. 40 Trigeminal System: It is well known that pain from the head is conveyed by sensory fib- ers in the 5th, 7th, 9th, and 10th cranial nerves whose proximal fibers enter the brain stem where they become associated with the sen- sory nucleus of the 5th trigeminal nerve. Here they synapse with second order neurons, many of which cross the midline and ascend with the contralateral medial lemniscus, while others do not cross and ascend with the spinothalamic tract to brain stem reticular formation, sub- thalamus, and to medial and intralaminar thalamic nuclei. Two anesthesiologists have done basic neurophysiologic research on this system. After more than a decade of intense studies by many investigators had failed to demonstrate nociceptors in the trigeminal complex system, Kitahata and collaborators were the first to find cells responsive primarily to nociceptive stimulation by combining physiologic and histologic techniques. These central trigeminal nociceptors were located in the magnocellularis zone of the caudal portion of the nucleus caudalis located in the dorsal horn of the upper cervical spinal cord. They also found cells responding to low threshold cutaneous stimuli applied to the ipsilateral face dorsal and rostral to these central trigeminal nociceptors. Nitrous oxide (75%) in oxygen suppressed the spontaneous firing frequency of the central trigeminal nociceptors by 31 to 35%, but facilitated spontaneous activity of the low threshold cutaneous receptors of the nuc- leus caudalis by 20 to 31%. My colleague, Richard G. Black, has done basic neurophysiologic study of the trigeminal system to show a relationship between central pain states and epilepsy. He has found that ex- perimentally induced epileptic foci in the spinal trigeminal system of cats and monkeys re- sulted in a clinical syndrome characterized by greatly increased sensitivity to touch on the ipsilateral face, spontaneous episodes of in- tense pain-like behavior, and accompanying epileptic-like neural activity seen with mic- roelectrode recording. Dr. Black’s work has been extended to implicate peripheral nerve damage including dental trauma as an etiology for focal neuronal hyperactivity in the spinal trigeminal complex and hence for trigeminal neuralgia. Strong clinical conformation of this model has come through recordings made from patients during surgery for trigeminal neural- gia and the response of this clinical condition to anti-convulsant medications. Descending Influences: During the past two decades much evidence has been acquired showing that supraspinal descending neural systems have marked influence on synaptic transmission in the dorsal horn and all along the course of the ascending somatosensory projection system. The pyramidal tract, rub- rospinal tract, and reticulospinal tract, long considered as exclusively motor pathways, have recently been shown to influence trans- mission in the spinal cord. Moreover, each structure below the brain which sends fibers to the cortex were found to receive descending fibers from the cortex that can influence transmission in the thalamus, recticular forma- tion, the dorsal column relay station, and the trigeminal system involved with sensation of the face and head. There are also descending fibers from these various structures below the brain which impinge upon and can influence transmission in lower relay stations. One of the most exciting new series of in- vestigations has shown that electrical stimula- tion of the ventrolateral part of the central gray substance of the mesencephalon and periventricular grey and caudate nucleus pro- duces a profound analgesia without apparently interfering with motor function or with the animal’s responsiveness to other sensory stimuli. The degree of analgesia produced is comparable to that produced with very large doses of morphine. The evidence also suggests that the analgesia is due to activation of an in- hibitory neural system which blocks transmis- sion of pain in the spinal cord and other parts of the nervous system. Moreover, there is evi- dence that this group of inhibitory nerves is part of a larger neural system that is selec- tively stimulated by morphine to produce analgesia. It has been found that analgesia from cen- tral grey stimulation is blocked by drugs which have been shown to block the analgesic action of morphine, such as tetrabenazine (TBZ), which depleted monoamines, and p-chlorophenylalamine (CAPA), a serotonin synthesis inhibitor; and that such anti- analgesic action can be reversed by a serotonin 41 precursor. Moreover, analgesia produced by stimulation can be antagonized by nalaxone (Marcan), the narcotic antagonist. The analgesic system is presumed to act at spinal levels because spinal nociceptor reflexes are inhibited. Brain stimulation in the cat consist- ently inhibits the responsiveness to noxious stimuli of interneurons in lamina V of the spi- nal dorsal horn. Various groups have already begun applying the technique of brain-stem stimulation to the treatment of intractable pain in humans with some success. Psychologic Factors During the past quarter century we have acquired much scientific data which impres- sively emphasizes the importance of the moti- vational, affective, cognitive, emotional, and other psychologic factors on the individual's total pain experience. Moreover, it has put in sharper focus the influence of perceptual fac- tors, learning, personality, ethnic and cultural factors, and the environment; and it has helped to clarify the psychodynamics of anxiety, de- pression, attention, and the significance of pain. One of the most important advances in pain research has been the recent introduction of the “signal detection (decision) theory” technique, which permits the separate meas- urement of the sensory sensitivity to pain stimulation and the attitudinal bias to it. These two measures are obtained independently of each other and together they account for the interaction of sensory experience and the wil- lingness of the subject to admit feeling pain. With this technique several workers have shown the unreliability of the pain threshold as quantitative measurement. They have shown that placebo does not change sensory sensitiv- ity to pain—i.e., it does not increase pain threshold as suggested by older studies, but produces a significant change in response bias. ACUPUNCTURE ANALGESIA Research in the United States DR. CASEY: Much of the ongoing re- search in the United States related to acupuncture has been reviewed in the Proceed- ings of the NIH Acupuncture Research Con- ference (Jenerick, 1973). Since the publication of those proceedings, additional work in human psychophysics has been performed by Clark and Yang (1974). They showed that acupuncture produced no change in dis- criminability of thermal stimuli although an elevation of the criterion for identifying a stimulus as painful was observed. In previous work, Andersson et al (1973) showed that elec- trical stimulation at acupuncture points dramatically raised the pain threshold deter- mined by electrical dental stimulation. In a continuation of previous work, Chapman et al (1973 and in press) have reported that both acupuncture and 33% nitrous oxide signifi- cantly modify detectability of painful dental stimuli. Innocuous electrical stimulation has also been shown to modify clinical pain (Wall and Sweet, 1967) and to elevate pain tolerance while depressing cortical somatosensory evoked potentials (Satran and Goldstein, 1973). I am not aware of ongoing research, if any, on the use of acupuncture anesthesia or analgesia in animals. There are, of course, numerous neurophysiological and behavioral experiments which continue to be done in an effort to learn more about the neural basis for pain and its modification. Scattered reports appear in newspaper ar- ticles and in journals (Franklyn, 1974) describ- ing the use of acupuncture in surgery in the United States. To my knowledge, no systema- tic clinical study of acupuncture analgesia in surgery has been published. Research in the People’s Republic of China I accompanied the Acupuncture Anes- thesia Study Group which went to the People’s Republic for three weeks in May 1974, to ob- serve the use of acupuncture as an analgesic technique in major surgery. The full report from this group is being prepared for publica- tion. In summary, we observed 48 operations ranging from simple dental extractions to major thoracic surgery. Of these cases, 73% were judged to have had satisfactory or proba- bly satisfactory analgesia by American stand- ards although the patients were completely awake and alert throughout the procedure. These results provided the background from which we also observe research being done in 42 China related to the mechanisms of acupuncture analgesia. Since one of the major purposes of our visit was to learn about the possible mechanisms underlying this phenomenon, we took particular interest in learning about the relevant research being done in China. Human Psychophysical Studies: At the Peking Medical College and the Shanghai First Medical College, both mechanical and electri- cal needling applied to the hand (Ho-Ku) or the leg (Tsu-san-li) was found to produce an eleva- tion of pain threshold generally over the sur- face of the body. The elevation in threshold was comparable to that produced by 50 mill- igrams of meperidine. Testing of the pain threshold was performed by potassium ion- tophoresis and by mechanical and electrical stimulation. In all cases, the hypalgesia was found to develop to maximum levels over a period of 15 to 20 minutes and then decay over a 30- to 40-minute period following termination of the acupuncture stimulus. These findings are consistent with those of the Swedish group (Andersson et al, 1973). In China, the hypalgesic effect of acupuncture is markedly reduced or eliminated by local anesthetic blocks at the acupuncture point or by the pre- sence of somatosensory deficits due to neurologic disease. Animal Behavioral Experiments: Rabbits are used for animal behavioral research in China. In all cases observed and reported to us by the Chinese, the reaction time to with- drawal from a noxious stumulus was measured before and during acupuncture stimulation of a point similar to that used in humans. The acupuncture stimulation increased the reaction time in each case. The pain stimulus employed was either electrical, chemical (potassium ion- tophoresis) or thermal. It should be noted that in Shanghai we were told that approximately one-half of the rabbits tested did not withdraw from the stimulus and hence could not be used for behavioral testing. Furthermore, the acupuncture stimulus itself was noxious and the extent to which this stimulus produced de- layed reaction by inducing a behavioral “freez- ing” or “still” reaction could not be deter- mined. Additional animal studies have shown that sectioning of the contralateral ventro- lateral columns of the spinal cord eliminates the effect of acupuncture; electrical stimula- tion of the caudate increases the acupuncture effect. Experiments employing the techniques of cross-circulation and cerebrospinal fluid col- lection and injection have suggested that some or all of the hypalgesia produced by acupuncture is hormonally mediated. Neurophysiological Experiments: The neurophysiological basis for acupuncture analgesia is one of the most actively pursued problems in Chinese biomedical science. Some experiments are directed at learning about the types of receptors stimulated by acupuncture. At the Shanghai Institute of Physiology, the discharge of muscle afferents was being studied in response to inserting a needle into rabbit or cat muscle. The results thus far had shown that the smaller diameter group II and group III muscle afferents were activated by such stimuli; it is speculated that these affer- ents may play a critical role in pain modulation because most acupuncture needling involves deep insertion of needles. Stimulation of nociceptors, however, is not thought to be crit- ical for the acupuncture effect since innocuous cutaneous electrical stimulation is frequently used in successful acupuncture analgesia at surgery. In other experiments, electrical stimulation of cutaneous or muscle nerves was found to inhibit the discharge of spino-cervical tract neurons and brainstem reticular forma- tion neurons responding to noxious stimuli. Similarly, Chang (1973) at the Shanghai Institute of Physiology has studied the effect of somatic stimuli in inhibiting the discharge of thalamic neurons in nucleus centralis lateralis and parafascicularis responding specifically to noxious stimulation. Although some inhibition of the response of these cells could be produced by a variety of somatic stimuli, the more effec- tive inhibition was produced by electrical stimulation of points similar to acupuncture points in man. At the Chung Shan University in Kwanghow, stimulation of C fibers in the cat saphenous nerve is said to produce a distinct evoked potential recorded at the cerebral cortex. This potential is apparently depressed for approximately one minute following elec- trical stimulation at acupuncture points. Evaluating the analgesic effect of acupuncture includes the same difficulties in experimental design and interpretation found in 43 the evaluation of any analgesic method. It is not surprising, therefore, that both human and animal studies have thus far failed to provide a reasonable explanation for the acupuncture analgesia or hypalgesia seen in major surgery. The evaluation of acupuncture as a treatment for chronic pain is even more difficult and can- not be adequately assessed at the present time. There is no doubt, however, that in China major surgery can be performed under acupuncture with little or no analgesic medication and with satisfactory analgesia in most but not all cases. In humans, the mechanism of action is obscure; it is not clearly and simply a peripheral or seg- mental blockade of impulses from nociceptors. In fact, the extent to which acupuncture nee- dling or stimulation is necessary is an open question. Many features of the acupuncture analgesia phenomenon emphasize the impor- tance .of suprasegmental brain mechanisms in the control of pain. Clearly, further research on the central mechanisms of pain and its control is required before (nearly) drugless analgesia can be understood and, perhaps, used effectively. In interpreting the Chinese research ef- fort, it should be kept in mind that research in China is highly directed on the basis of its pre- sumed immediate practical application and en- hancement of the scientific credibility of acupuncture in particular, and Chinese tradi- tional medicine in general. In the United States, the relevant clinical and basic research should continue to follow the customary lines of scientific rigor and objectivity applied to the investigation of any potentially useful therapeutic tool. DISCUSSION DR. KITZ: These last three papers all dealt with basic mechanisms. The basic mechanisms of anesthesia, pain, acupuncture, Would it be in the best interest of the American people if the funds that are going into these ef- forts were to be focused more in clinical areas, rather than basic sciences? Dr. Eger, you said, for instance, that we are tantalizingly close to understanding the fundamental mechanism of anesthesia. Of what use is that in the clinic to me, tomorrow? DR. EGER: There is no answer. I think we can say that there remains an unsolved problem that has potential implications to the practice of anesthesia and the discovery of new anesthetic agents. How that relates to the needs of children who are hungry or to the needs of people undergoing coronary bypass, I can’t tell you. DR. BONICA: I think in order to devise better drugs with less side effects, we must first look closer at the mechanisms of pain and related mechanisms of anesthesia. In these target areas there is a lot of tantalizing evi- dence that certain drugs will affect, say, lamina I or lamina V and prevent pain much more than they interfere with other functions. If we could get the whole picture, and then de- vise a drug that affects just the required sites and has no effects on the other sites, we would have the ideal anesthetic. DR. MODELL: We need new ideas, be they in the operating room or in the basic sci- ence building. There should be a broad base of support; we should not think in terms of buying the result in one area and not doing anything in 44 another area. The money is best spent where the greatest productivity can be obtained. But it may be that we have to give preferential treatment to one area or another, where there are people with the ideas and with the exper- tise to help solve those problems. DR. CASEY: In the area of pain, it is very difficult to separate basic and clinical research. Pain is not uniquely a human phenomenon, but there are many situations in which man is the only appropriate organism for a study which may have very basic implications. I don’t think the division can be made, particularly in this area. DR. FINK: In the area of acupuncture, in particular, we are still in the anecdotal stage, and the kind of research that should be sup- ported in that area is research which is not simply trying to prove that it does happen, but perhaps research that proves that it doesn’t. Or research which tries to examine what other explanations are possible for these results, on the basis of what appears to us as classical mechanisms. PANEL DISCUSSION: ANESTHESIOLOGY RESEARCH CENTERS ADVANTAGES AND DISADVANTAGES WILLIAM K. HAMILTON, Moderator John J. Bonica, Henrik H. Bendixen, Nicholas M. Greene, Jerome H. Modell, Panelists DR. HAMILTON: This morning, Dr. Black reviewed the development of the center concept and its present state in anesthesiolo- gy. We are going to look at some specifics this afternoon, and perhaps even define what a re- search center is. The research center has come in for a fair amount of criticism. There are, however, people who believe that they are a good thing. Both views will be discussed. We will hear from two anesthesia research center directors and two investigators independent of the centers. The first will be Dr. Bonica. THE ROLE OF CENTERS DR. BONICA: I shall review briefly the history and development of anesthesia re- search centers, ask some crucial questions about the need for such centers, and provide background information for this Panel's con- sideration. The following is a quote from the report on Anesthesiology by the Committee assembled by NIGMS in 1966 to identify major problem areas in the field: “The main thrust of the research center’s activities should be one of problem- solving. The research and research train- ing aims of the programs undertaken at these centers would be of such nature, breadth, and scope in anesthesiology as to best satisfy the public health needs of the nation and serve as a focal point for such research activities in the region in which the center is situated. While these grants would not provide for construction, they should promote collaborative programs of research and training involving other uni- versities, government agencies, and inde- pendent research institutes in the area.” At the time the Anesthesia Research Cen- ter effort was initiated, program projects were being supported at Columbia, Pennsylvania, and Stanford. The first Anesthesia Research Center was established in 1967 at the Univer- sity of Pennsylvania under the direction of Dr. 45 Robert Dripps. The program project at Pennsylvania was also retained. These, to- gether with the 32 individual grants brought the level of anesthesia research support by NIGMS to $2.2 million. The following year Anesthesia Research Centers were established at Harvard and the University of Washington, and the program project at Columbia was designated a research center. An award was also given to the Uni- versity of California, San Francisco, which qualified as a research center but because of University restrictions was designated a pro- gram project. A program project was also awarded to Northwestern University. Support for these four research centers, the three pro- gram projects, and 34 individual grants totaled $3.3 million. In 1969, NIGMS awarded $4.2 million to support the aforementioned research centers, program projects and 30 individual grants. During the ensuing three years, support by NIGMS for anesthesia research totaled $4.1, $3.8, and $4.3 respectively, while the total number of grants, including the research cen- ters, was reduced to 24, 13, and 15 respective- ly. During the period 1969-1973, the four re- search centers cumulatively were allocated $2.8, $2.8, $2.6, $3.2 and $2.9 millions of dol- lars, respectively. These amounts represented about 70% of the total NIGMS support for anesthesia research. During FY "74, the total support dropped to $3.2 million. At this time the University of California program was des- ignated a research center. This combined sup- port of the five centers was $2.4 million, repre- senting 75% of the total support given by NIGMS. These amounts are significantly lower than those projected for center pro- grams by the Director of NIGMS in 1966. However, it is important to note that sub- sequently Congress appropriated only $1 mil- lion annually as a line item for Anesthesiology. There are three reasons for reduction of total funds and total number of research proj- ects in anesthesiology: 1) termination of two program projects; 2) reduction in the number of projects assigned to NIGMS because of the categorical nature of the research; and 3) a re- duction of funds imposed by the administra- tion. Distribution of Funds In view of the fact that, since their incep- tion, the anesthesia research centers have been allocated two-thirds to nearly three-quarters of the NIGMS budget for anesthesia research, we have to ask the following questions: Are anesthesia research centers needed? Are they worth the amount of invest- ment? What have been their accomplishments? Has the research productivity come up to expectation? What are the advantages and disadvan- tages of research centers? What problems does this mechanism of research support pose? These questions have been in the minds of, and indeed have been asked by many members of NIGMS staff and the scientific community. Soon after the activation of the research centers pro- gram, concern was expressed by the scientific community that this mechanism of research sup- port would decrease the quality and quantity of biomedical research and impose certain lim- itations and disadvantages on investigators. Three years ago, almost to the day, the General Medical Research Program-Project Committee, which at the time was the review body of NIGMS for all research centers and program projects, devoted an entire day considering these concerns and questions pertaining not only to anesthesia but to all disciplines within its jurisdiction. The Committee considered various issues within the framework of its experience. After a wide-ranging and vigorous discussion, the Committeee agreed to a set of theoretical advantages and disadvantages, noted numerous research accomplishments by trauma, anes- thesiology, and radiology research centers, cited problems with the center mechanism, and made suggestions how these may be solved, all of which Drs. Bendixen, Greene, and Modell will consider in detail from the perspectives of their experience. 46 To answer the question—Do we really need anesthesia research centers?—we must consider the number of well-trained inves- tigators, the quality and quantity of research productivity, and the type of research on anes- thesia and related problems done in the United States before and after the activation of cen- ters. I think it is safe to guess that the five research centers probably have three-quarters of the research manpower dealing with anesthetic problems in our country. This is suggested by the fact that three-quarters of the panelists discussing current and future re- search in anesthesia at this workshop are cur- rently, or at one time were, members of the five centers. The fact that members of these research centers will present 35% of the total of 161 scientific papers during the forthcoming annual meeting of the American Society of Anesthesiologists is another criterion. The fig- ure is even higher if one considers fundamental research. Also, it has been shown that inves- tigators in these centers publish about 25% of their papers in basic science journals and most of the others in prestigious clinical journals. These data are not cited to disparage research being done by other investigators, but to indi- cate that the center mechanism is conducive to high quality and quantity research. Could these results and others have been achieved through individual grant mechanisms? Yes, the research of some of the investigators in centers could be done on an individual basis, but not as economically. Moreover, much of the research is of the type that could not be done without the collabora- tive effort of a number of basic scientists and clinical investigators working as a well- coordinated team. On the basis of my experi- ence, I am convinced that the center mechanism is the most effective way to en- courage scientists from different disciplines to become members of research teams essential to the solution of clinical problems. Many of these problems require such in-depth and in- breadth studies that they can only be solved through the center mechanism. Whereas indi- vidual projects tends to separate inves- tigators, centers tend to “force them togeth- er.” A number of projects done in our research center and other research centers have been of such comprehensive nature, entailing meas- urements of many variables simultaneously, that they could not have been done without the well-coordinated efforts of several inves- tigators from different disciplines and the availability of a pool of technicians and expen- sive equipment provided by the central facili- ty. In our own case, this was particularly true of the studies done by the sections of Obstetri- cal Anesthesia, Biochemical Mechanisms, Pulmonary Physiology, Circulation, Regional Anesthesia, and Bioengineering. I am also convinced that research centers are critical to the development of what I call scientifically deprived disciplines, such as anesthesiology. Experience has shown that funding of anesthesia research centers mar- kedly increased the research capability of the discipline both directly and indirectly. In addi- tion to the direct benefit of large funds, the awards enhanced the acquisition of more funds and space from their respective universities. These in turn helped the programs increase their capability to recruit outstanding clinical investigators and made possible recruitment of basic scientists who otherwise might not have joined a clinical department. In our own case, the number of basic scientists in the depart- ment increased from zero to eight, all of whom have joint appointments in the appropriate basic science departments. Their active par- ticipation has helped to improve the quality and the quantity of anesthesia research. Thus, the center grant has helped to break the vi- cious circle of former years and replace it with a highly beneficial self-enhancing process of more resources—better environment—easier recruitment of scientists—better and more re- search—greater capability of obtaining more funds, space and resources—better environ- ment. Application of Knowledge: In addition to their research productivity, basic scientists have helped through communication with clini- cians to eliminate the chasm which has hereto- fore impaired rapid application of new knowl- edge to patient care. On the other hand, as a direct result of this interaction, the basic sci- entists have been better able to appreciate clinical problems and in some instances this has prompted them to change their research to a more productive direction. For example, in our own program the interaction with clinicians prompted Fordyce to develop his operant con- ditioning hypothesis and then to apply it to pa- tients, and Chapman has obtained a clearer picture of chronic pain as a clinical problem and consequently has completely changed his di- rection of research. Core Facilities Research center grants have made possi- ble the development of central or core facilities which increase the efficiency of all of the pro- grams in the center. In our own case, by pool- ing our resources we have been able to acquire a large computer and other expensive equip- ment which would not be available through in- dividual research grants. Moreover, the avail- ability of core facilities permits new faculty to begin a research program and carry out feasi- bility studies prior to submitting an individual application for research funds. The pooling of personnel permits specialization, producing work of higher quality and greater quantity. Similarly, centralizing all fiscal and adminis- trative matters obviates duplication of effort and increases administrative efficiency. Anesthesia research centers have helped bring cooperation, coordination, collaboration, and communication among the investigators. These are critically essential ingredients for successful multidisciplinary research. The commonality of objectives, the necessity of using core equipment and personnel of the cen- tral facility, weekly research seminars, and the better appreciation of other people’s problems and research efforts foster a spirit of unity of efforts and goals. While in many programs this spirit existed before, the center grant has had a great impact, far beyond that of increasing research capability. I believe it correct to state that this has been especially important at Har- vard, where the establishment of a Depart- ment of Anesthesiology is ascribed to the uni- fying effects of the Anesthesia Research Cen- ter. The centers have also provided an envir- onment and capability for research training which would not have been possible through individual grants. The influence of these five centers on research training will be described by Drs. Epstein and Steinhaus tomorrow. Equally important has been the impact on clin- ical anesthesia training. As a result of having a 47 better scientific environment, the quality of the training program has been greatly en- hanced and this, in turn, has increased the capability to recruit from among the best of the recent medical graduates. Whereas nationally less than 70% of the anesthesia residency posts are filled and over half of these are filled by foreign graduates, the five centers have been able to fill most, if not all, of the positions with American graduates. Do we need anesthesia research centers?, the answer is “Yes.” And we need more of them. There is a critical need to increase the amount of high quality research in anesthesia in order to solve the many problems which remain. ANESTHESIA RESEARCH CENTER: ADVANTAGES DR. BENDIXEN: The concept of the anesthesia research center capped the main growth period of NIGMS anesthesiology sup- port. The takeoff point was the traditional re- search project grant; and with time, new forms of funding were introduced, including program projects and the various training grants. We welcomed the deliberate decision to boost the scholarly activities of the specialty, which stood with one leg firmly planted in clinical ac- tivities and the other leg too infirmly planted in research activities. We recognized and wel- comed the desire to further the early applica- tion of research findings to patient care and clinical training. The Outlook at Inception When in 1967 support was offered to es- tablish anesthesia research centers, it was seen as a tremendous opportunity for the spe- cialty. In trying to define the advantages of the anesthesia research center, it may be fair to ask: What were the advantages we visualized, to what extent have we obtained these advan- tages, and how do we evaluate the situation today? First, the research center would provide opportunity to do more research and do it bet- ter; in particular, an opportunity to broaden the scope and conduct investigations in wider areas, including good clinical research. The re- sources of the research center should make it easier than in the past to obtain consultation and effective collaboration with other disci- plines and specialties. I, for one, was not think- ing just of the traditional links with phar- macology, physiology and chemistry, but also of the need to work closely with bioengineers, mathematicians, systems analysts and statisti- cians. Clearly, more active consultation and collaboration should lead to improved quality and improved quality control. Economies and efficiencies were foreseen through effective administration and through the sharing of re- sources and core facilities. Additionally, the size of the center should provide an increased degree of flexibility, making it possible to promptly pursue promising leads. Second, it would provide an improved en- vironment with better communication among investigators and research groups. Inves- tigators in disparate fields could be brought together to learn about, and to criticize ongo- ing research, providing quality control while communicating. One result of bringing indi- viduals and groups together should be an en- thusiasm for the pursuit of new knowledge to the point of pervading the department. In other words, a substantial lifting of spirits to the level befitting an academic department. Third, although the words training and pa- tient care were not used prominently during the inception of research centers, no one failed to recognize that the concentration of talent and activity, as was visualized in them, could but have a tremendous impact on teaching, training and patient care. The potential for a much needed increase in academically qualified manpower was equally obvious. Fourth, by virtue of its sheer size and con- centration of talent, the research center should ‘be in a position to initiate scientific endeavors in directions which represent a departure from tradition. I shall return to this point. Fifth, it would be an error of omission not to mention that the development of an anes- thesia research center should bring to the de- partment much prestige, both within and without the institution. It is factual that the research centers helped anesthesia depart- ments obtain space and other support within their own institution which otherwise would have been difficult to obtain. And I agree with Dr. Bonica that it was not a complete coinci- dence that, shortly after a research center was 48 granted at Harvard, a department of anes- thesiology was established after many years of knocking on the door. Building from Strength One characteristic of the research center cannot be discussed in terms of advantages and disadvantages. From the outset, it was clear that a research center could not be based on the activities of four or five good investigators wishing to continue and expand their research pursuits. The center called for a critical mass of individuals, able to mount a large number of basic and clinical research projects, related or unrelated, but held together in a structure which established common pragmatic goals and ensured communication, quality control and optimum ulitization of resources. Undoubted- ly, a prerequisite for launching a research cen- ter was that the institution itself provide a set- ting rich in potential for cooperation among scientists as well as the expectation of substan- tial activity in both training and patient care. It follows that the center could be mounted only by the already strong department in the strong institution, capable of further growth in strength. It is my personal belief that the deci- sion to make the strong stronger was the only possible one. We have been through so many crises in recent years, both here and abroad, as to have almost forgotten that during the 1960’s the anesthesiology specialty had a crisis of its own. I do not wish to elaborate in purple prose, but I will suggest that NIGMS support during this period, culminating with the research centers, came at a critical time. Physician anesthetists had lived to some extent in self-imposed con- finement, concerned in part with technical pursuits. Despite a respectable amount of lab- oratory research within the specialty, its im- pact on clinical practice had been less than op- timum, and its contribution to medical school teaching very modest and sporadic. Con- sequently, the challenge and responsibility which the specialty had to offer a graduating physician had lagged behind the rising level of medical education and was not in line with career expectations of the good United States graduate. The result was very slow recruit- ment of good graduates into the specialty. I hold the bias that, at that time, we needed to break out of the little niche within 49 which we had studied the physics, chemistry and pharmacology of anesthetic agents, and to participate broadly in the lively trend to make patient care more scientific by taking full ad- vantage of scientific and technological ad- vances occurring at a rapid pace. I felt strongly that we needed to train specialists who could do more than produce the anesthetic state; who in addition could participate with competence and enthusiasm in the management of the ill patient, instead of talking about it wistfully. In order for this departure from tradition to oc- cur, not only was a change in philosophy neces- sary but also a change in emphasis in teaching and training. And we should not underestimate how much we have changed in the last decade. In reviewing the extent to which our hopes and aspirations have been realized, I shall make some general comments, supple- menting the specifics already cited by Dr. Bonica. I believe that the center concept has paid off richly in making it possible for us to do more research more competently, and the abil- ity to achieve economies and efficiencies has been established. In 1967, we were hoping that the research center would help us create a bet- ter total environment for the department. In my judgement, this anticipation has been ex- ceeded by events. The research centers have created very lively and inspiring environments for everyone, but especially for young people in training. In those institutions where re- search centers exist, the enthusiasm for pur- suit of new knowledge is indeed pervasive. And it is in this environment that we find the largest pool of young potential faculty. The shortage of qualified faculty continues to plague us, but the impressive qualifications of some of our young people is one of the impor- tant benefits of research centers. The improved communications and the im- proved quality control have materialized and helped create a new way of life in research which I hope will stay with us. Without any doubt, the centers have been critically impor- tant in making it possible for a department to expand its areas of interest and to quicken its pace; not just in research, but in teaching and patient care. Also, the centers indirectly have been critically important in allowing depart- ments to assume new clinical and teaching re- sponsibilities, significantly increasing attrac- tiveness of the specialty in the eyes of medical students, and in adding significantly to the clinical and basic research potential of the spe- cialty. The anesthesiologist’s role, and the way he is looked upon by his colleagues and his stu- dents, have changed significantly in the last decade; and the research centers have played an important function in bringing about this much much needed change. The effect of the centers upon recruitment of good trainees and on increasing the faculty manpower pool, al- though difficult to prove may be the greatest benefit received. Resource for Innovation I have saved to the end one additional po- tential of the research center, one that was visualized back in 1967 and which has now begun to materialize. This is the ability of the center to depart from traditional approaches and undertake something which is new and ex- citing yet so demanding in manpower, time and anticipated duration as to be forbidden except if undertaken by a center. A number of new initiatives have been taken, but I will simply choose to cite as an example the epidemiology study conducted by the Harvard Anesthesia Research Center. We must agree that we have inadequate knowledge of the quality, morbid- ity and mortality of anesthetic care. We have not even begun to estimate the effectiveness and efficiency of what we do. And we continue to debate as to what is the optimum use of manpower categories needed to provide anesthetic care. In the not too distant past such issues were considered unmentionable or to belong in the realm of politics. These mat- ters, however, can be subjected to scientific study although it is not easy. More than that, these areas hold sufficient promise for scien- tific advances to be made by our friends in mathematical statistics and related fields, so that the best available competence can be re- cruited for these ventures. The Harvard Anes- thesia Research Center epidemiology study aims at defining effectiveness and efficiency. It is already showing progress towards the prin- cipal goal as well as giving spinoffs in a variety of other areas. It is clear that the epidemiology study will continue to provide increasing bene- fits with time. This study has received its sole support through the anesthesia research cen- ter and is a kind of pursuit as rich in science as 50 anything else we do; it furthermore can serve as a model of interdisciplinary collaboration. In conclusion, the potential of the anes- thesia research center has been realized to a greater extent that I anticipated. The National Institute of General Medical Sciences has had a tremendous impact on those critical changes which have occurred and continue to occur. I hope that support of research centers will con- tinue; and that we can add additional mechanisms of support—taking off perhaps from some of the unusual departures intro- duced by the centers. ANESTHESIA RESEARCH CENTERS: DISADVANTAGES DR. GREENE: The first and greatest dis- advantage of centers for categorical research in anesthesia is that the concentration of re- search money, talent and personnel within four to five centers may be inimical to the growth and development of academic anesthesiology in the rest of the country. The amount of money available in the United States for anesthesia research is not infinite. Quite the contrary, it is finite indeed. Furthermore, the majority of the money allocated for anesthesia research comes from one source, the Federal government. Centralization of anesthesia research funds be- comes doubly unhealthy when, as at the pres- ent time, availability of Federal funds for anes- thesia research is restricted by public policy, which gives priority and emphasis to such specific areas of research as cancer, cardiovas- cular disease, and pulmonary disease. When such limited funds as are available for anes- thesia research are concentrated in a small number of institutions, the result can be dev- astating to anesthesia research in the rest of the country. The potential exists, therefore, that anesthesia research centers can work to the detriment of anesthesia research in the ratios as a whole. “Critical Mass” Argument One can argue that good research requires a critical mass of investigators in order to pro- vide depth of personnel, inter-personal con- tacts, and intellectual stimulation. One can argue that this critical mass can only be ob- tained by a concentration of researchers into a center. This, however, is by no means a verity. There are, for example, no data to prove that quality of research is a direct function of kilo- grams of investigators per research center. Nor are data available to prove how many in- vestigators it takes to establish the critical mass of research personnel said to be conson- ant with quality research. The implications of anesthesia research centers are that they have an inside track to quality research, that they are more productive, and that the ability of smaller research teams and individual inves- tigators to produce equally good research is not as great. I protest these implications. I also protest what these implications mean in practical terms. When research is not being done, the quality of an academic program in- evitably declines by that much. Teaching suf- fers. Intellectual curiosity declines. The spirit of academic anesthesiology weakens. Also, I remain unconvinced that the depth and breadth of academic anesthesiology in the na- tion as a whole is favorably affected by con- centration of a disproportionate amount of re- search funds and personnel in a few select cen- ters. I submit that the quality of academic anesthesiology across the country would be equally well served, if not better served, by more equitable and more generalized availabil- ity of research funds in a larger number of in- stitutions. The Factor of Productivity To return to the matter of the putative in- crease in research productivity, said to be as- sociated with concentration of relatively large numbers of investigators in one institution, certainly the research productivity of the in- stitution increases. It is bound to: there are more research workers. But does the prod- uctivity of each individual investigator neces- sarily increase under such circumstances? If the answer is said to be yes, where are the data to prove it? Where are facts and figures, cost accounting, if you will, to prove the efficacy of research centers in terms of increased prod- uctivity of individual investigators? Those data which I have seen and heard leave me uncon- vinced that research productivity per inves- tigator is necessarily increased by establish- ment of anesthesia research centers. One of the reasons research productivity may not be 51 increased in research centers is because in such a large group of investigators there may be, and frequently is, a certain amount of busybody research, trivial research carried out to keep personnel and facilities occupied. Busybody research can certainly occur outside research centers; but it can, and does, also occur within them. Research centers are not immune to this form of waste of research time, money and facilities. Indeed, the very size of research centers may even increase the inci- dence of undirected, nonproductive research. The prestige which research centers enjoy of- fers a patina of respectability to busybody re- search, but busybody research still remains just that, research for the sake of keeping busy and for the sake of justifying the funds granted to the center. An advantage of research cen- ters has been said to be that they allow inter- disciplinary research to be carried out. Indeed, one of the objectives of the anesthesia research center program is initiation of anesthesia re- search projects in conjunction with biochemists, pharmacologists, and others out- side anesthesiology. This laudable objective has been met in certain instances. By and large, however, the track record of anesthesia research centers in this regard has not been impressive. Interdisciplinary research proj- ects have been successfully undertaken, but their number is relatively small, despite the emphasis and publicity they receive. In fact, nationally the quality and quantity of product- ive and really meaningful interdisciplinary re- search programs involving anesthesiology bear little or no relation to the presence or absence of research centers. Outstanding, imaginative interdisciplinary research is as frequent out- side anesthesia research centers as within them. Certainly, interdisciplinary research does not require an anesthesia research cen- ter. Nor does the presence of an anesthesia research center guarantee high quality inter- disciplinary research. Anesthesia research centers have a disad- vantage to the extent that they carry with them the potential for adversely affecting anesthesia research and academic anesthesiol- ogy outside the centers. They also have the disadvantage for potentially adversely affect- ing anesthesiology intramurally. As Petersdorf recently noted in discussing academic departments of internal medicine (N. Eng. J. Med. 291:440-446, 1974), creation of a research center brings into being an adminis- trative unit which exists within the parent de- partment but which functions essentially inde- pendently of the rest of the department when such massive financial and personnel commit- ments are made to but one section of a depart- ment, to one group of faculty who have a com- mon interest in categorical research. A real danger exists that such powerful yet autono- mous units may adversely affect faculty mem- bers who are not members of the research cen- ter. This is particularly true for faculty whose forte is teaching, not research. It is also true for faculty whose interest in research may lie outside fields of research dictated by the re- search center. The disadvantages of research centers can be as great intramurally as ex- tramurally. PROBLEMS IN DEVELOPMENT DR. MODELL: In 1967, the first Anes- thesia Research Center grant was awarded to the University of Pennsylvania. Shortly there- after, center grant awards were made to Har- vard University, Columbia University College of Physicians and Surgeons, and the Univer- sity of Washington. A program project grant approved during the same era for the Univer- sity of California at San Francisco was sub- sequently changed to a center grant when it was approved for renewal. No other university has applied for anesthesia research center grants to date. Thus, while the “batting aver- age” for approval is excellent, there appar- ently has been great reluctance on the part of other institutions to apply for funds. On Lack of Applications Why have these applications not been forthcoming? One possible answer might be apathy, on the part of chairmen of departments of anesthesiology or directors of research within those departments. I question the valid- ity of this argument since the best seven years has resulted in expansion and growth of the discipline of anesthesiology throughout the United States. Most departments have grown in breadth and depth, even in many institu- 52 tions where anesthesiology was purely a serv- ice division. Another possibility for the lack of new ap- plications is lack of expertise in research. Anesthesiology is thought of as a clinical dis- cipline and clinical science, and one could ques- tion whether there is a real interest or adequate training for basic research. Again, when one reviews the record, the past seven years have resulted in a substantial increase in the number of trainees. Many of these persons have been supported by research training grants, while others have availed themselves of research career development awards to gain further knowledge. The number of orginal sci- entific papers being published in quality jour- nals both within and without the specialty by members of departments of anesthesiology has increased considerably. The number of com- petitive manuscripts submitted for the annual meeting of the American Society of Anes- thesiologists has increased by 223% since 1968, and the numbers actually presented in the pro- gram has increased by 208%. Thus, I doubt that this alone could account for the failure of additional applications. An important deter- minant in the failure of additional applications may be based on the realization that one cannot have an anesthesia research center without a substantial center grant to fund it. On the other hand, one is not in a position to apply for a center grant unless an anesthesia research center of significant magnitude already exists within the institution regardless of the source of funding. On the surface, this statement might appear as an excuse, but I do not believe it is. There are reasons for making this state- ment. In almost all but the newest medical schools, the discipline of anesthesiology has grown up as a division of the department of surgery. Then at an appropriate date in time, anesthesiology achieved department status. By that time, most of these institutions al- ready had filled all available space within its buildings and also had allocated most of its re- sources to existing departments. Thus, de- partments of anesthesiology were created with inadequate space and resources. To further complicate the picture, the last few years have not been generous ones with regard to hard money funding, the source of funds not- withstanding. The trend has been for hard monies to be used primarily to support those departments which are not capable of support- ing themselves through generation of patient fees. Thus, it is not uncommon for the basic science departments in the medical school to receive a greater portion of their monies through budgeted items, whereas the clinical departments must rely more and more on pa- tient generated income for overall support. The Problems of Faculty One is then faced with the problem of pro- viding adequate numbers of faculty to provide clinical care and clinical teaching and yet pro- vide adequate research time for each of them. The type of personnel within the department will vary somewhat depending on already existing resources. For example, many de- partments of anesthesiology are relatively new. As such, they suffer from the growing pains of a relatively unstable staff. It is well known that 20% of the positions in academic anesthesiology are unfilled at the present. Also, the stipend is low when compared to what the same individual might achieve in pri- vate practice. Furthermore, the stipend of- fered for purely research positions is often lower than that for anesthesiologists within the same department who actively participate in patient care. Once an anesthesiology de- partment has adequate numbers of personnel to provide for the clinical care of its patients, the next priority frequently is developing a stable core of teachers with diversified inter- ests so that all of the subspecialties within anesthesiology might be covered. For exam- ple, Obstetrics, Cardiology, Neurosurgery, Pain, Pediatrics, Intensive Care, etc. In the initial growth period of a department of anes- thesiology, the emphasis is on clinical care and diversification of interests. Neither of these are necessarily conducive to establishing an anesthesia research center, since in such a cen- ter the prime goal must be research and pref- erably the research should be oriented around a general area of endeavor. Once the clinical and educational needs of a department of anesthesiology are met, the re- maining resources, if any, are usually used to support an investigative program. Unfortu- nately, due to limited hard money funding, 53 only a very few departments are in a position to invest a substantial quantity of money in attracting the type of faculty member who is willing to devote his life to research. Individu- als who are heavily research oriented, and who are prepared to settle for a lower stipend in order to pursue their interests, may be more likely to gravitate to anesthesia departments which already are heavily vested and funded in this area rather than being “on the frontier” to help develop new areas. The other approach, of course, is to develop the research interests within one’s own faculty. This also is desirable. However, as I have stated, it usually means having to expand one’s faculty in order to pro- vide adequate time for research and research development. Collaborative Efforts Finally, there is the question of a multi- disciplinary or multi-departmental approach to research. This, I believe, is not a problem in the field of anesthesiology. The research proj- ects that anesthesiologists usually pursue fre- quently cross into the field of pharmacology, physiology, or biochemistry in the broadest sense. It has been my experience that many of our colleagues in the basic sciences are in- trigued with the possibility of working with a counterpart in a clinical specialty, in order that the basic research in the basic science labora- tory can be integrated with the clinical re- search that may have direct applicability to pa- tient care. The key again, however, is funding. It perhaps is somewhat of a paradox that while there is a shortage of anesthesiologists to fill the available positions in academics today, we are told that there is a surplus of basic scien- tists (Ph.D.’s) in excess of the number of posi- tions available. Thus, any additional positions that might be available within an anesthesia research center with adequate grant funding should have no trouble attracting collaborators from other disciplines. In summary, I believe that the biggest problem in organizing an anesthesia research center is one of establishing the department research along lines of an anesthesia research center even before making grant application. This requires original productive ideas, an ex- cellent staff of accomplished investigators, suf- ficient space to provide for such a program, and last but not least, adequate hard core fund- ing from the university to provide a sound sci- entific base of research within the department which can be integrated with, but must not be dependent upon, clinical care and generation of income from patients. If my analysis is correct, then it is not un- like some of the thinking underlying the estab- lishment of research career development awards for individual investigators who had demonstrated some expertise and great prom- ise for the future. If one is willing to accept this analogy, then thought should be given to the establishment of a departmental research de- velopment grant. In this way, the department that already has achieved its fulfillment of an excellent clinical care and clinical teaching base, and possesses individuals with either common or diversified interests (who, in turn, have acceptable research training or a proven research productivity) could apply for grants to expand. Thus, the resources would be avail- able to obtain the needed additional personnel and support so that research could become a high priority item rather than one that was done after the other responsibilities of the de- partment were fulfilled. I firmly believe that if such developmental grants were available, we rapidly would see the development of a signifi- cant number of well-planned, and productive anesthesia research centers in the United States. DISCUSSION DR. WOLLMAN: I would explore for a moment the potential disadvantages of anes- thesiology centers suggested by Dr. Greene. One was that the concentration of talent in five centers is inimical to the development of anes- thesia research throughout the country. It can be said, on the other hand, that these five cen- ters are producing people who are seeding other departments throughout the country, and here one can look at any level. For exam- ple, consider just these chairmen of non-center departments who have developed in anesthesia research centers: Larson, from San Francisco to Stanford; Katz, Columbia to UCLA; Ep- stein, Columbia to Virginia; and from Harvard, Brown to Arizona, Deutsch to Oklahoma, Flack to Arkansas, and Brunner to North- western. One can carry the list on, but the point is, personnel at this level and levels be- low, all of whom developed within the research centers, are being seeded into other depart- ments. Dr. VAN DAM: Most of the people you mentioned, however, initially were in their de- partments before those departments had re- search centers. Indeed, the same kind of turn- over, where people were being seeded, has usually occurred, long before there were cen- ters. DR. WOLLMAN: Nonetheless, this has come from a concentration of talent, whether we call it a center or not, and my point is that the process, quite to the contrary, is not inimi- cal to development in other places. DR. THEODORE SMITH: My own situa- tion occurs to me, in that I happen to come from the University of Cincinnati and was trained at the University of Wisconsin. I per- sonally suspect that if I had gone back to either of those institutions I would not be in this meeting today. For one thing, the research center gives the junior investigator the oppor- tunity to advance more rapidly by working with a team. For another, instruction coming from a group of people prepares one to submit a better application. Thus, the renewal appli- cation of the research center grant almost in- evitably is better done. And eventually, when one of this team leaves to go elsewhere, his or her work is done better. DR. WOLLMAN: A second factor noted by Dr. Greene was the serious danger of not funding worthy research other than that in the centers. As I understand the mechanism, the review of research center grants is a project- by-project review which literally involves the assignment of a priority by peers to each indi- vidual project within the center proposal. Therefore, it really is competing on the same peer review basis as the regular research proj- ect, and the funding is essentially done on the basis of individual merit. DR. BONICA: Mr. Chairman, you are an NIH Study Section member. How many re- search applications from non-center institu- tions, in your review experience, have been submitted and found sufficiently meritorious of approval over the last three or four years. DR. HAMILTON: I don’t have exact fig- ures handy, but the numbers we saw in the 54 Surgery Study Section were small. Even when looking at the total submission of grant appli- cations to the Division of Research Grants that could be identified as anesthesia, as far down as the tertiary interest, the number of applica- tions is still very small. DR. BLACK: The NIGMS has found that no more than three to five grant applications are received for each Advisory Council review, if that many. And judging by the applications data of the DRG, their number is almost in- finitesimal compared to the numbers submit- ted by other clinical disciplines. In this same connection, I want to make it very clear— center grants are not funded by the NIGMS at the expense of project grants. DR. GREENE: Referring to the presen- tation by Dr. Bonica, a marked dropoff was shown in NIGMS funds going to individual projects, starting in 1966 and reaching nearly a 50% reduction between 1968 and 1969. Might he elaborate further? DR. BONICA: A major reason for this was extension of the Heart Institute’s mission in 1969, and its redesignation as the National Heart and Lung Institute. Thus, many of the grants originally supported by NIGMS, as they came up for renewal, were administra- tively deployed to NHLI, largely on the basis of their clinical or categorical disease orienta- tion. DR. EPSTEIN: Another aspect of the data, leaving out the centers and program project applications, is that approximately 140 individual research grant applications were reviewed by 21 Study Sections over a two-year period, with an overall award rate of almost 50%. That seems a rather respectable batting average that I hope to address more at length tomorrow. DR. HAMILTON: In conclusion to our panel, Dr. Larson wishes to speak on a topic not hitherto discussed, the mechanism of Study Section review. QUESTION OF PEER REVIEW DR. LARSON: We all should realize that most research institutions in the United States deal far more in terms of individual project grants than centers. Accordingly, I think the most serious, fundamental and far-reaching problem that we face today lies in the peer re- view system, as it exists for the field of anes- thesia. As you know, the peer review system is part of the decision-making process for any kind of research. It is the one that affects us in anesthesia. To have evaluation without adequate representation is not peer review. Peer review of individual grants is done by study sections. There are approximately 47 study sections at the present time, under the Division of Research Grants. They include such fields as bacteriology, biophysics, com- municative sciences, hematology, radiation, etc. There is no study section for anesthesia. Our only full-time continuous representation is to surgery study sections; Surgery A, where we are represented by Harry Wollman, and Surgery B, where I am the representative. Why do I say this representation is in- adequate? Very few of the total anesthesia- generated grants ever come to Surgery A and B study sections. In my first year, we have seen only two. I suspect that Dr. Wollman’s experience is not much greater than that. Con- sequently, most of the research on anesthesia-generated grants are going to other study sections, such as physiology, pharmacol- ogy, neurology, etc. Each of these study sec- tions is evaluating probably one to three anesthesia-generated grants per year. There are no anesthesiologists on these study sec- tions, and there is little likelihood that the re- viewers will develop expertise in certain areas: First of all, the importance of the questions being asked to the field of anesthesia. Second, the quality of experimental design in relation to the environment in which the anesthetist must work. Third, the uniqueness of the proj- ect in the clinical setting. Fourth, the track record of the applicant. Fifth, the appreciation of the need for, or the promise of emerging, young investigators in anesthesia. In a sense, it is a clinical discipline being evaluated primarily by non-anesthetist scien- tists in which their frame of reference and standards are being applied, and their value judgments about the relative merits of anes- thesia studies determine the priorities as- signed. I don’t wish to denigrate the perform- ance of any study sections or to impugn the integrity of the individual members who are, in my opinion, very talented scientists who per- 55 form their responsibilities very conscientiously and in a very dedicated fashion. However, their frame of reference is not necessarily that of a clinical anesthetist. When expertise in a specific area is lacking, the NIH requests opin- ions from ad hoc consultants. But these are not always satisfactory. For example, the written reports by consultants do not offer an oppor- tunity for clarification of the issues or comment about the relative importance of the various points being made. With peer review, past accomplishments of the principal investigator are usually known to his peers, but in the case of anesthesia this is not available. The principal investigator in anesthesia is generally unknown to the mem- bers of the assigned study sections. Hence they do not enjoy the benefits of special con- siderations that this kind of personal interac- tion might bring. How do we regard this unfavorable situa- tion? There are many options one might choose. We heard developmental grants men- tioned. That would be an excellent idea. I think it is important, however, that we consider the possibility of this with other options. Another is the establishment of an anesthesia study section. This has been proposed before, but the argument against it is there are not enough grants to warrant a separate study section. It is said there is not enough science in the field of anesthesiology. The kind of information 56 that you heard today would indicate that this is not the case. Likewise, the quality of the jour- nals, the New England Journal of Medicine, JEAP, JPAT, which published the material coming out of NIH-supported anesthesia re- search would also not support that comment. There are several advantages to such an anesthesiology study section. It would estab- lish peer review and would stimulate research. Also, it would dispel some of the hopeless feel- ings that exist in many institutions. Young in- vestigators might leave center programs and go to other institutions if they had some hope of research funding elsewhere. An anesthesia study section would establish uniform criteria for the evaluation and decision-making regard- ing anesthesia-generated grants. These criteria would then become known to anes- thetists who are proposing grants. As a conse- quence, the quality of the grants would be much improved over what exists at the present time. Next, it would establish a direct avenue of communication between the NIH and the anesthesia research community as a corporate body. Such a group also could be responsible for systematically evaluating the completed research as well as proposed research. This is not an idea original with me. In conclusion, I would say the specialty has grown up. And it is entitled to the best efforts and responsibilities from a peer review system. ANESTHESIOLOGY RESEARCH TRAINING—PAST ACCOMPLISHMENTS AND PRESENT STATUS ROBERT M. EPSTEIN, JOHN E. STEINHAUS FACTORS IN TRANSITION DR. EPSTEIN: Provisions of the recently enacted National Research Act make it ex- tremely important and timely that we review the past record of the research training grants program in anesthesiology and its current status. Substantive information is derived from NIH sources and from the Subcommittee on Academic Manpower of the American Soci- ety of Anesthesiologists, headed by Dr. Steinhaus. My role is to assess the past record of this program and key factors in its transition under the new legislation. I will try particularly to indicate what position we must take regarding this legislation since it will significantly govern our future research training activities. Dr. Steinhaus, in turn, will convey to you what the ASA subcommittee has felt to be the needs in academic manpower, based on our analysis of what is optimum for an anesthesia department in a typical medical school, and how this con- trasts with what we have found to be the actual manpower situation and the likelihood of re- cruitment in the near future. The anesthesiology research training grants program started in the early 1960's, when programs at a few major university cen- ters were established under the review aegis of the NIGMS Pharmacology Training Grants Committee. At the time, physician specialists in anesthesia with capability and interest in teaching and research were in desperately short supply. It also was clear that without a mechanism to help develop highly qualified in- dividuals for positions in university anes- thesia, their production would not flourish. In addition, it was apparent that the nationwide shortage of anesthesiologists would likely re- main acute or even become worse due to the field’s failure to attract young students to its ranks. As with any other disciplines of medicine, the interest of bright young physi- cians depends on the stimulus of inspiring teachers. These were in desperately short supply 15 years ago and the state of recruit- ment to the specialty so indicated. 57 Moreover, serious scientific problems, many unsuspected, remained to be solved. The pool of individuals with the scientific educa- tion, interest and opportunity for attacking these problems simply did not exist. Anesthet- ic mortality was a very real public health con- cern, limitations in anesthetic care posed seri- ous roadblocks to the development of enhanced surgical capability; and the attack on serious problems of emergency care, resuscitation, respiratory and intensive care, perinatal and infant health was only being launched. A Fed- eral program was required to meet these chal- lenges and solve the problem of providing well-trained individuals in increased numbers both for the teaching role required to attract and educate specialists, as well as to train indi- viduals in the conduct of research of anesthesia and its related disciplines in order to provide for the improvement of health care. As early as 1959, support was begun for a handful of trainees. By 1961, after eight indi- viduals had completed the program and when annual expenditures for the first time passed the $100,000 mark, the program could be con- sidered to be well under way. During the early 1960’s the annual output of trainees increased from 11 to 18. In 1967, the Anesthesiology Training Committee was established, and the program expanded to a level of 30 graduates annually from 15 research training programs, funded at a level of about $1 million annually. This has remained the high water mark. Of the 15 training programs, 10 remain active and are still producing annually a substantial number of young physician graduates to augment uni- versity faculties and contribute their talents to the development of the science of anesthesia. By their leadership, they encourage others to follow in their paths. In June 1971, a summary of the research training program was compiled by a subcom- mittee of the NIGMS Anesthesiology Training Committee. A total of 173 trainees had graduated from the program by June 1969, of whom 11 were still in military service, 63 (36%) were in non-academic positions, and 99 were in academic positions. These represented 61% of the graduates of anesthesia research training programs not in military service. Subsequent accomplishments: It must be recognized that these individuals have fully met the expectations. Those entering univer- sity positions have quickly risen to prominence in the specialty. Many associate and full pro- fessors, and at least a dozen department chairmen, now in major university centers, have come from this program. Graduates of the research training program have served on NIH Study Sections and the editorial board of Anes- thesiology and other medical journals. Truly, with the background of specialty education and research training provided by this program and with the contributions of talent from recip- ient individuals, anesthesiology is coming of age as a medical specialty. You have heard today of the wide spectrum of research interest and activities engaging many of these indi- viduals. Practical results from research done by former trainees are indeed many, including reduction in mortality and morbidity in inten- sive care units, tremendous improvement in respiratory mortality rates in premature in- fants, prevention of cardiac arrest and the major complications during anesthesia, better management of operative and post-operative bleeding problems, and more rational treat- ment for thousands of patients with cerebral vascular problems. The record is a good one. What is the present situation ?: One would have to say that during the past four to five years the program has not been without diffi- culty. Since 1970, there have been numerous policy shifts which have made academic planning very difficult. A program of fellowships in- itiated by Secretary Weinberger became effec- tive in July 1973 but was superseded a year later by the National Research Service Act of 1974. As with any major program change, it takes time to communicate details of the new program and time to adjust individual and uni- versity plans. It was not surprising, therefore, that no fellowship applications were received under the Weinberger program. In the mean- time, all 10 of the surviving research training programs are being phased out gradually, so that by 1978 no more support will be provided through this mechanism. As part of the Gov- ernment’s effort to reduce the number of ad- visory committees, the Anesthesiology Train- 58 ing Committee was disbanded in June 1973, making it necessary for the new fellowship ap- plications in anesthesiology to be reviewed by Study Sections of the Division of Research Grants. In the face of these changes what has been the recent performance of the program? It would be worthwhile to review the training ac- tivities of the last few years with a view to determining whether the program continues to be effective, and how it compares to its earlier phases. Data for all anesthesia research trainees were compiled in the fall of 1973 and what follows was extracted from them. During the academic years 1970 through 1973, a total of 181 individuals completed their research training on these grants. Substan- tially all of those trainees finishing during the earlier years of this four-year cycle had made their career choices clear. Sixty-one percent were in academic positions three years later, while 32% had entered the practice of anes- thesiology. Three percent were still in military service. Thus, the earlier record, compiled be- tween the start of the program and 1969, was maintained. For graduates completing their period of support later, in the four-year cycle, career decisions were less apparent, of course. Seventeen percent of these individuals were still in training as of the fall of 1973, although no longer supported by the NIGMS. Twenty- one percent were in national service, while 59% had made an initial commitment which in- dicated their career pathway. Of these, 41% were in academic situations, while only 18% were in practice. If the distribution of the re- maining 38% as yet uncommitted to a long- term position is comparable to that of their fel- lows, the 60+% proportion entering academic positions may be expected to continue. Inci- dentally, I am told that this is approximately par with the long-term recruitment to academic medicine of individuals in other clini- cal disciplines who receive federally supported research training. Effect of Program Size: One item of inter- est which it was possible to explore from these data was the effect of program size on the ulti- mate career selection of the trainees. Five re- search training programs were conducted in institutions with anesthesia research centers, and these each produced more than 10 graduates of the program during the four years under review. Five were smaller programs not associated with anesthesia research centers, and these each produced 10 or fewer graduates during the five-year period. Although the numbers are different, the proportion of indi- viduals going into academic medicine is simi- lar. A statistical analysis of the two groups, based on 137 graduates on one hand and 40 on the other, revealed no significant differences in the graduates’ final career choice. The conclusion one may draw from all of this is that the program, despite its retrench- ments, moratoria, and a generally more strin- gent climate of Federal support has continued to be productive. Good research training and a favorable environment give results. Whether the number of graduates is adequate is another question, which Dr. Steinhaus will discuss. Unfortunately, at this moment one cannot be sanguine about the future. The NIH staff, here today, is fully familiar with the change in the legal authorization for research training which was enacted last summer. For those of you who are not familiar with the changes, I shall review them very briefly. The National Research Service Act of 1974 repealed all existing authority for research training, al- though it provided that commitments made be- fore July 12, 1974 would not be affected. The result is that the existing, traditional training grants we have been discussing will continue to be honored, but as the periods of commitment expire, they cannot be renewed. Under Title 1 of the Act, a National Re- search Service Awards program for the sup- port of research training was authorized, re- quiring that a set of new conditions be met. The detailed regulations and guidelines for awards under this program have not been completed, but they will by law include at least the following: e There will be fellowship awards as in the past to institutional applicants for the support of pre- and postdoctoral fellows. e There will be individual fellowship awards to postdoctoral fellows. e The period of support for any one indi- vidual is limited to three years, unless waived by the Secretary of HEW for good cause. e Each individual receiving a National Re- search Service award will be obligated to 59 a pay-back program. This may include either 12 months of health research or teaching for each year of support, 12 months of service in the National Health Corps if no faculty or research position is available, or 20 months for each year of support in a specified geographic area or in a health maintenance organization in such an area. There are alternative fi- nancial pay-back arrangements which are rather discouraging. Finally, and most important, after July 1, 1975, no research training may be of- fered in a subject area in which an exist- ing need for personnel has not been de- termined. The definition of subject areas in which there is a “need for personnel” will be based on an annual study by the Secretary, conducted by the National Academy of Sciences or a similar group, and reported to the Congress annually. Until July 1, 1975, the NIH individual institutes have been given authority to set priorities in which there is a “need for personnel.” Accordingly, the Na- tional Institute of General Medical Sci- ences is now offering support for indi- vidual fellowships in anesthesiology under the new Act. I am concerned that anesthesiology con- tinue to be acknowledged as an area of national need. The efforts of a decade to establish that a shortage exists in our specialty should be famil- iar to almost everyone at this conference. It has been the subject of numerous surveys by the American Society of Anesthesiologists, con- cerned with the overall need for anes- thesiologists to serve the sick. With respect to university requirements, a short fall amounting to as much as 30% was predicted for 1976 as the result of a preliminary survey done by the As- sociation of University Anesthetists in 1971. Without considering the impact of new medical schools, this represented a potential deficit of approximately 600 individuals working in academic medical centers, or more, if optimal numbers of faculty are to be hoped for. Not all need be research scientists, of course, but many should. Nothing has happened in the last three years to suggest these estimates were exagger- ated or that they are inaccurate. Dr. Steinhaus will review the background and details of the survey which supports this conclusion. The need is great, and it is our responsibility to reach and convince those who will determine the areas in which research training programs under the new authority will be approved. We must do it. We must be heard. ADEQUACY OF PRESENT FACULTIES DR. STEINHAUS: Adequate anesthesia care by academic anesthesiologists as judged by peer review requires, on the average, a minimum of one anesthesiologist in attendance for each two simultaneous anesthetic adminis- trations by residents or nurse anesthetists. With a further allowance of 20% non-clinical time for each faculty, and faculty assignments in research, obstetrical anesthesia care, res- piratory or intensive care and pain therapy, a standard of staffing patterns for minimally ac- ceptable anesthesia care will require between 1.5 and 2.0 faculty for each regularly scheduled operating room. Using data collected in our surveys of academic anesthesiology, the prevailing fa- culty to operating room ratios were calculated for 91 out of 106 medical schools. Statistics were not available from a number of new schools which have not as yet established all of their clinical departments. Ratios ranged from a high of 3.5 to a low of 0.25 with a median of 0.75 faculty to each regularly scheduled operating room. The following table shows the distribution of schools into four levels of staf- fing: Distribution of Faculty to O.R. Ratio 0.51 0.76 1.01 Faculty to to to to O.R. <0.50 0.75 1.00 1.50 >1.51 #Schools 14 32 20 22 3 Should all budget positions be filled there would be approximately a 10% movement to higher ratios. A number of the low ratios of faculty to anesthetizing locations were medical schools with very large patient loads and anes- thesia care characterized by severely limited physician participation. Conversely, medical schools with limited patient loads often had higher ratios since fewer faculty were required for administration of anesthetics. While in- terpretation of these data must be limited, it appears that 75% of the medical schools sur- veyed have faculties of anesthesiology below the minimal standards approved by academic anesthesiologists. Future Requirements for Academic Anes- thesia Manpower: Whatever their quality may be, our academic anesthesia programs will de- termine in large part the chances of recruiting the bright and talented young physician as he selects a research career. The serious deficien- cies of present academic faculty must be cor- rected if effective programs in anesthesia re- search are to be developed in more than a lim- ited number of medical centers. The guidelines and standards adopted by the Task Force on Academic Anesthesia Manpower include one faculty in attendance for each two anesthetiz- ing locations, a minimum of 20% of the faculty member’s time for non-clinical activities, 20% of the total faculty time devoted to research, and at least minimal allowance for obstetrical anesthesia, pain therapy, respiratory and in- tensive care. Under these recommendations, an average medical school in our survey would require 27 faculty, of which five positions or their equivalent would be devoted to research in anesthesiology. Based on the Task Force guidelines and the present clinical loads reported by 95 medi- cal schools, the total faculty should be in- creased from the present 1155 to 2998, or ap- proximately 150%. If new medical schools without anesthesia departments are added, the increase needed will be over 160%. If one ac- cepts a minimum 20% research effort as essen- tial to all academic departments, a minimum of 366 faculty positions of the above increase should be devoted to research. Needs for Research: Unfortunately, our survey did not ask for the percentage of faculty time devoted to anesthesia research; however, on a projected 20% basis, 233 anesthesia fa- culty positions, or their equivalent, should be research. Since the amount of faculty time so allocated is likely to be less than the above fig- ure, the future need for anesthesiologists trained in research will be even greater than the 366 positions indicated above. . Unless there is a marked change in the pattern of medical services, future increases in 60 the demand for anesthesia care must be con- sidered. There was almost unanimous agree- ment from those surveyed that the overall workload will increase approximately 25% in most areas of anesthesia, including increases of 23% in surgical anesthesia, 31% in outpatient anesthesia, and 21% in intensive care and duties outside the operating room suite. In planning for personnel to handle this increased load in the next five years, it was estimated 61 that 6.1 anesthesiologists will be added to the present average staff of 12.3, an average in- crease of 40% in the academic anesthesiologist faculty positions presently available. It was anticipated that similar increases in nurse anesthetists and/or physician assistants will be needed. This projected increase in personnel would be utilized 57.8% in clinical care, 35.4% in teaching or research, and 9.6% in adminis- tration. II. FUTURE DIRECTIONS FOR ANESTHESIOLOGY RESEARCH VIEWS FROM A DEAN’S OFFICE JAMES E. ECKENHOFF Departments of a medical school can be di- vided into three broad groups. The first is the basic sciences, each with a large and obligatory teaching load condensed into one part of the academic year, leaving the remaining months free for research and scholarly activities. The second includes most of the clinical depart- ments with a much less condensed teaching load, shared by a larger faculty and supported by a body of house officers in various stages of graduate training, who provide the basic pa- tient care. The third is the few departments which have a large patient care load with a smaller faculty and resident staff, who must complete their patient obligations on a day- to-day basis, at the call of other physicians and in addition to teaching and research activities. The Priority of Service Anesthesiology is obviously in this latter group. Because of the often oppressive service responsibility, many university anesthesia de- partments never are able to rise above provid- ing service, never fulfill their teaching or academic obligations, and never have either the will or the aggressiveness to become in- volved with research. Often, they do not have the support of their clinical or basic science de- partments or of hospital or medical school ad- ministration to surmount the service respon- sibilities. In fact, in too many institutions they are thwarted in reaching their true potential by other disciplines and by administration. The aggressiveness, determination and personality of the program director in overcoming the ob- stacles is often lacking. I have little doubt that this explains the reason so few departments have reached a position of academic strength. Support from the National Institutes of Health has aided materially in allowing many individuals and some departments to gain sub- stantial and equal footholds in academia. The Institutes have provided the monetary means for recruitment, training and research support that allowed for the development of excellence. I would point out to those who extoll the vir- tues of the anesthesia research centers, that 63 the centers just didn’t appear as full-fledged operations but went through painful growing stages before being designated Centers. Three of the five have had 20 years of National Insti- tutes of Health support and the other two at least 10 years of support. One must be careful in attributing too much to the offspring and not enough to the parent. Unfortunately, placed into perspective of more than 110 medical schools, five anesthesia research centers are too few. I cannot find the justification and have not heard it in this meet- ing. I do not recommend an equal distribution of research monies nor do I believe in funding substandard projects; however, some attempt must be made to encourage growth of new cen- ters and also to limit the expansion of existing ones. If, as was alleged yesterday, the re- search centers stand for academic excellence, then one of the challenges to the National In- stitutes of Health must be to foster a more even distribution of academic excellence. Of equal concern to me is the aggregation of competence within a few departments. No one, least of all I, wants to lose outstanding fac- ulty. However, being a source of good recruits is one of the indices of a truly fine academic department. Some directors discourage movement; few encourage good faculty to leave, but regardless of the conditions of leav- ing, when a new director builds a successful department his previous chief will always take the credit. With or without encouragement, most young, capable faculty are reluctant to leave a well-established department despite what would be considered by my generation as eye-bulging inducements. Regardless of excel- lent salary offers and tremendous potentials, we hear complaints: the service load is too heavy, there isn’t enough space, there isn’t money for research personnel or equipment. In short, the larger, well-funded departments in most disciplines, not just anesthesia, acquire and retain large groups of qualified individu- als, and prevent them consciously or uncon- sciously from moving to institutions desper- ately in need of their services. New Policy Is Needed I believe that a new National Institutes of Health policy might help alleviate this prob- lem. Would it not be in the interest of a better distribution of teachers and investigators if the National Institutes of Health provided guaran- teed support for research and teaching to proven investigators moving to a location in need of an academic anesthesia department? Isn't it likely that the broader the training base the greater the output, or have we heard that a decision has been made that the base is broad enough? This is a problem that I have been faced with more times in my four years as Dean than I care to think about. One prospective basic science charman didn’t want to move be- cause he did not want to give up an endowment yielding $25,000 per year for unrestricted re- search. Few institutions can come up with a $500,000 endowment for research, but such funds guaranteed by the National Institutes of Health for a few years might go a long way to provide an otherwise denied flexibility. Watching from the vantage point of a Dean’s Office, I become increasingly concerned with the drifting apart of the basic science and clinical departments. I was interested to hear yesterday of the close rapport claimed by some of the anesthesia research centers and various other disciplines, but my conversations with deans suggests this is far from fact in most medical schools. Too often the basic scientists isolate themselves from clinical problems and clinical faculty. Some isolate themselves from other basic science disciplines. They do their required teaching, not always completely rel- evant to medical education, and fall back more happily to their research and Ph.D. candi- dates, becoming defensive if someone with an M.D. degree wants to join the faculty or par- ticipate in a seminar. On the other hand, too many clinical departments are tending to di- vorce the basic scientists. They either go their own way doing their own research, often with- out adequate basic science foundation, or hire their own biochemists, physiologists and so forth. This fosters an unhealthy atmosphere and leads to suspicion and distrust by basic sci- entists, who begin to teach less clinically rel- evant material and question the reason for their existence in a medical school. In turn, the clinical departments understand less and less 64 about the basic sciences, and wonder if they are needed in a medical school. This leads to a compression of the curriculum and a squeezing of the basic sciences to a point of ridiculous- ness. Funding of grants which encourage hir- ing basic scientists in clinical departments without a strong attachment to the basic dis- cipline should be of concern to the National In- stitutes of Health. I believe that it alienates basic scientists and clinicians, and it is divisive to the overall goals of the institution. Why not try to find the basic scientists in one of the institution departments? It would go a long way to healing rather than opening wounds. If you doubt the rift that exists, try to find a Cancer Center Director today. You will im- mediately find that the candidate’s biggest concern is academic appointments for his fa- culty. He knows from experience that basic scientists don’t want to give faculty appoint- ments to individuals who will work in a cancer center. Since centers generally cannot give fa- culty appointments, the usually suggested solu- tion is that a Department of Oncology must be created so that the Director can make his own academic appointments and forget the basic sciences. What is next? A Department of Mul- tiple Sclerosis, a Department of Strokes, or a Department of Total Joint Replacement? The broad problem is one that the NIH must share because it has fostered the self- contained research program and has not really had to deal with its by-products. I believe it must, and it should insist that a basic scientist working in a clinical department have a dual appointment in his basic discipline. A directive from the National Institutes of Health that a request for support of basic re- search in a clinical area must contain evidence of collaborative effort between scientists in the basic science departments and faculty in clini- cal departments would have a most salutary effect. The directive would foster closer rela- tions between departments, would inject clini- cally relevant material into the basic sciences, would upgrade research in the clinical depart- ments and would reduce duplication of effort, space and equipment. I never cease to wonder at the lack of communication between neighboring departments, nor do I cease to wonder at the failure of institutions to be able to utilize the talents available to them. In one medical school I recently inspected, students were learning little of the pharmacologic ef- fects of anesthetic agents and vasoactive drugs, yet an anesthetic department with a long history of excellent work in the field was located in the institution; and the NIH had funded that department in excess of one million dollars over the years. Individuals in anes- thesia departments are deeply engrossed in pharmacologic, physiologic, biochemical, car- diovascular, respiratory, metabolic and neurologic studies. Some effort must be made to integrate such activities with similar work going on within the institution and throughout the country. An attempt must be made to break down the barriers that inhibit communi- cation among researchers and prevent the dis- semination of coordinated relevant material. Another by-product of such collaboration might be a significant saving in purchases of equipment and efficiency in utilization of equipment. As an example, how can one justify the existence of five electron microscopes in one building when the overall utilization of them is only 50% in a 40-hour week? The Important Problems Let us next look at the anesthesia research field. Many of the studies being reported are of excellent quality, important, and cover a wide scope of interest. However, one cannot help but pause to make a few comments. One is that it is a bit depressing to see some investigators continuing to beat a tired horse. A technique is devised to measure an anesthetic effect—then every anesthetic under every conceivable con- dition must be tested at the cost of uncountable dollars, man hours, and papers published and read. I question funding of repetitive efforts with diminishing returns. Another observation is the failure of many anesthesiologists to tackle formidably some important problems. One of these relates to monitoring during anesthesia. I would agree that monitoring today is much better than it was 20 years ago. Most patients are monitored with a chest or esophageal stethescope and we are moving toward a more routine monitoring of the electrocardiogram during every anesthetic. Just what value the latter is to most anesthesiologists and to most patients I'm not sure. As I watch the scopes in the operating room, only one-third are supplying anything more than the regularity of heart. I suspect that in most instances the electrocar- diogram has become to the anesthesiologists what the St. Christopher’s medal is to the faithful being operated upon. Both anes- thesiologists and patients will take any help they can get. However, we are still, on the average, measuring blood pressure with a de- vice introduced before the turn of the century. The Riva Rocci technique is fraught with inac- curacies, yet we continue to use it routinely as our most important monitoring guide. I submit that the routine resort to our current monitors is unbecoming to a country able to land men on the moon. I have so little faith in all the monitors that I still berate the staff or resident who sit behind a screen and fail to stand and watch the wound, which I think gives the most reliable information. The second area that requires attention concerns anesthesia in the critically ill. Nearly all of the studies done on the effects of anes- thesia on this or that organ system are on nor- mal individuals. We know that healthy man is amazingly resistant to damage from anesthet- ics; most morbidity and mortality in healthy persons is preventable. However, it is in the really sick person where the inherent lethal ef- fects of anesthesia are uncovered. It can be said that anesthesia probably contributed to the death of one in 32 of such patients in Physi- cal Status IV and one in 16 in Physical Status V. As we operate more and more on the ex- tremes of life and are called upon to anes- thetize the critically ill, I think we need infor- mation on anesthetic effects on unhealthy tis- sue as well as healthy. A third area is the relationship between duration of anesthesia and operation to mor- bidity and mortality. We anesthesiologists say that there is a relationship, but there are pre- cious few data to prove the point. Studies would be difficult to do but not impossible, and there are ample means for obtaining meaning- ful data. I have said repeatedly that we need a renaissance in speed in surgery. The implica- tions of such a renaissance to you, to the pa- tient, to the hospital, to the supply of physi- cians, and to the government are tremendous; but you know, as do I, that the renaissance will never come until hard data are developed which prove it is important. 65 PANEL DISCUSSION: RESEARCH OBJECTIVES Respiration, Cardiovascular System Studies, Metabolism, New Inhaled Agents, Fixed Anesthetic Agents, New Local Anesthetics, Basic Mechanisms, Central Nervous System, Peripheral Nervous System, Pain, Acupuncture, Hypalgesia, Obstetrical Anesthesia HARRY WOLLMAN, Moderator John W. Severinghaus, Ellis N. Cohen, Edmund I. Eger, Raymond B. Fink, Henry Price, Luke M. Kitahata, Shih-hsun Ngai, John J. Bonica, Frederick L. Kerr, Soloman Shnider, Panelists DR. WOLLMAN: Yesterday's panel, chaired by Dr. Kitz, was on current research. Today we are charged with discussing research objectives, where might we be going in the next decade in anesthesia research? I have di- vided the discussion into three areas: car- diorespiratory effects of anesthesia, chemical considerations, and the nervous system. Our panelists will proceed. RESPIRATION DR. SEVERINGHAUS: The identifica- tion of important gaps in knowledge is an on- going task of every scientist. Everyone's list is different, fortunately, or we would all be try- ing to fill the same gap. I have chosen to iden- tify a small number of problems that are either under investigation now, or should be. Anesthesia and Regulation of Respira- tion: Our knowledge of the respiratory de- pressant effects of anesthetic agents is quite good, but it fails to explain their effects when combined clinically. For example, N20 is not a respiratory depressant, yet when given to a patient pretreated with narcotic and barbitu- rate and who has a reasonably steep CO2 re- sponse curve, it can completely flatten his re- sponse and even induce apnea. Or another example: patients who have apparently recov- ered from anesthesia with large doses of narco- tic may become comatose and apneic when given Compazine hours later. And again, en- flurane is a potent respiratory depressant, but the studies would not lead one to expect PCO2 values over 100 when it is used clinically, with N20, at anesthesia levels with normal ventila- 67 tion and unchanged blood pressure. Yet it often does produce hypercapnia. Is it the in- teraction of several agents, the missing drive in some patients, or the mysterious “wakeful stimulus” to respiration? Since such events are potentially lethal, unpredictable, or at least unpredicted, and go far beyond the depressant effects of the individual agents studied in the healthy young volunteer, I would place this gap in our knowledge as first in priority on respiration. I recently enumerated 10 “dangerous in- teractions” causing unexpectedly severe re- spiratory depression. Some are well under- stood, such as the antibiotic-relaxant effect. Most need study. Examples are medullary re- spiratory center depression by hypoxia, made manifest when carotid endarterectomy has de- stroyed carotid chemoreceptors; and interac- tion between inhalational agents and relaxants or antibiotics with neuromuscular junctional blocking tendencies. The message is that we need to move away from “pure” laboratory studies of one dose of one drug, to clinical situ- ations where disease, age, multiple drugs, ab- normal postures, and sequential exposure to multiple physicians perhaps unaware of prior therapy can lead to these interactions. An example is the need for study of the effect of repeated dosage of Innovar, to determine the impact of cumulation of the longer lasting tranquilizer component, droperidol, when re- peat dosage demand is based on response to painful stimuli. Here again, investigators must be aware of the possibly very different re- sponses obtained when subjects are asleep than when awake. A major gap exists in all our knowledge about respiratory depressants, in that almost without exception the stimulus used to test ventilatory response has been CO2. Hypoxia is the most dangerous stimulus, and one might say, therefore, also the more important parameter to study, could such studies be made safely. We really know very little about the comparative depressant impact of anesthetics and narcotics on the peripheral chemoreceptor versus the central chemorecep- tor responses. One study, done in trained dogs in my laboratory several years ago, found that halothane depressed the hypoxic drive at least as much as it depressed CO:2 response. There are two or three ways in which more informa- tion can be obtained about hypoxic sensitivity. New rapid linear accurate and dependable gas O:2 analyzers make possible breath-by-breath control of alveolar PO2, such that brief periods of hypoxia (i.e. 1-2 minutes) can be rapidly in- duced and reversed, permitting peripheral chemoreceptor sensitivity to be tested. The blood flow per unit weight of carotid bodies achieves a complete washout in a few seconds, and the response is usually stable in less than one minute. An alternative is to utilize a drug which stimulates ventilation via the carotid chemoreceptors if it can be shown to alter re- sponse in parallel to the hypoxic response, in the face of drug depression. Of the known stimulants—lobeline, nicotine, cyanide, and doxapram—the last shows the most promise and the least objectional side effects as a sub- stitute for hypoxia. And lastly, the use of trained dogs with chronic tracheal stomata and carotid arterial loops makes possible studies including awake controls as well as anesthetic states. Anesthesia and the Lung: Anesthetic agents have relatively few direct effects on the lung, so the special interests we have in pul- monary physiology, anatomy, pathology and pharmacology are indistinguishable from interests of our medical, surgical, physiological and pharmacological colleagues. However, our special ability and interest in ventilatory sup- port, airway management and intensive care of pulmonary problems gave anesthesia a head start in several fields which should be con- tinued. Continuous Positive Airway Pressure: 68 This method of preventing and treating atelec- tasis, introduced by anesthesiologists about seven years ago, is undergoing study widely. We do not yet know what factors limit the lung’s tolerance to such pressure, which, ex- ceeded, result in pneumothorax or pneumomediastinum. Whether periodic defla- tion would permit higher safe pressures has not been studied. Methods of determining the optimum pressures need clarification, particu- larly in identifying the earliest safe time for reduction and termination of positive pressure therapy. The long-term effects of such therapy on lung need investigation. Membrane Oxygenators: There seems to be little need for additional support here, al- though the day seems near when long-term partial bypass will be part of the intensive care scene, and anesthesiologists will have oppor- tunities for study of patients on bypass. The possibilities of manipulating pulmonary flows, pressures, gas tensions and volumes to study cardiopulmonary reflexes is very interesting and can be predicted to be a future field of much promise. Pulmonary Circulation, Especially Pul- monary Edema: Intensive study is needed of methods for detecting changes in lung water, particularly methods that can be applied easily to anesthetized man or to patients in intensive care units. Several possibilities are undergoing evaluation at present. These include electrical impedance of lung by external electrode methods, uptake of soluble gases by the Can- der and Forster method, and double indicator dilution methods, in which one indicator is freely diffusible into lung water. These are especially needed by anesthesiologists because the clinical guidelines for fluid therapy are too insufficient to be certain of avoiding overload or under replacement, when either peripheral circulation, or central venuous pressure, or even pulmonary arterial and left atrial (wedge) pressure, are measured. To be useful, lung water measurement would have to yield quan- titative answers within a few minutes and be capable of being done in awake or anes- thetized, spontaneously or artificially respir- ing patients. More investigation of the causes of pulmo- nary edema observed in clinical anesthesia and intensive care is needed, as for example “neurogenic” pulmonary edema in connection with head injury, stroke and neurosurgery; narcotic-induced pulmonary edema (primarily heroin intoxication); embolic pulmonary edema (air, fat, clots, foreign material); and toxic and bacterial edema. Support is further warranted for enzymat- ic determination of lung damage by analysis of the plasma lung converting enzyme of an- giotensin, for which preliminary evidence suggests a useful procedure. CARDIOVASCULAR SYSTEM DR. NORMAN T. SMITH: The cardiovas- cular effects of anesthesia, surgery, and trauma, as modified by age and disease, are still most important to the anesthetist in terms of prevalence and impact. Therefore, this has been one of the most extensively studied areas in our specialty. Nevertheless, there are ques- tions which need answering. Myocardial Function: Here, several basic questions remain unanswered. What are the effects of anesthetics on myocardial contractil- ity? For that matter, what is contractility and how do we measure it? It may be easier to de- termine the evasive mechanism of anesthetics by studying the heart rather than the nervous system. Perhaps anesthetic agents are nonspecific depressants of excitable tissue. Is the mechanism of myocardial depression an in- terference with the calcium activation of con- tractile proteins, and therefore should we study an even simpler model, the excitation- secretion coupling phenomenon? Is myocardial depression always undesirable, or may it be desirable in some patients? How can we ferret out those patients in whom modification of con- tractility would be beneficial? What are the ef- fects of anesthetics on the oxygenation and metabolism of the heart, particularly in man? Cardiac Surgery: The effects of the com- plex procedures needed to accomplish cardiac surgery should be examined. This includes a host of factors poorly understood about whole body perfusion, profound hypothermia, and as- sisted circulation effects on the myocardium, various organs, and pulmonary vessels. Regional Circulation: We still do not know the impact of anesthesia or surgery on regional circulation. We have begun to 69 examine intraregional “steal” phenomena, but have neglected any interregional steal. Does the latter occur, for example, with isoflurane? When is a given regional perfusion insufficient, adequate, or excessive? An increase in cereb- ral perfusion may be advantageous to a patient with increased intracranial pressure. When is coronary perfusion adequate? Should regional perfusion anywhere be allowed to become ex- cessive, with the resultant increased load on the heart? We have just begun to scratch the surface in studying the microcirculation. We may find significant variations among micro- circulatory responses according to the tissue or organ perfused. Pulmonary Circulation: What about pul- monary circulation, the forgotten circulation? Measurement and interpretation are still con- troversial in this area. Mechanisms responsible for the development of pulmonary hyperten- sion, as well as its therapy and the effects of anesthesia on pulmonary function are all unre- solved. The relationships between anesthesia and pulmonary edema are virtually un- explored, as are those between anesthesia and the metabolic and circulatory homeostatic functions of the lung. Ventilation-Perfusion Abnormalities: We can now measure the continuous distribution of ventilation-perfusion ratios, rather than rely- ing on descriptions which divide the lung into two or three compartments. The analysis re- sults in the definition of the position, shape, and dispersion of the distribution. In every pertinent case in which the technique has been used, hypoxemia and changes in arterial PCO2 could be explained quantitatively by the ob- served ventilation-perfusion inequality, shunt and deadspace, and their combined interaction with cardiac output and minute ventilation. Several important questions can be answered with this technique. What are the effects of intravenous and inhalation anesthetic agents, muscle relaxants, and the pattern of ventila- tion on the V/P distribution? What are the in- fluences of age or disease; or duration, depth, or type of anesthesia? What are the effects of positive end-respiratory pressure or the use of nitrogen as an alveolar stabilizing agent? How useful are some of our maneuvers of prevent- ing postoperative pulmonary complications? Drug Interaction: Drug interaction is an extremely complex problem, if for no other reason than the sheer number of agents which the anesthetist alone uses per case (8-12 routinely). We need satisfactory techniques for quantitating multiple drug interaction. A few existing techniques have proved useful for examining two agents; one barely suffices for three agents, but none can serve for more than three. Bioengineering: Anesthesia offers unique opportunities for collaboration with engineers and bioengineers. For example, perhaps a re- cent technique for spectral analysis of heart sounds in the diagnosis of myocardial ischemia could be applied by the anesthetist and bioen- gineer together. For too long we have been studying the individual components of the car- diovascular system as if they had nothing to do with each other. We must now examine the cir- culation as a whole, with all of the complex interactions involved, including baroceptor and volume control, as Guyton, Noordergraaf, Beneken, and Rideout have begun to do. Simi- larly, we cannot consider the cardiovascular system separately from the rest of the body. Recent work on the profound pulmonary im- pact of the hypoxic brain hints that the brain has more influence on the heart than we previ- ously suspected. To study the complex interac- tions among anesthesia, surgery, and the vari- ous physiological systems will require a sys- tems engineering approach, with computerized multiple modeling to guide us to proper studies and to help interpret the results of these studies. Computers: Computers must be put to work, preferably to perform tasks which are impossible or difficult for humans to do. For example, regional myocardial hypoxia can be detected and localized with the vector cardiog- ram plus digital filtering and multidimensional pattern-recognition techniques. Fast Fourier or Hadamar transformers can be used to pro- vide a continuous, packed display of the ECG or vectorcardiogram. Computers are rapidly becoming faster, smaller, more reliable, more versatile, and most importantly, less expen- sive. One commercial microprocessor, with the capacity of a PDP-11, costs about $300, and the price will soon come down. Even the cost of prodigious memories has dropped considerab- ly. A computer for producing a spectral analysis and display of the EEG, or for cal- culating beat-to-beat pulse contour cardiac output, costs less than $2,000 and will ulti- mately fit into the amplifier module of a stand- ard strip-chart recorder. Automation: The anesthetist’s task is to maintain physiological stability if not home- stasis. This process should be automated, as with the following examples: Arterial pres- sure, central venous pressure, heart rate, and urine flow can be used to control halothane concentration, fluid infusion, and patient posi- tion. Calcium ion reverses the myocardial de- pressant effects of general anesthetics, but the fear of arrhythias prevents the routine use of calcium. Perhaps CA + + can be infused slowly by a servo pump to maintain a desired level of myocardial function, thus avoiding dangerous concentration peaks. Ventilators can be pro- grammed to maintain optimal PaCI., ventila- tory work, and/or circulatory status. Monitoring: Probably the weakest point in applied cardiovascular-anesthesia research is monitoring. We spend millions of dollars annu- ally on elaborate systems, yet we cannot routinely assess myocardial function. Our sys- tems are expensive, cumbersome, and com- plex. They usually are appropriate mainly in a university center, assume a certain amount of adroitness on the part of the anesthetist, and require invasive techniques. New devices and systems must be developed and tested. They should be made as anesthetist-proof as possible and fully automatic, with only an on-off switch and a warning red light when a device is not plugged into the wall. Any system should be reliable, inexpensive, and small. Anyone who has fought a tangle of wires will appreciate the need for telemetry. How can we assess the im-- pact of monitoring techniques on peri- operative morbidity and mortality? Actually, the operating room has historically been the optimal testing ground for new techniques in the care of acutely and/or seriously ill patients, and should take the place of the intensive care unit in many studies. The greatest deficiency in routine monitoring is the measurement of blood loss and adequate fluid replacement. A continuous or frequent safe measurement of blood volume would obviously be ideal. Ulti- mately, monitoring must be totally noninva- 70 sive. Recent developments, such as an exter- nal tonometer which gives a calibrated arterial pressure pulse through modeling and parame- ter optimization, indicate that this is possible. The realization of noninvasive monitoring, however, will require several years. Until then, we need a rapid, simple pre-operative screening test to detect patients who are headed towards cardiovascular trouble and hence need elaborate monitoring. Preliminary evidence suggests that the ballistocardiogram and a blood pressure cuff will give the needed information. These studies must be confirmed. The anesthetist could ultimately be faced with the possibility of having a multitude of values presented to him by monitoring. One monitoring project alone described 17 simul- taneously measured variables. Assuming that the anesthetist will rebel at the thought of this mass of data, the computer will have to come to his rescue by processing information to a di- gestible form. Alarm systems using parameter optimization pattern recognition, adaptive sys- tems, and industrial trend analysis will be necessary. Display techniques are still primi- tive. Compressed and density-modulated spectral arrays represent a beginning. It should be possible to present four or five vari- ables on one strip chart channel in such a way as to allow quick recognition of any problem. By using anesthetic agents which seldom decrease arterial pressure we have not solved a basic problem. We seem to have substituted hypertension for hypotension in the same questions we have been asking for several dec- ades: How much hypertension can a patient to- lerate? Which patients are the most suscepti- ble? How do we detect these patients? Should we treat hypertension? Which therapy do we use? Will the ECG be a good monitor for exces- sive hypertension? How do we follow post- operatively for permanent myocardial is- chemia? Can the ECG indicate if coronary per- fusion is adequate? If so, how many leads and what configuration are necessary? What kind of analysis should be used—multidimensional pattern analysis, with “cloud templates” of carefully chosen normal and abnormal patients to go by? The problem of arrythmias has not been solved. Which arrythmias should be treated, which observed closely, and which ignored? Do these vary from patient to patient? Can recog- nition and therapy be instituted by computer? Certainly a computer could remember patterns and interpret changes better than man, and it need never take its eye off a pattern. The newer cardiorespiratory models of up- take and distribution, along with parameter optimization, can be used to “measure” inac- cessible variables by using easily measured ones. For example, it may be possible, know- ing PA COz2, PA and halothane, as well as arte- rial pressure and heart rate, to monitor cerebral and coronary blood flows. There is no dearth of problems in the study of the cardiovascular system and anes- thesia. Probably the most needy area is that of monitoring. Simple, reliable, small, and inex- pensive monitoring systems must be de- veloped, so that first-rate monitoring can be the property of all anesthetists, not just those in university centers. DISCUSSION DR. WOLLMAN: The first question con- cerns the area of prevention, etiology, and treatment of pulmonary edema, which occurs so frequently in the operative and post- operative patient. Dr. Marshall, where do we go in this area over the next decade? DR. MARSHALL: The first problem is the use of blood, which is in short supply and has a limited storage life. It is expensive. It contains the hepatitis virus, and we are all aware now that it deteriorates with storage by forming microaggregates. Many of us are using microfilters in the clinic to prevent damage to the lung by microaggregates. But actually, evidence now shows that microaggregates may not be bad for the lungs. There might be some- thing else in stored blood that damages the lung and causes pulmonary edema. This is an area that certainly needs to be investigated. Open heart patients get edema, post- operatively, which does not seem to be due to a pressure change effect. One would wonder whether the metabolizing role of the lung in regulating fluid balance by hormones is not in- volved. This is a second area for study. The use of blood fractions would be one way of avoiding the difficulty of storage and limited supplies. It would provide much more efficient usage, but 71 would require anesthesiologists to be much more specific in their diagnosis and require- ment. Certainly, we need a lot more work on how efficiently we can use frozen cells, trans- fusion, and finally, artificial blood. If these problems can be solved, then the most pressing problem that I see is a method of measuring capillary permeability in normal and damaged lungs. There is no existing way of measuring it except indirectly. We need a method for use in patients. Thirdly, I would spot nutrition, with regard to these kinds of abnormalities, as being an area almost totally neglected by anes- thesiologists. DR. WOLLMAN: Another area that we have frequently touched on is equipment de- sign in anesthesia, the necessity for better and more noninvasive monitoring. I wonder, Dr. Kitz, if you would comment on the state of the art and where we should be going. DR. KITZ: I am sure it bothers all of us that the anesthesia delivery systems we use were designed at least a quarter century ago. Some perhaps are even older. Not more than one or two major contributions other than new boxes for them have been introduced since that time. Why should we be forced to use this kind of equipment? For instance, why are all the knobs of our anesthesia machine the same? Why aren’t some of them different? Why have we had to change all of our oxygen knobs to an octagon shape? These simple kinds of things are usually only thought about after there are major accidents. Why can’t we have a better way of measuring regional blood flow, for instance? This is criti- cally important, as Dr. Smith mentioned, and represents the types of things that can be done. Recently, I learned about intravascular materials which have magnetic properties. We tried some of the material in the limbs of dogs and were able to measure the flow by first holding it in one place with a magnet and then releasing it. Industry, because of the cost, is not willing to put out a new machine or system integrating all of these various components. Thus the burden is put on us to develop the kinds of equipment we need. DR. WOLLMAN: Another area which Dr. Smith mentioned is the use of computers. I would like to ask Evan Frederickson to review where computer applications might be sought. 72 DR. FREDERICKSON: This subject was covered very well by Dr. Smith. There are many areas where the computer could be used and certainly support for such studies has come from NIH, but information acquired has not been applied. Actually, at the present time, the use of computers in other areas is much more sophisticated than in anesthesia. Even simple things, such as vital statistics are not universally used. It still upsets me when I have to keep an anesthesia record with a pencil and five carbon copies. Remarkably, in contrast to our use of anesthesia machinery developed 35 years ago, the computer as a communication tool has not been used as yet in the operating room, even for very simple procedures. DR. de JONG: On the topic of computers, there certainly is the very exciting possibility alluded to by Dr. Smith that perhaps we may at last be able to measure anesthetic depth with somewhat more precision than by judging whether or not a patient jumps off the table when the incision is made. I think one of the crucial things ahead of us, in terms of patient care and utilization of anesthetics, is knowing exactly how deep the anesthetic level is, by means other than looking at blood pressure and respiration. In the past, the electroenceph- alogram has been used to assess agents such as ether and cyclopropane. However, following introduction of the halogenated agents, EEGs fell into disuse because the patterns were so extremely difficult to unravel. But conceiva- bly, with computer applications to facilitate spectral and discriminatory analysis for exam- ple, perhaps we shall be in a better position to measure instantaneously anesthetic depth from moment-to-moment in the operating room, and so improve our patient care. Much developmental work needs to be done on this, but the tools are at hand and it seems just a matter of time. DR. SMITH: I mentioned that spectral analysis can be done with a computer which costs less than $1,000. It is linked to a slip- chart recorder to achieve three-dimensional display of the data. Even for one not fully ac- quainted with the EEG or EKG, the display makes it possible easily to detect the difference between the awake patient and the patient under halothane. In fact, one can tell the dif- ference among depths of anesthesia quite eas- ily. The patterns presented are readily recog- nizable, ranging from 0.5 MAC up to 1 MAC, 1.5 MAC and 2 MAC. We also can tell from the patterns which anesthetic agent was given. Finally, even CO: patterns have distinct likenesses; we can see what happens when we have 60 TOR COz2, 40 TOR CO2, and 20 TOR CO2. The patterns are different, not only among themselves but in the different depths of agents. Most importantly, IT hope that the old concept of expensive computers no longer exists. ANESTHETIC METABOLISM DR. COHEN: Studies in anesthetic metabolism may be divided into two areas: the direct effects that the anesthetic exerts upon the metabolic functions of the body, and the indirect effects associated with metabolism of the anesthetic itself. Although these processes may be interrelated, they are quite distinct. The administration of an inhalation anesthetic represents the uptake of foreign molecules of high lipid solubility. As such, the body possesses limited means for their elimi- nation. While highly volatile anesthetics are rapidly eliminated via the lungs, agents of lower volatility remain in the body for longer periods of time and undergo slow excre- tion via the liver. Fortunately, the body pos- sesses an alternate route for the elimination of lipid soluble compounds. In this process, excretion is accomplished via the kidneys, which can efficiently handle large amounts of foreign drugs. However, in order to utilize this elimination mechanism, the body must first convert the lipid soluble anesthetic to water soluble metabolites. The latter is accomplished through the availability of a variety of enzymatic processes including oxidation, re- duction, conjugation, etc. Biotransformation: The biotransforma- tion of foreign compounds provides an impor- tant means for drug elimination; without it, many lipid soluble compounds would have ex- tended duration in the body. Brodie has calcu- lated that if thiopental were not metabolized, its short half-life would be extended to over 100 years. Generally, the process of metabolism results in compounds that are less active and less toxic than the parent drug. To a significant extent, this is simply because they 73 are less lipid soluble. The metabolites are more readily excreted, and the existence of lipid cel- lular barriers prevents their wide distribution. On the other hand, not all anesthetic metabo- lites are of low toxicity. With some inhalation anesthetics, metabolites of higher reactivity are created. There is increasing evidence that many of the long-term toxic effects associated with the inhalation anesthetics result from their biodegradation. It has been shown for certain anesthetics that if one prevents metabolism by the use of antimetabolite drugs, one also prevents toxicity. These brief introductory remarks serve to emphasize two relevant points: 1) the impor- tance of the physical-chemical characteristics of an anesthetic in influencing uptake, dis- tribution, and metabolism; 2) the fact that the toxicity and metabolism of an anesthetic are closely associated. Based on these established concepts, there would appear to be a number of fruitful areas for investigation. If anesthetic toxicity depends to a large extent upon anesthetic metabolism, obviously useful effort might be spent in the creative de- sign and synthesis of new anesthetic agents that are minimally biodegraded. Although a number of drug manufacturers have made sig- nificant efforts to design non-metabolizable halogenated anesthetics, these efforts have en- joyed only limited success and each of the cur- rently used halogenated anesthetics is metabolized. Fortunately, other designs re- main available with several alternate direc- tions. In a different approach we might gain by extending the original studies by Cullen et al., and further examine the inert gases as anesthetic agents. Ignoring its expense, xenon is a very satisfactory clinical anesthetic and there can be little doubt as to its biostability. Yet another possibility is to consider the preparation of certain clinically useful com- pounds that have antimetabolite action. The successful use of antimetabolite drugs such as SKF 525A or disulfuram in the experimental animal offers support for the development of similarly designed compounds for trial in man. The protective role of antioxidants, glutathione derivatives, etc., in preventing anesthetic toxicity is beginning to be ap- preciated and provides another area for inves- tigation. I should not like to convey the impression that all anesthetic metabolism is necessarily bad. As indicated in our opening remarks, metabolism actually offers an important route for the rapid elimination of many foreign drugs. It is only when associated with the for- mation of reactive and potentially toxic metabolites that we have a serious concern. There is some evidence that the biodegrada- tion of an anesthetic and the formation of metabolites may represent an individualized process. We know that both environmental and genetic factors are operative, and that signifi- cant species variation occurs in the metabolism of inhalation anesthetics. One recent example is the metabolism of fluoroxene to tri- fluoroethanol with resultant toxicity in several experimental species. By fortunate circum- stance, man is excluded from this route of metabolism. Thus the careful screening of selected individuals as to the degree of anesthetic metabolism and the nature of the metabolites formed would be of theoretical and practical importance. If variations in metabolic pathways exist between individuals, this in- formation might allow us to separate out a population of increased risk. The suggested in- creased incidence of “halothane hepatitis” in our Mexican-American population may be a case in point. One of the first preliminary steps to any such screening studies would be the identification in man of the individual metabo- lites and the definition of normal metabolic pathways for each of the clinically used anesthetics. To the largest extent, this re- mains to be accomplished. Model Systems: Although definitive inves- tigations into anesthetic metabolism must be made in man, both in vitro and intact animal studies may also be contributory. The use of model systems provides readily controllable methods with which to study a variety of anesthetic properties including toxicity, po- tency, the action of anesthetics on metabolic processes, ete. For example, a recent report suggests that the mitochondrion may serve as a useful anesthetic receptor model. Other studies confirm the important binding proper- ties of a number of inhalation anesthetics to cytochrome Paso, although of the agents tested only chloroform and halothane appear suffi- ciently reactive to interfere with the binding of carbon monoxide. The use of mitochondria and synaptosomes for study of the effects of anesthetics on phospholipid metabolism, glutamate-dependent oxygen consumption, calcium uptake, ete., provide the tools for ad- ditional areas of investigation. Recent investigations into the effects of trace anesthetics on the health of operating room personnel are of considerable public health interest. Results of these studies dem- onstrate that female operating room personnel are subject to serious occupational hazards. Although a cause-effect relationship be- tween these responses and anesthetics (and/or their metabolites) remains to be defined, sup- porting data are provided by animal studies, and such a relationship seems to offer the most reasonable explanation. On the assumption that these occupationally associated diseases are anesthetic-induced, it becomes of interest to define further the nature of the interrela- tionship between anesthetic metabolism, teratogenesis, and carcinogenesis. A common denominator here would appear to be biodeg- radation of the anesthetic molecule. Van Duuren et al. have shown that high levels of carcinogenicity are associated with metabolism of the a-haloethers. The presence of the halo- gen on the carbon atom to the ether oxygen creates a metabolically active compound and a powerful alkylating agent. These compounds closely resemble the clinically used haloge- nated anesthetics, many of which are also a-haloethers. Intermediate Metabolites: We already have evidence to indicate that reactive inter- mediates are formed during metabolism of the halogenated anesthetics and covalently bound molecular fragments in the liver may be shown both chemically and autoradiographically. The question of the metabolism and possible toxie- ity of nitrous oxide is also of interest. Nitrous oxide is the most widely used of the inhalation anesthetics, and its metabolism to nitrates and to nitrites would appear to be theoretically possible. If the human liver is capable of biodegrading nitrous oxide to nitric oxide or to nitrite ion, the possibility of mutagenicity and carcinogenicity would be present. Thus, theoretical mechanisms are available in the metabolism of many inhalation anesthetics to account for an association between anesthetic 74 metabolism, teratogenicity, and carcinogenic- ity. In selecting important areas of anesthetic metabolism that merit future investigation, such studies would appear to enjoy high prior- ity. NEW INHALED AGENTS DR. EGER: In discussing objectives in the area of new inhaled anesthetics and the likelihood of their achievement, it would seem by implication that currently available agents are imperfect and that we have some idea of what we want in an anesthetic. For example, all of us agree that the agent should not have toxic effects (defined as injury remaining after elimination of the anesthetic), should not be flammable or pungent, and should not predis- pose to the induction of arrhythmias. Intracra- nial pressure and cerebral metabolism (and blood flow?) should decrease or at least not change during anesthesia. The anesthetic should relax muscles and/or potentiate the ef- fect of muscle relaxants. No adverse interac- tions with other drugs or with physiological changes (e.g., changes in blood gases, blood pressure) should occur. The agent should cause analgesia, yet should not have residual sub- anesthetic effects. Finally, it would be nice if it didn’t corrode our anesthetic machines and cause the disintegration of rubber hoses and bags. From this agreeable catalog of charac- teristics we proceed to a list where the consen- sus is less than complete. For example, there are arguments for and against an agent causing cardiovascular depression. Dr. Ty Smith al- luded to this earlier. Many anesthetists would prefer that blood pressure be sustained at awake levels to protect tissue perfusion while others would like the work of the heart re- duced by decreasing blood pressure and perhaps cardiac output. Similarly, there is dis- agreement on the need for respiratory depres- sion including depression of laryngeal reflexes. Do we want a poorly or highly soluble agent? Do we want one that causes uterine relaxation? The answer to these and other similar ques- tions depends on the particular needs of the patient. It also implies two things. First, that there cannot be a single “perfect” anesthetic, and second, that we must know the properties 75 of both new and old agents so that we can choose the one most appropriate to the needs of a given patient. A good bit of our discussion this morning has been, and will be devoted to this point. I would like to emphasize the areas that I believe worth pursuing in depth. Toxicity and Drug Interactions: We need to know how closely each anesthetic ap- proaches the characteristics described above for a “perfect” anesthetic (including those where there is some disagreement) and what situations might adversely alter the charac- teristics of the anesthetic. For example, a given agent might not reduce blood pressure in a young patient but might do so in one who is elderly or on particular medications. We need more information about toxicity, including not only hepatorenal effects noted by Dr. Cohen but also short and long term effects on the heart, the brain, the gut, and the fetus. We also need to know about short and long term interactions of drugs with anesthetics. In par- ticular, we need to know what circumstances alter toxicity or drug interaction. I would like to be able to anticipate which patient is at greater risk from, say, halothane hepatitis or enflurane convulsions or methoxyflurane nephritis. Would it be possible to develop a blood test or clinical profile which would allow us to recognize such patients? We need to know more about the equip- ment used to deliver new (and older) anesthet- ics. For the most part we have left “research” in this area to manufacturers who obligingly have given us many shining variations on a few themes but little if any data on how such equipment interacts with patients. What is the effect of such equipment on humidity; on the concentration of anesthetic delivered; on the incidence of respiratory infections? There have been no well-controlled studies that I am aware of which adequately examine the conse- quences of using unsterile equipment for en- dotracheal intubation and the delivery of anesthetics. And yet, the results of such a study might have enormous implications to the quality and cost of patient care. Where Do We Stand in the Development of New Anesthetics?: Let us return to the de- velopment of new inhaled agents. What chance might we have of finding a new anesthetic which would meet our needs and where should we look? To answer this question requires that we briefly survey the development of our cur- rent agents. The first anesthetics, nitrous oxide, ether, and chloroform were taken from the pharmacist’s shelf. With the exception of cyclopropane, no significant new agents ap- peared until advances in fluorine chemistry made possible the manufacture of fluorine con- taining carbon compounds. This peripheral re- sult of the uranium purification process neces- sary to fabrication of the atom bomb has given us a number of anesthetics, among them fluroxene, halothane, methoxyflurane, en- flurane, and isoflurane. It also has given us hundreds of unacceptable compounds. The reasoning behind the development of enflurane and isoflurane may be particularly instructive. A set of primary essential criteria similar to those listed at the beginning of my discussion were drawn up by the manufac- turer. Several compounds within various chemical series appeared to meet most of the primary criteria, then a larger number were prepared; otherwise the series was discarded. The alkane and cyclic series soon were aban- doned because they predisposed to ar- rhythmias. The ethers appeared not to have this drawback and hence were examined in de- tail. The dimethyl, methyl isopropyl, and ethyl isopropyl ethers proved to be unstable. The diethyl ethers produced convulsions and cellu- lar toxicity. Only the methyl ethyl ethers gave promise of possessing the sought-after proper- ties. Compound 347 (enflurane) and compound 469 (isoflurane) were discovered in this group. Altogether, over 700 compounds were synth- esized and tested at a cost estimated to be be- tween six and eight million dollars. We might ask whether there is any hope of finding still better agents than those now available (including isoflurane). As better anesthetics are introduced, the task of finding still better agents becomes more difficult. Furthermore, the thorough and rational ap- proach to the development of enflurane and isoflurane suggests that there are few avenues left to explore. And yet, enflurane and isof- lurane are not perfect agents: both are car- diorespiratory depressants; both increase cerebral blood flow; both have residual sub- anesthetic effects on mentation; both are somewhat pungent; both obtund laryngeal re- flexes; and both cause uterine relaxation. The definition of subtle hepatic and renal side ef- fects of these agents awaits the results of their administration in several million patients. It is obvious that there is room for a better agent—but where might it be found? One sur- prising place may be in a manufacturer’s catalog of widely available gases and vapors. The commercial exploitation of an anesthetic (or any drug) requires that it be patented. Many non-patentable fluorinated compounds have never been adequately tested, simply be- cause they offered no significant financial re- turn. A company would be foolish to expend several million dollars on the development of an anesthetic that anyone could market. I wonder if it would be appropriate to use public funds to survey non-patentable compounds for anesthetic efficacy. The discovery of an excel- lent anesthetic might offer a two-fold benefit: such an agent might be better than available agents; it certainly would be far cheaper. Three other avenues may lead to improved new anesthetics. First, some unreleased man- ufactured compounds may be better agents. However, the development of these com- pounds is at the discretion of their owner. Sec- ond, not all potential anesthetics in the alkane or ether series have been synthesized and some of these may be better agents. Consider- ing the extent of past work in this area, how- ever, I believe there is little promise of success in additional explorations. Nonetheless, sev- eral companies apparently are more hopeful than I and we may someday see the results of their work. Third, perhaps progress towards a better agent will have to await advances in chemistry analagous to the advance in fluorine chemistry which made possible our current generation of anesthetics. All is not lost if a better new agent is not thrust upon us. The ones we have approach perfection in many ways. Perhaps we merely need to learn how to deal with their imperfec- tions. DISCUSSION DR. WOLLMAN: We heard from Ellis Cohen about the toxic effects of trace concen- trations of general anesthetic agents in the OR 76 atmosphere. Speaking to Dr. David Bruce, what is the chance that we might learn more about this from studies in the area of anesthet- ic effects on cell division and cell maturation? DR. BRUCE: I think very good. Data de- rived from an American Society of Anes- thesiology Ad Hoc Committee study, which Dr. Cohen referred to and which will be pre- sented in its entirety at the ASA meeting next Monday (October 14, 1974), suggests only a re- lationship between working in the operating room and these various phenomena. It is not possible to get a direct cause-effect relation- ship by such an epidemiological approach. It is of interest that Alestair Spence did a very similar study in the United Kingdom and found almost exactly the same results. The odds are rather slim that everybody in England, Scot- land, Ireland and the United States mop their floors with the same preparation and are otherwise exposed to all the other possible al- ternatives. So I think the favorite culprit in this is the anesthetic agent. I have done a study on concentrations of halothane and fertil- ity in mice and got essentially nothing. On the other hand, Tom Corbett of Michigan has done a rather narrow, limited sort of study on preg- nant rats exposed to traces of nitrous oxide comparable to those which can be experienced in an unvented operating room, finding very striking fetal wastage and loss. So the question of nitrous oxide metabolism, I think, is absolutely critical. In England, activated charcoal filters are used to absorb all the halogenated agents from the anesthetic compounds, but no concern at all has been given to nitrous oxide; it simply blows around the room. The only animal data we have showing toxicity at these trace levels concern nitrous oxide, yet we know nothing about the metabolism of nitrous oxide. It is a formidable problem, and I think it absolutely critical to look at the whole question of trace anesthetics, trace nitrous specifically, and its effects on cell division. DR. WOLLMAN: Is there more to say for looking—in the test tube, in the beaker—at the effects on cell division and maturation, rather than the epidemiological approach? DR. BRUCE: Yes. We now have the clini- cal indication for basic laboratory studies in an attempt to get meaningful data. We have a 7 very strong clinical lead. We have gone as far as we can from the epidemiologic sense. Now we must go into tissue culture, embryogenesis, or what-have-you, to get further information. DR. FINK: I would like to make some negating comments on nitrous oxide. We have not published this study because I, for one, have become very skeptical about the results. In rats, we have not been able to show any effect from trace concentration of nitrous oxide throughout the period of pregnancy. However, I don’t think it is conclusive. Before incriminat- ing nitrous oxide or any anesthetic, we need very sound, strictly controlled data in large quantities. This is the kind of study we should be projecting. DR. WOLLMAN: The two of you are pointing to two areas, then. More epidemiol- ogy as well as work studies, in a controlled laboratory situation. DR. COHEN: As to epidemiology, the ASA Ad Hoc Committee plans within three years a follow-up study to the present one. Hopefully, it will establish a cause-effect rela- tionship, if indeed we are able to successfully vent the operating rooms and remove most of the waste anesthetic gases. This doesn’t mean that we should not attempt animal studies, bacteria studies, or all possible studies of this type. But I think further epidemiologi- cal study is indicated. DR. EPSTEIN: Dr. Cohen mentioned car- cinogenic effects in passing, which brings to mind the problems with vinyl chloride. For those of you not immediately adept at this chemical translation, it is monochloryl- ethylene, which is very close to some of the agents we use. We know about its history— that long-term occupational exposure appar- ently has produced very rare sarcomas in some persons. Therefore, while three-year studies are very valuable, we really must think in terms of nearly life-long exposures since the latency period, we now know, may be very long. DR. BRUNNER: I think we would be neg- ligent if we did not consider studies being done on the behavioral effects of trace amounts of anesthetics, and the effect of this exposure in consideration of general health care. It’s been shown that trace amounts of anesthetics in the operating room do in fact alter the perform- ance of the anesthesiologist, the surgeon, and others who daily are taking care of the mass of surgical patients. DR. GREENE: Another subject which should be an important and fruitful area for future investigation in anesthesia relates to the non-ventilatory function of the lungs, in- cluding the lung not only as a metabolic organ for xenobiotics but also as a mechanism for regulating the levels of circulating peripheral blood which contains many hormones and biogenic amines. I think this is an area that will require a great deal of attention in man in fu- ture years and is a perfect example of the kind of contributions an anesthesiologist can make in studying the non-respiratory function of the lung. A pharmacologist can study this ad nauseam in guinea pigs, rabbits and dogs, but anesthesiologists logically are the only ones who can really study this in man. Here, we can make a unique contribution. FIXED ANESTHETIC AGENTS DR. EGER: Injected depressants differ from inhaled anesthetics not only in their routes of administration and elimination but also in the uses to which they are put. We call on them to allay anxiety, cause amnesia or analgesia and add to the anesthetic process both during induction and maintenance. We may use them alone for anesthesia. And after anesthesia, we may give them to provide pain relief and tranquility or prevent nausea and vomiting. The variety of tasks to which they are put almost precludes the application of a single class of agent; and so we have the bar- biturates, narcotics, tranquilizers (which, of themselves consist of several families) and anesthetics such as ketamine. Each of these classes of agents have draw- backs which might be reduced by the develop- ment of new agents. Detailing all these draw- backs would require more than the time avail- able. However, I would like to designate some rather specific goals, instead of saying only that we need more efficacious and less toxic, less costly drugs. Antagonist Compounds: One of the major problems with this group of drugs is reversibil- ity. It would be advantageous to be able to end their actions with a specific or even a non- specific antidote. Such a development has made narcotics much more useful anesthetics, and anesthetic adjuvants, than they otherwise would be. One problem remains with this agonist-antagonist relationship: sometimes the narcotic action far outlasts that of the an- tagonist. It would be helpful to know more about the pharmacokinetics of both the agonist and antagonist so that new compounds can be better matched. Apart from the narcotic an- tagonists, we have only a few “reversal agents” which do not have side effects that preclude their usefulness. Physostigmine and doxapram may lie in this limited group, and they require further definition of their effects in man. I would like to see the development of more drugs of this sort. We need either drugs or antagonists which have greater specificity—for example, a narcotic analgesic which doesn’t cause respiratory depression and nausea, or an antagonist of respiratory de- pression and nausea which doesn’t reverse the analgetic effect. We need drugs that are effective orally and intramuscularly, as well as intravenously. A potent, rapid onset, short-acting oral hypnotic quickly would find a place in pediatric anesthesia. This might be an impossible de- mand if the short action required hepatic metabolism since orally administered medica- tions must pass through the liver before they can act. It would appear that ketamine nearly meets these requirements but, in fact, we have found that kentamine is a very long-acting agent. Other defects of ketamine—particularly its propensity to produce hallucinations, exci- tation and muscle rigidity—preclude its wide- spread use as an anesthetic or even anesthetic adjuvant. Dose Related Effects: Much more is known about the dose related effects of inhaled as op- posed to fixed anesthetics because inhaled agents are far easier to measure. The ease of measurement follows from the many methods available for rapid gas analysis and from the fact that a measurement of alveolar anesthetic partial pressure is a measurement of anesthet- icactivity. The recent development of methods for the rapid measurement of blood and tissue concentrations of fixed agents (still not nearly as rapid as for inhaled anesthetics), will aid in 78 our assessment of the dose related effects of these agents. However, even with these new methods we are not measuring activity. Future measurements of effects should not only include the standard assessment of acute cardiorespiratory and central nervous system changes but also the definition of ef- fects after several hours. For example, in an occasional subject we have found that the or- thostatic hypotension which follows narcotic administration may persist for 12 hours. Simi- larly, Dr. Bruce's studies on the behavioral ef- fects of trace concentrations of inhaled anesthetics (i.e., increased reaction time, de- creased memory retention) would suggest that fixed agents, with their slower clearance from the body would exert behavioral effects for hours to days following administration. The implications are considerable: for example, when is a patient fit to drive a car after receiv- ing a premedicant sedative for an outpatient anesthetic procedure? I would like to know more about the in- teraction of these agents with the inhaled anesthetics they are supposed to complement. How does the combination affect vital func- tions and what effect does concomitant ad- ministration have on the pharmacokinetics of each. For example, we have found that halothane prolongs the effective blood level of ketamine, both by altering ketamine metabolism and ketamine uptake and distribu- tion. The implications to the clinical use of both agents is considerable. Finally, I would like to know if the fixed agents used as partial or complete substitutes for inhaled anesthetics are any less toxic. We are led to believe that the metabolism of halogenated agents is a cause of hepatic and renal impairment and that such impairment does not follow anesthesia with fixed agents such as barbiturates or narcotics, or is far less frequent following their use. I am not sure that this is the case. Nor am I sure that other com- plications (i.e., respiratory, circulatory) that may follow anesthesia with fixed agents are not greater than with inhaled agents. To test this would require a prospective study of con- siderable size. I think that determination of the relative safety of these modes of anesthesia would be well worth the cost. 79 NEW AGENTS—LOCAL ANESTHETICS DR. EGER: One colleague suggested that the “introduction of new agents is more an exercise in advertising and corporate profits than an exercise in significant research,” but several others thought that much remained to be done—both in the area of new drugs and research on pharmacokinetics, toxicity and mechanisms of action. Most of my correspon- dents have expressed a desire for a longer act- ing agent (2 to 4 days duration). The develop- ment of bupivacaine indicates that manufac- ture of such an anesthetic may be possible using variations on current classes of drugs. An interesting new class of long acting com- pounds are derivatives of the neurotoxins, such as tetrodotoxin which Dr. Bonica already has discussed. The use of such compounds is appealing because of the specificity of their ef- fect on sodium conductance. However, in their present form they are too toxic to consider for clinical practice. The problem of toxicity, both general and local, continues to be of concern. Any factor which reduces uptake from the site of injection also should reduce toxicity, and for that reason an agent which causes vasoconstriction might be sought. The synthesis of such an agent might allow us to dispense with the use of con- comitant epinephrine injection. This would be of benefit since epinephrine has its own poten- tial for adverse pharmacological effects. An al- ternative approach to toxicity would be the de- velopment of a drug which was quickly broken down by the blood (but not by tissues) so that high systemic levels could not be attained. An example of such a drug is procaine. Would it be possible to synthesize an agent which reverses the effect of local anesthetics? Such an agent would be useful not only to terminate anes- thesia but also might specifically oppose the toxic effects of anesthesia. We need to measure toxicity not just in animals, but in man. Human studies impose a heavy moral responsibility on the investigator; but until they are undertaken, we will be un- able to say which agent has the highest benefit/cost ratio. We need to measure local neurotoxicity and its relationship to dose and effect. Is an allergic response possible with local anesthetics, and if so, what is its inci- dence and consequences? And do local anesthe- tics have teratogenetic effects in humans? Finally, I would like to know more about the pharmacokinetics of local anesthetics. I want to know about their movement around and within the nerve trunk(s) following a perineural or epidural or subarachnoid injec- tion. I am glad that Dr. Fink already is well started in such investigations and will speak to us about them. I would like more information on their systemic uptake, distribution and biotransformation, and the effects of phar- macological and physiological factors on such pharmacokinetics. Specifically, what do epinephrine, local and systemic, pH, local dilu- tional acidosis, aging, and anesthetic-induced hypotension do to uptake? I believe that the solution of these problems would enable us to administer local anesthetics more rationally and effectively. DISCUSSION DR. de JONG: Within the context of re- search objectives, I would like to use the topics reviewed by Dr. Eger to state my concern about current anesthetic agents and the lim- ited options available to us. Exaggerating perhaps a trifle, our current anesthetic agents are little better than prehis- toric methods. They are largely empirical. The new crops of derivatives aren’t all that much better than the original. Why is this? My reply is, for lack of knowing we can’t design and build a better anesthetic molecule. We still don’t know where anesthetics act, what they do and why they do it. The one characteristic that we can identify about general anesthetics is that they are lipid soluble; and despite five research centers, it is like looking for a Smith in the phone book. You need at least a first name to narrow your search. Yesterday the question was raised about a local anesthetic re- ceptor, a catch-all phrase, for a lack of knowl- edge about the site of action. It is sad that we have not progressed to the stage of identifying an anesthetic receptor. All we can point out at the moment is a broad region of neural junc- tion. If we estimate any progress at all in de- signing more specific agents, we must know what anesthesia is, where anesthetics act, and why they alter neural function. I think this is perhaps the most critical area of our research needs. CARDIORESPIRATION STUDIES DR. PRICE: In the course of a single day, I have had the disquieting experience of hear- ing several times the implication that previous studies of the circulatory actions of anesthetics have answered all relevant questions and so foreclosed the need for any new research, at least in the near future. My own view is that the quarter-century devoted to this problem by myself and my colleagues has only raised questions, not answered them. When I entered the field, there was felt to be a problem in identifying in advance those patients who were unusually likely, because of their specific disease, surgical requirements, or general status, to present an extraordinary anesthetic challenge. It had already been es- tablished that morphine increased the ten- dency of fit-prone patients to faint when sub- jected to upright tilt, and it was supposed that other narcotics would have a similar effect, which turned out not to be so. Attention then turned to the use of positive airway pressure as a screening technique for discovering those in cardiovascular jeopardy, with the quickly realized result that subjects anesthetized with cyclopropane or in congestive heart failure were extraordinarily resistant to this chal- lenge. In short, we have come forward 25 years without developing satisfactory methods for anticipating circulatory collapse; and we are left mainly with the time-honored criteria of weak, irregular pulse, clammy skin, tachypnea and “poor color” to aid us in our prescience. If the patient won’t make a diagnosis for us prior to our inducing anesthesia, we have a hard time doing so thereafter. I have arranged my current shopping list of needs within the cardiovascular domain under two main heads—monitoring require- ments and knowledge of basic mechanisms. These two categories are in fact inextricably interlinked—we cannot achieve a ready ap- preciation of cardiovascular status without knowledge of where and how our drugs act— but it is convenient to separate them in this discussion. 80 In monitoring, we need on-line analogue generating computers which can assess the functional adequacy of the circulation with re- spect both to the heart and to the peripheral circulation. What good does it do us to know that arterial pressure or cardiac output is re- duced if we know neither why this is so nor whether the peripheral tissues are having to resort to anaerobic metabolism as a conse- quence? I am not suggesting that there is any easy answer to these questions. Even if we had evidence of the overall adequacy of major organ function, how could we know during anesthesia that all necessary functions were preserved? We are all aware of instances in which anesthesia and operation appeared to be uneventful but the patient was found post- operatively to be blind, amnesic or decorticate. In agreement with Rene Dubos’ “despair- ing optimist,” I strongly suggest the need for increased knowledge and cite the following areas as being particularly weak: Autonomic nervous system: There is no satisfactory way of studying these actions in man; animal studies have yielded conflicting results, reflecting species difference, experi- mental design and methodology, and investiga- tive bias. Myocardium: Despite the existence of an almost pure culture of similar cells, knowledge of anesthetic action here is perhaps even more rudimentary than it is in the central nervous system. The action of anesthetics on the heart is ascribed to non-specific depression, meaning that we don’t understand it, yet two anesthet- ics with the same (CNS) potency may have cardiac actions which differ by two- or three- fold. The basis of these actions and differences in actions is utterly obscure. Cardiac conducting tissue: It is widely recognized that certain anesthetics predispose the heart to various arrythmias and it is sup- posed that these perturbations flow from the effect of the agents on the conducting tissue of the heart. However, agents which have very different electrophysiologic effects on indi- vidual cells of the conducting system are found to cause grossly similar types of arrythmia. The basic mechanism behind these effects needs to be brought forward. 81 Blood vessels: Our knowledge of the ef- fects of anesthetics on the blood vessels is equally lacking that of the myocardium. Formed elements in the blood: Interac- tions of anesthetics with hemoglobin erythro- cyte membranes, platelets, leukocytes, plasma protein and clotting mechanisms have been shown or suggested. Tissue circulation: Anyone who has pre- sided over the surgical bloody field and com- pared it with the nearly bloodless one produced by spinal or regional anesthesia knows that anesthetics have the ability to disrupt circula- tory homeostasis at the tissue level. Although some attempts to study these actions have been made at both the whole organ (CNS) and tissue (mesentery) level, the field is largely virginal. Circulatory collapse in sepsis and cancer: A disquieting number of such patients suffer cardiac arrest or ventricular fibrillation when anesthetized with standard “safe” techniques. The cause of this is completely unknown. BASIC MECHANISMS DR. FINK: Ever since its discovery, sur- gical anesthesia has been an essentially empir- ical art, depending minimally on an under- standing of basic mechanisms. Anesthesiologi- cal research has grappled mainly with side ef- fects, the incidental menaces to circulation, ventilation, hepatic function and renal func- tion. Now that working control over these dangers has been obtained, more intensive ef- fort can be devoted to unraveling the distur- bances that the anesthesiologist deliberately seeks to produce: suspension of awareness, memory, pain perception, and movement. History presents examples of two differ- ent approaches to basic research. In the first, basic research precedes the applications. Faraday’s discovery that electricity could be induced by magnetism is an example. After a public demonstration someone asked Faraday, “Of what use is your discovery?” To this he is said to have replied, “Of what use is a newborn baby?” Anesthesia is in a different category. His- torically, the empirical practice came first and understanding of basic mechanism lagged far behind. An interesting parallel may be found in the history of engineering. Newcome de- veloped a practical steam engine by 1725 and Watt perfected it in 1769, but it was not until 1824 that Carnot identified the theoretical effi- ciency limits of heat engines and founded the science of thermodynamics. One hundred and fifty years later, thermodynamics is a cor- nerstone of technological civilization. In anes- thesiological neuroscience, however, the Car- nots and Clausiuses have as yet barely begun their researches. As to strategy, I have time only to point out the necessity for a long-term, say a 10-year policy for training anesthesiological neuro- scientists. In my opinion the present training system is inadequate because it is geared to attract workers to areas already under inves- tigation. It discourages innovation and per- petuates the existing balance or imbalance in research effort. As to tactics, first let me refer to the fol- lowing sketch of the subject matter: NEUROSCIENCE The jelly roll in my imagination represents the cake of neuroscience. The affected systems can be, and have been studied at every level of the knowledge spiral, proceeding from the macroscopic to the particulate, broadly in the inverse order of organic evolution. In the course of organic evolution, new and increas- ingly complex units of action appear at each major level. Several disciplines share or dis- pute the cake at each level, each level needing to be understood if the anesthesiologist is to have rational control at the level of thinking or mind. 82 The immediate targets are the phenomena at the surface: awareness, memory, pain- sensibility, movement, whose neurological substrate is studied in the relatively new sci- ence of neuropsychology, the science of the working brain. Anesthesiology’s piece of cake overlaps others such as that of neurosurgery. Specifically, I will now review briefly a few of the basic mechanisms crying out for study, classified under these headings: Neuropsychological: The neuronal cir- cuitry involved in the memory of pain heads the list because the performance of an opera- tion safely without memory of pain epitomizes the goal of the anesthesiologist. The ideal anesthesiological regimen will include specific inhibition of information storage in the pain memory circuit. Specific inhibition of move- ment already can be accomplished. There is reason to hope that specific inhibition of mem- ory or awareness may also be attainable. Clearly, intensive research toward these ends is within the province of basic anesthesiological studies. The tools of signal detection or decison theory are now available for evaluating results at the clinical level. Suspicions about toxic effects of chronic subliminal concentrations of anesthetics pro- voke concern over whether frequently re- peated administration of general anesthetics, as in plastic surgery for example, affects men- tal development in the young, or even mental performance in the adult. The commonest iatrogenic complications of neurosystemic anesthesia—nausea and vomiting—are neglected problems although they seem to indicate that neurosystemic anes- thesia is not a reversible reaction in the ther- modynamic or even physiological sense. As to the mechanism of these complications, we are in the dark. Neurochemical: Despite the probability that disturbances of electrophysiological transactions mediate the action of anesthetics, it is quite likely that perturbations of metabolism may yet prove a potent factor in the maintenance of general neurosystemic anesthesia. This seems rational because, as is well known, acute interruption of the cerebral oxygen flow abolishes mental function in a few seconds. A similar effect is conveniently exemplified in the Carlisle experiment, where pressure on the eyeball abolishes vision in a few seconds when the subject breathes air but takes much longer when the subject breathes oxygen. This suggests that differences in reac- tion rates may be critical to mental function and that the effect of anesthetics on regional cerebral turnover rates, as distinct from con- centrations, must receive much more study than hitherto accorded, particularly in energy metabolism, intermediary metabolism, and RNA metabolism. If, for example, RNA metabolism underlies the long-term memory trace, then a regional disturbance of cerebral RNA metabolism should be present during anesthesia when memorizing is in abeyance, and should be looked for. In a nutshell, the neurochemistry of anesthesia is still of un- known extent. Physical Mechanism: New paths to the molecular physics of anesthesia were opened by the volume occupancy hypothesis of Mul- lins. The measurement of anesthetic induced perturbations in membranes by means of reso- nance techniques promises detailed informa- tion on the conformational changes critical to anesthesia if measurements in synthetic or semi-synthetic membranes can be extended to nerve terminal and synaptic membranes. The opportunity for productive studies with the electron microscope is self-evident but has only just begun to be exploited. Specifically, the ef- fects of anesthetics on the plasticity of neurons, the aggregation state of polymeric proteins and the stability of synaptosomal membranes are some of the important fields awaiting study. For my last point, I ask you to imagine an extra turn of the spiral on my jelly roll, a level of higher organization, the level of culture, containing the organizations evolved by human culture. One of these is the National Institutes of Health. Somewhere within that extra turn is the sub-institute level which includes research centers: Anesthesia Research Centers, if you will. The centers represent an evolutionary cultural response to the challenges of clinical ignorance. They fill an ecological niche charac- terized by opportunity for concerted, com- municative research. It would be clearly re- trogressive to scrap the Anesthesia Research Centers without developing an alternate form of organization to fill that niche. In summary, the mechanism of aware- ness and its reversible abolition by drugs, of memory and its suspension, pain and its pre- vention, movement and its control, emotions and their modification, are the basic problems of anesthesiological research. They are strictly interdisciplinary problems with specifically anesthesiological aspects. The problems exist at all levels of biological organization and re- quire a correspondingly wide variety of exper- tise for their solution, concerted in a pro- grammed effort. CENTRAL NERVOUS SYSTEM DR. KITAHATA: General anesthetics exert various effects on the central nervous system—e.g., changes in cerebral blood flow, cerebral metabolism, and excitability of cen- tral nervous system structures as measured by neurophysiological variables. Likely explana- tions for the state of general anesthesia may be offered on the basis of changes in central nerv- ous system excitability. One of the tools used to measure central nervous system excitability is the electroence- phalogram first recorded by Berger. The ef- fects of anesthetics upon the EEG of human subjects were studied by Brazier and Finesinger in 1945 using barbiturates. They demonstrated that regions of the cortex, most recent in phylogenetic development, are most vulnerable to the action of barbiturates. Faul- coner and Bickford studied the EEG during anesthesia extensively. In subsequent studies, however, it proved impossible to make an abso- lute correlation between various EEG patterns and the concentrations of anesthetics adminis- tered. This is to be expected since the EEG is influenced by many factors, including respira- tion, circulation, body temperature, and the physical states of the patient. In addition, in order to understand the various patterns of the EEG, a considerable amount of training is re- quired. EEG changes that occur in relation to anesthesia are, however, of great practical im- portance because of the ease with which the EEG can now be recorded in the operating room. Future investigations in this field should consider the following: 1) strict control of the factors influencing EEG patterns, and 2) in- creasing the ease with which EEG patterns can 83 be interpreted. Recently, Myers and his col- leagues presented a compact picture of EEG changes in anesthesia by the use of power den- sity spectral analysis. Effects on Neural Activity: It has become apparent that the effects of anesthetics should be studied on neural activity which is better organized than the EEG. The term “evoked potential” identifies the electrical change that may be recorded in some parts of the central nervous system in response to the deliberate stimulation of sense organs or of the afferent fibers of peripheral nerves. A well-known ef- fect of anesthetics upon the reticular activating system was demonstrated by French, Ver- zeano and Magoun in 1953. They showed that the multisynaptic “reticular activating sys- tem” was more vulnerable to anesthetics when compared with the paucisynaptic classical “lemniscal system.” Further studies done in our laboratory included comparison of effect of anesthetics at three levels of the medical pathways: cortex, thalamus and mid-brain. We have shown that the higher the recording site (with an increasing number of synaptic connec- tions) the greater the effect of anesthetics upon evoked responses from the medial path- way. With recent advances in experimental technique, however, it is possible to demon- strate that the classical lemniscal pathways do not escape the effects of anesthetics at therapeutic concentrations. The recovery cycle of the somatosensory system was first studied by King et al. The effect of anesthetics on the recovery cycles of the auditory system was studied in our laboratory. These findings added to the body of evidence suggesting that the classical lemniscal pathways are not im- mune to the influence of general anesthetics in therapeutic concentrations. The latter studies were done with the microelectrode recording technique. In search of the mechanism and site of action of anesthetics upon the central nerv- ous system, a study of the effects of anesthe- tics upon single neurons with known function is of the utmost importance. Using a semi-microelectrode recording technique, Schlag and Balvin in 1963 intro- duced multiple unit activity (MUA) as a meas- ure of central nervous system activity. MUA is, in essence, the high frequency component of potentials recorded with a semi- microelectrode. Several studies have been published recently, in which MUA was used as an indication of central nervous system excita- bility, and Mori and his colleagues concluded that general anesthetics are not mere central nervous system depressants but sometimes are excitants. However, MUA, as recorded by them, is critically sensitive to cell size, spike polarity, temporal patterning of unit activity and cell population. Any of these variables may be concerned with the observed changes, which thus may not represent the true excita- bility of the structures in question. Schlag and Balvin themselves concluded that “meas- urements of background activity cannot in themselves reveal whether a given structure is more active in functional performance.” Using a mircroelectrode recording technique, Shimoji and Bickford studied the ef- fects of anesthetics on the single unit activity of mesencephalic reticular neurons with incon- clusive results. They found that the suscepti- bility of the spontaneous activity of the units to depression by anesthetic agents varied widely from unit-to-unit. What is needed is the study of anesthetic effects upon the single unit activ- ity of cells with known functional properties. The spinal cord is the ideal site in this regard for the study of the effects of anesthetics upon the central nervous system because 1) it con- tains the site of the first synaptic transmission for an afferent input, 2) its cellular components can be easily identified, 3) basal narcosis can be eliminated (in decerebrate animals) by the placement of electrolytic lesions in the brain stem and 4) it can be easily isolated by spinal cord section, thus eliminating effects from rostral structures. Microelectrode recording techniques have contributed greatly to recent developments in neurophysiologic and neuropharmacologic re- search. They have a distinct advantage when compared with macroelectrode recording techniques or multiple unit activity recording techniques, in that unit activity can be sampled cell-by-cell, thereby enabling the physiologic as well as the pharmacologic study of single cell activity. Extracellular microelectrode re- cording techniques have the advantage over intracellular recording in that extracellular re- cording can be maintained for several hours, a condition essential for pharmacological studies of anesthetics on single unit neuronal activity. Dorsal Horn Laminae: According to the cytoarchitectonic investigations of Rexed, the dorsal horn of the feline lumber spinal cord is organized into six cytoarchitectonic laminae, rather than into globular clusters of neurons as has been previously supposed, each laminae having its characteristic cell size, orientation and dentritic arborization. The original study of the effect of anesthetics on dorsal horn unit activity was carried out by Wall, demonstrat- ing lamina non-specific suppression by bar- biturates. Later, de Jong and his colleagues also showed lamina non-specific suppression by nitrous oxide and halothane. Lamina-specific suppression of dorsal horn unit cellular activity was first demonstrated in our laboratory. The vital signs of the animals were maintained strictly within physiologically normal limits. All electrode placements were confirmed his- tologically. The results of our study indicate that the anesthetics tested significantly de- press the activity of those dorsal horn units associated with nociception and do not affect the activity of those dorsal horn units uncon- cerned with nociception. The effect is dose- related, and occurs in the clinically effective anesthetic dose range. How much anesthetic modulation at the spinal level contributes to the overall analgesic action of anesthetics re- mains for further investigation. A similar dif- ferential effect was shown in our laboratory in the trigeminal neuronal complex, in that nitr- ous oxide suppressed cells located in the lamina propria of the trigeminal caudalis nuc- leus, responding primarily to nociception, while cells located somewhat dorsal to the nociceptive cells, responding only to low threshold mechanical stimulation, were not depressed by nitrous oxide. From these studies it appears that the ac- tion of anesthetics may be related to the sup- pression of the activity of key neurons as- sociated with nociception in various relay sta- tions of afferent pathways. Future research in anesthesiology may be extended to the study of single unit activity in more rostral areas. Another logical approach may be the application of iontophoresis to elucidate the transmitter substance as well as 85 possible specific antagonists for the synaptic transmission of the key neurons previously studied. Control of Chronic Pain: In addition to the control of pain during surgical anesthesia, another important area of research associated with anesthesiology is the control of chronic pain, especially that due to denervation. The management of this phenomenon, as well as the clarification of its mechanisms, is of paramount importance because of the large population of patients suffering from dyses- thesia following various types of denervation. PERIPHERAL NERVOUS SYSTEM DR. NAGI: Discussion on research objec- tives in respect to peripheral nervous system will have to involve studies on central nervous system and circulation relevant to anesthesia. Drugs we use, with the exception of neuromus- cular blocking agents, act on both the peripheral and central nervous systems. The autonomic nervous system is intimately re- lated to circulation, among many other visceral functions. This presentation will be divided into two parts: research on the somatic nerv- ous system and the autonomic nervous system. Somatic Nervous System: We know that among general anesthetics, ethers are more potent in relaxing skeletal muscles than hy- drocarbons. We also know about interactions between general anesthetics and muscle relax- ants. From the pharmacologic point of view, we have to look further into mechanisms in- volved, using single fiber preparations or ani- mal models. It was shown some years ago that potent anesthetics stabilize postjunctional membrane and/or act presynaptically to pre- vent firing and release of acetylcholine. Is this the complete story? Do anesthetics act at points beyond the motor endplate? In vivo studies in animals and in man showed that chloroform and cyclopropane increase twitch response following direct stimulation whereas diethyl ether and enflurane depress twitch re- sponse. Ethers also cause “fade” during tetanic stimulation. The effects of ethers on neuromuscular functions could be explained on the basis of their actions on motor nerve ter- minals and/or postsynaptic membrane. How- ever, anesthetic-induced increase in twitch re- sponse is difficult to explain on the same basis. It is highly probable that general anesthetics affect intracellular ionic movements, especially that of calcium, metabolic pathways and con- tractile elements. Recent studies of Price, Me- rin, Rusy and their respective co-workers suggest that at least in the myocardium, po- tent anesthetics have these actions. There have been a few studies of anesthetic effects on skeletal muscles. These studies are concerned with muscles from patients who recovered from malignant hyperthermia and certain breeds of pigs in which malignant hyperther- mia could be triggered by potent anesthetics and muscle relaxants. The questions are: do chloroform and cyclopropane (which increase twitch response) have subcellular actions dif- ferent from those of ethers? Do anesthetics change calcium binding with sarcoplasmic re- ticulum in skeletal muscles (as in the case of myocardium), ATPase, cyclic nucleotides? Local anesthetics have been well studied in respect to the mechanisms of action, phar- macokinetics and toxicity. Recently, two new long-acting local anesthetics, bupivacaine and atidocaine, were developed. Indeed, we now have a wide choice of agents to suit the occa- sion. Fink and his colleagues described the phenomenon of “neurotoxicity” induced by local anesthetics—inhibition of rapid axoplas- mic transport associated with disruption of microtubules, using in vitro models. This is a cause of concern. However, in vivo studies in our laboratories failed to show inhibition of axoplasmic transport in the presence of nerve block. We should look into reasons for these contrasting observations. The most likely ex- planation is that the intraneural concentrations of drugs attained in vitro (with the nerve in tissue baths) are higher than that in vivo. At least to my knowledge we do not know the in- traneural drug concentration required to pro- duce 100% (or 50%) conduction block in a mixed nerve. If we do, then together with existing knowledge on the rate of anesthetic uptake by nerve trunk we would have some scientific basis to choose the appropriate drug concen- tration for regional anesthesia. Lastly, according to a survey conducted by Eger on muscle relaxants, everyone wishes to have a short-acting, non-depolarizing neuro-muscular blocking agent. Reasons for 86 this have been stated by Kitz, Karis and Ginsburg. A non-depolarizing blocking agent would not have some of the side effects of de- polarizing agents. Short duration of action would obviate the need for antagonists, but in case of overdose, antagonists would be effec- tive. We are making progress in this area. The final answer will have to wait until newly de- veloped compounds have been tested for selec- tivity of site of action in man. They should be confined to the neuromuscular junction, and to duration of action. Experience with dacuronium and AH 8165 should teach us about peculiarities of man. Dacuronium was a prom- ising drug, according to studies in animals, but proved to be not suitable for clinical use. AH 8165 is a short-lasting, non-depolarizing neuromuscular blocking agent in cats, dogs and monkeys (15 minutes or less for 90% recovery), but in man it takes 40 minutes or more for ini- tial signs of recovery of twitch response. AH 8165 also causes hypertension and tachycardia which were not observed in animals unless higher doses (5-25 times the paralyzing dose) were administered. Autonomic Nervous System: There have been extensive studies on the cardiovascular effects of anesthetics as well as controversies in the interpretation of experimental findings. While anesthetics are known to affect vas- omotor control systems, ganglionic transmis- sion and peripheral organs, we are just begin- ning to study the biochemical basis for anesthetic-induced changes in “receptor” sen- sitivity. (“Receptors” are referred to concep- tually as post-synaptic membrane, responding to neurotransmitters, including that of central neurons, ganglionic cells and peripheral target cells.) It should be noted also that recent de- velopment of more sensitive assays of biogenic amines and their enzymes has been exploited in anesthesia research on the autonomic nerv- ous system. At least three areas deserve attention. First, the effects of anesthetics on the release of catecholamines should be re-examined, if possible in man. Studies with ketamine, using brain slices or perfused heart of animals, indi- cate that this drug interferes with re-uptake of norepinephrine. Does this occur clinically? During morphine analgesia, the arterial pres- sure frequently increases. Is this a response to morphine, or cardiovascular responses to sur- gical manipulation that are not abolished by morphine? The role of biogenic amines in the central nervous system in morphine-induced analgesia, the development of tolerance and dependence, has been extensively studied. But the effects of morphine on the peripheral sym- pathetic nervous system have not. In man, anesthesia with almost all potent anesthetics is associated with increase in cutaneous blood flow. One may assume that this is an expression of drug action on the thermoregulatory mechanism. But, is this the answer? It is interesting that diethyl ether and cyclopropane, the two anesthetics supposedly activating the sympatho-adrenal system, pro- duce more cutaneous vasodilation than other anesthetics (with the exception of isoflurane). Muscle blood flow also increases during anes- thesia with all agents studied so far. What is the basis for this common action of anesthet- ics? Is it beta-adrenergic receptor activation, direct action of anesthetics on vascular smooth muscles, or, do anesthetics activate the sym- pathetic, cholinergic vasodilator mechanisms (the “defense” response)? These questions need to be answered because hemodynamic changes induced by various anesthetics cannot be explained on the basis of sympathetic de- pression or activation alone. Secondly, interaction between anesthetics and drugs being used in concurrent therapy for cardiovascular, neurologic and psychiatric dis- orders requires study. Most of the commonly used therapeutic agents for these purposes have their primary action on the synthesis, storage, release or re-uptake of ca- techolamines. Examples are reserpine, alpha derivatives of catecholamine precursors, dopa and tricyclic antidepressants. From clinical experience we come to realize that it is desira- ble to maintain drug therapy prior to anes- thesia. Studies in animals tells us about how these drugs act. But do we know that this is the case in man? For instance, does reserpine, as it is being administered clinically, com- pletely deplete catecholamine stores? Are there changes in receptor sensitivity to catecholamines in patients being treated with reserpine? Do tricyclic antidepressants in- crease the liability to arrhythmias because these drugs interfere with re-uptake of 87 norepinephrine? To answer these questions, we have to carefully observe patients receiving concurrent drug therapy and where possible study human tissues in the laboratory. The third area deserving study is the clini- cal pharmacology of new beta-adrenergic agonists and antagonists, and the interaction of these drugs with anesthetics. Propranolol is being used with increasing frequency. Its ac- tions on the heart and bronchial smooth muscle are of concern. Should we arbitrarily discon- tinue the administration of propranlol even when the patient’s disease requires continued therapy? If the drug is to be continued, what would be the choice of anesthetics least likely to cause serious disturbances in circulation and ventilation? There are new beta-adrenergic agonists and antagonists, some of which are still inves- tigational in the United States. Proctolol is a selective antagonist of adrenergic transmitter in the heart with less negative inotropic and bronchoconstrictor effect. When this drug be- comes available for clinical use, we will have to find out more about its interaction with betas anesthetics. Terbutaline, a beta,-adrenergic agonist, is now approved by the Food and Drug Administration. A few other beta-adrenergic agonists are being studied. We will have to know about the action of these agents during anesthesia. In summary, our objectives are to look for better drugs and to study the mechanism of action of drugs we use with emphasis at biochemical and molecular levels. PAIN DR. BONICA: While recent advances in our knowledge of acute pain are encouraging, we need to do much more in the future. Still missing are innumerable pieces of information which must be acquired before we solve what Melzack calls “the puzzle of pain.” This in- cludes the need for much greater knowledge about the anatomy, biochemistry, physiology, pathology, and psychology of acute pain pro- duced by surgery, injury, and disease. This is an essential prerequisite to the study and elucidation of the mechanisms of anesthesia— an objective which has eluded us for some 13 decades. Accurate knowledge of the mechanisms of pain and anesthetics is essential to the development of new and, perhaps, dif- ferent local and general anesthetics which have a more specific action of producing analgesia and motor block required for surgical operations and obstetric pain relief. Equally important is the need for much more knowledge about the mechanisms and physiopathology of chronic pain states. We have little or no scientific information on the exact mechanisms by which arthritis, herni- nated disc, postherpetic neuropathy, trigemi- nal neuralgia, amputation of a limb, disease of, or injury to peripheral nerves, visceral disease, and cancer and other neoplasms produce chronic pain. To be sure, there are many specu- lations and hypotheses, but there are few or no scientific facts. This lack of knowledge mar- kedly impairs our ability effectively to relieve pain. Consequently, chronic pain today re- mains the most disabling disorder and thus constitutes one of the most important world health and economic problems. Although accu- rate statistics are not available, data from a variety of sources suggests that chronic pain states cost the American people between $25 and $50 billion annually. Even more important is the cost in terms of human suffering. Mil- lions of patients with headache, arthritis, and other chronic disorders do not obtain the relief they deserve, are often exposed to iatrogenic complications, many eventually resort to quackery, and some even commit suicide. There are numerous reasons for these de- ficiencies which seriously detract from our biomedical scientific achievements; foremost among them is the lack of sufficient informa- tion. Much of the new information acquired during the past several decades has not been as beneficial to patients with chronic pain as one might anticipate. This less-than-optimal payoff from many research efforts is due, in turn, to the fact that the new knowledge and technol- ogy have not been applied to the study of chronic pain states, or have not been applied properly. The future challenge to the biomedical-scientific community, health pro- fessionals, and society as a whole is to mount a multi-pronged program which will eventually help solve these problems. The future course of research on pain re- quires a very different direction from that of the past. For one thing, we must exploit the 88 vast amount of scientific knowledge and technology in all of the scientific disciplines and bring them to bear on the problem of pain in a collective and collaborative fashion. Sec- ondly, in addition to continuing and expanding the experimental laboratory approach, we must study pathologic pain states in patients. Coordinated Efforts: These objectives re- quire the concerted and well-coordinated ef- forts of interested neurophysiologists, psychologists, pharmacologists, biochemists, and virtually every other kind of applicable basic scientist and clinician. The clinical need of this multidisciplinary approach to pain re- search, which I have repeatedly suggested for two decades, was re-emphasized by Professor Patrick Wall at our pain symposium last year. “In the challenge of pain,” Wall said, “the clini- cian and basic scientist must play an interde- pendent role. It is the job of the clinician to collect and describe a phenomena of pain: the signs, symptoms, and pathology of patients. He should organize and present the facts in terms of questions asked, and see to it that the basic scientist understands the facts. The basic scientist must grapple with the entirety of the real facts and not just select the easy and con- venient phenomena and ignore or deny the un- easy ones.” At the time, Professor Wall suggested a number of areas worthy of future research. One area readily accessible to study in both patients and animals is the biochemistry of local tissue damage and the products of cel- lular breakdown which apparently sensitize nerve endings and produce hyperalgesia. We know that tissue damage due to injury or dis- ease causes a liberation of intracellular chemi- cal substances into the extracellular fluid sur- rounding nerve endings, and that, in some way, these substances induce pain. These in- clude potassium, acetylcholine, histamine, 5-hydroxytryptamine (serotonin), prostaglan- dins, bradykinin, and histamine. Other than the last two, these compounds have not been thoroughly identified, nor have we accurately defined the mechanism of their pain producing action. Thus, while there is some evidence that aspirin produces pain relief by blocking the ac- tion of prostaglandin, the research so far has been carried out by relatively few workers using what Wall calls “primary 19th century methods.” Similarly, while many hypotheses and a voluminous literature are available on the role of these agents in producing tender- ness and hyperalgesia and their mechanisms in producing headache, angina, and other chronic pain states, most of these are largely specula- tions based upon meager evidence acquired from crude animal and human studies. Since we have extremely powerful biochemical techniques to extract, purify, and analyze compounds, we can and should identify the ex- citatory substances. We also have the elec- trophysiologic technology which would permit us to study and accurately define how these substances provoke the primary afferent sig- nals that trigger pain. Once these are done, we can then develop substances which will pre- vent the synthesis or release or antagonize the action of the pain producing substance. Physio-Pathology of Neuropathies: There are great needs and opportunities for study of peripheral nerves, especially for the under- standing physiopathology of neuropathies. We now have the technology for intensive dissec- tion and analysis of the anatomy, physiology, and biochemistry of peripheral nerve and roots. Those techniques developed particularly in Sweden, which permit the recording of neural activity in multiple fibers and single units and which have been used so successfully to study experimental pain in man, should now be extended to the study of physiopathology of peripheral nerve lesions. A crucial question with great clinical relevance is whether the pains of neuropathy are to be explained by the generation of nerve impulses at some irritable focus as traditionally believed, or by block of inhibitory fibers as proposed by Wall and others. The neurophysiology of herniated disc, like its biochemistry, is a subject readily amenable to studies in animals and humans. The frequent occurrence of this condition in achondroplastic dogs, such as the Daschund, has been ignored as a source of information about this common crippling condition in man. Moreover, it is now technically feasible to in- sert in man very fine electrodes into the af- fected foot to measure spontaneous firing and correlate this to the influence of factors which increase the pain and those that relieve it, as 89 well as the influence of the associated muscle spasm and injury of local tissue. Another research area of great clinical im- portance in pain disorders is the autonomic nervous system and its neurophysiology, biochemistry, and pharmacology. Although it has been known for a century that the au- tonomic nervous sytem is in some way involved in causalgia and other reflex sympathetic dys- trophies, its exact role remains a mystery. It is, of course, well known that block of the re- gional sympathetic ganglia or sympathectomy relieves the pain. Is this due to interruption of the afferent fibers which pass through the sympathetic ganglia on their way to the spinal dorsal roots, or is it due to interruption of effe- rent discharge? The combined use of regional sympathetic block and the systemic adminis- tration of ganglionic blocking agents or peripheral sympatholytic agents should help clarify the problem. Recently, Patrick Wall has provided basic neurophysiologic data highly relevant to im- portant clinical problems. Although a great deal is known of the anatomic structure of neuroma, no modern neurophysiologic study has been carried out. Wall and his col- laborators, who have interacted with clinicians on pathologic pain states, have studied various aspects of neuromas using an ingenious animal model. They found no signs of excitatory or inhibitory interaction between volleys in one group of nerve fibers and the activity in other groups of fibers in neuroma. Alpha-active sympathetic amines excited the ongoing activ- ity, while beta agents (isoprenaline) had no ex- citatory effect. This suggested that alpha blocking agent might be useful to test if the sympathetic system is involved in particular pain. Similar studies are possible in man by placing recording electrodes into the sciatic nerve at a certain site along its course and into spinal nerves and roots that contribute to the sciatic as they lie within the intravertebral foremen or just lateral thereto. The monitor- ing of fibers would not only provide informa- tion about neuropathology of neuromata, but would permit correlation of neural activity with phantom limb pain and pain in the stump. If the pattern of firing in man is similar to that found in rats, these can be correlated with the onset of spontaneous and provoked pain in the stump as well as in the phantom limb. Moreover, it will be possible to evaluate the effects of sympathetic agents and alpha block- ing agents, as suggested by Wall. Although study of the ubiquitous small cells in the central nervous system poses great technological challenges, partly because of our present rather crude techniques, there are substantial opportunities even if the observa- tions are restricted. Studies of the firing of nerve cells in freely moving animals, for exam- ple, would provide the possibility of making correlations between the observed behavior and nerve cell discharge. Such a preparation would permit the more comprehensive study of such phenomena as convergence, inhibition, and descending influences. There should also be a much greater effort to study patients with chronic pain problems in the course of neurosurgical operation, which permits record- ing of neural activity in the central nervous system as done by Kerr, Albe-Fessard, Nashold, and Sweet. In addition to continuing experimental psychologic investigation, it is essential greatly to expand the work started by Sternbach, Fordyce, and others in deter- mining what factors contribute to chronic pain behavior. Role of Anesthesiologists: Anes- thesiologists should have major interest in fu- ture pain research and should actively partici- pate in various roles. Moreover, we must en- courage younger academic anesthesiologists to become interested in pain research. The few persons skilled in basic research must be sup- ported and encouraged to expand their pro- gram. The leads of De Jong, Heavner, Kitahata, and their collaborators should be pursued, and a national collaborative effort should be mounted to carry out more com- prehensive studies of the effects of different inhalation anesthetics, and barbiturates, ketamine, neuroleptics, narcotics, ataractics, and other drugs on all those systems currently known to be the neural substrates of pain. Ef- fects of these various agents on the cells of each lamina of the dorsal and ventral horns of the spinal cord, on the trigeminal system, on the ascending and descending systems, on the various parts of the reticular formation, on dif- ferent thalamic nuclei, and on forebrain struec- tures should be studied to produce information 90 on the mechanisms of pain as well as anes- thesia. In this way we could greatly expand Eger’s concept of MAC as a measure of the level of anesthesia and thus provide more com- prehensive and precise criteria with which to evaluate different anesthetics. Since MAC is based on only one of the many reflex responses to noxious stimulation—skeletal muscle movement—and since available data suggests that different anesthetics probably act on dif- ferent structures concerned with the pain phenomena, MAC, as defined, may not be a valid method to compare the cardiovascular ef- fects of two different anesthetics. We must remember that noxious stimulation provoked by the surgeon’s knife not only produces skeletal muscle spasm but also causes tachycardia and increase in stroke volume, with a consequent increase in cardiac output and blood pressure, increase in endocrine re- sponse, and alteration of ventilation. The ob- jectives of surgical anesthesia are not merely to prevent movement but also to maintain vital function as nearly normal as possible. Accord- ingly, the ideal general anesthetic simultane- ously would prevent pain and movement while sufficiently depressing the segmental and sup- rasegmental reflex responses as to maintain circulation and ventilation of normal levels. In evaluating a new anesthetic, it would be much more useful if we could compare the new agent with the standard of reference. Thus, we might find that a specific anesthetic might act primar- ily to depress activity in lamina V cells and segmental and suprasegmental reflex re- sponses without altering other parts of the neuraxis; and that another might have much more depression on those central cells con- cerned with proprioception, with minimal or no effect on pain. Such information would not only permit better selection of anesthesia with a specific benefit in mind, but would also lead to the development of more specific drugs. The anesthesiologist can be a valuable col- laborator in a team effort on pain research in both animals and man because of his unique knowledge and expertise with the clinical pharmacology of local and systemic analgesics, anesthetics and other depressant agents. For basic scientists and clinicians not versed with these drugs, anesthesiologists can provide perspectives in regard to optimal dose, best method of administration, and how to minimize side effects of basic scientists and clinicians not familiar with these drugs. Some anesthesiologists have the skill to accurately place the bevel of very fine needles on/or within spinal, cranial, or autonomic nerves at specific sites. It is feasible to insert fine electrodes through the needle to record the firing of individual and multiple fibers. The combined use of differential block and pressure on nerves, achieved through a cuff on an ex- tremity, may provide useful information on the pain mechanisms of postherpetic neuralgia, herniated disc, postamputation pain, including phantom limb pain, and other nerve disorders. The findings of Denny-Brown about der- matomal pattern can be studied in man by using discrete perineural and intraneural in- jection of small amounts of local anesthetics. The potential use of blocks as a research tool is limitless. Future Needs: An expanded research ef- fort of this type will require adequate funding by the appropriate research agencies and the commitment of resources—e.g., space, lab- oratories, etc.—by medical institutions. A de- cade ago, I suggested the idea of a pain re- search center in which basic scientists and clinicians worked side-by-side in a coordinated fashion to carry out research, teaching, and the care of patients. Our experience at the University of Washington with such a center is most encouraging. As in the case of other types of centers, such a resource would be more con- ducive to multidisciplinary and interdiscipli- nary efforts. Finally, we must mount effective pro- grams which will enhance communication and cross-fertilization among the various basic sci- entists and clinicians. The poor interaction among basic scientists has virtually precluded the application of vitally important new infor- mation acquired (i.e., by neurophysiologists to other scientific disciplines). Moreover, it has impaired cooperation among various basic sci- entists and clinical investigators—a condition necessary to solve clinical problems. This has also resulted in a great lag in the clinical appli- cation of new pertinent information to the care of patients with chronic pain. Other needed areas include the development of an interna- 91 tional standard terminology for pain syn- dromes, epidemiologic data on pain as a disease state, and the national and international pain data bases or data pools. These are essential requisites for nuturing a greater research ef- fort. It is hoped that the recently founded Internal Association for the Study of Pain and its publication, the journal Pain, with Profes- sor Wall as editor-in-chief, will help us achieve these goals. ACUPUNCTURE HYPALGESIA DR. KERR: Before discussing this topic some prefatory remarks are necessary. My qualifications for the task are modest and in- clude a visit to hospitals in the People’s Repub- lic of China where acupuncture hypalgesia was used for surgical procedures and some elec- trophysiological studies were being performed to determine the CNS mechanisms of acupuncture. Identification of research objectives is, to some extent, contingent upon prediction of fu- ture developments. Based on established facts, some speculation and some educated guesses are made. In the case of acupuncture, established facts are few and one of the main objectives will be to try to determine what these facts are. This will not be an easy task since there are those who, having seen major surgery per- formed under acupuncture hypalgesia without any signs of discomfort on the part of the pa- tient, conclude that it must be a psychological phenomenon, perhaps akin to hypnosis. Others, observing the same events reach the conclusion that a change in pain perception must have occurred and that this is probably due to mechanisms at a much lower level. However, neither side has the information to settle the issue. Whatever the outcome of this controversy (whether the explanation be physiological, psychological or some of both), there can be no question that critical and ex- perienced Western observers have failed to de- tect the slightest evidence of discomfort in ap- proximately 50% of the patients undergoing surgical procedures in the People’s Republic of China, procedures that unquestionably are known to evoke intense pain. If the mechanism is psychological, we should also try to determine the level of the nociceptive pathway at which the pain mechanism is being influenced and in what manner this occurs. While this is a worthy en- deavor, it should be remembered that, after nearly a century of research on pain mechanisms, we have only the barest outlines of nociceptive neurophysiology, we know very little about the mechanism responsible for anesthesia, and are usually hard put to find physiological explanations for clinical manifes- tations of pain. By analogy, the explanation of acupuncture hypalgesia may be equally ellu- sive. The three major problems with acupuncture hypalgesia which are encountered by acupuncturists and surgeons are: 1) in- adequate control of pain in some patients, 2) relatively poor control of visceral pain, and 3) lack of muscular relaxation with the con- sequent problems associated with abdominal surgery. Based on the foregoing comments, several research objectives can be proposed in humans and in animals. Human Objectives: The use of acupuncture in humans can be broadly divided into surgical and nonsurgical applications. Re- garding surgery, it is impossible to estimate at this time the extent to which acupuncture may be useful for control of pain during operations in our environment. However, some tentative predictions do seem possible in the light of what we now know. On the positive side, the use of acupuncture instead of conventional general anesthesia would have the advantages of eliminating anesthetic drugs with their moderate degree of toxicity and rare fatalities, and enable the patient to cooperate effectively with the surgeon and others engaged in the operative procedure; also, if effective, acupuncture could be used in areas with mini- mal resources, since in the case of manual or mechanical acupuncture it requires almost no equipment other than needles. Postoperative pain and discomfort (ileus, etc.) are said to be much less pronounced, but the more gentle manipulation of incisions and of bowel by the surgeons may account at least in part for this. On the negative side, it must be remembered that in the People’s Republic of China acupuncture analgesia is considered satisfac- tory for only some 15% of surgical patients; if, furthermore, the results are acceptable in about three-quarters of these selected pa- 92 tients, the overall number of cases in which acupuncture can be used is relatively small. Furthermore, at present it is not possible to predict whether adequate pain control will be obtained; converting from acupuncture to con- ventional anesthesia in the course of an opera- tion may be difficult and hazardous. Induction of acupuncture hypalgesia for surgical procedures of any magnitude takes approximately 20 minutes; general, regional or local anesthesia can be induced more rapidly in most instances and an anesthetic state can be guaranteed. Thoracotomies can be carried out under acupuncture hypalgesia successfully without intubation, but there is of course a def- inite impairment of respiratory exchange. Exploration of the abdomen is hindered by the absence of muscle relaxation, and traction of viscera is usually painful. In summary, it appears to me that most of what can be done successfully under acupuncture hypalgesia could be equally well performed with regional and in some instances local anesthesia, and with considerably less stress on the patient and surgeon. These com- ments are in no way derogatory of acupuncture as a striking and possibly important phenome- non, but are set forth simply to emphasize the pragmatic aspects of the use of this modality of pain control. In line with these comments, the evalua- tion of acupuncture as a means of controlling pain during operations should, I believe, be undertaken by perhaps two or at most three selected groups which include anes- thesiologists as well as physiologists and psychologists. Such pilot studies could be car- ried out for a one to two-year period. Because of the natural history of the com- plaints for which it is used, evaluation of acupuncture for non-surgical disorders pre- sents innumerable difficulties to the patient and to the observer. It seems unrealistic to at- tribute any curative powers to acupuncture in most of the conditions for which it is advo- cated, such as cerebrovascular accidents, mi- graine, coronary thrombosis, hepatic cirrhosis and paraplegia. On the other hand, its use for control of some chronic pain syndromes may have some merit in view of the influence it ap- pears to have on operative pain. It may there- fore be appropriate to evaluate the application of acupuncture to the management of certain selected varieties of chronic pain syndromes such as postoperative lumbar disc pain, phan- tom limb pain, atypical facial neuralgia and post hepatic neuralgia. However, because of striking vagaries in the course of nearly all chronic pain syndromes, results will probably be difficult to assess. Animal Experimentation: Several objec- tives can be envisioned in this area, all of which will ultimately depend on the development of an appropriate research model in which repro- ducible and quantifiable results can be ob- tained. Behavioral Studies: Evaluation of pain in animals has been relatively well standardized in one instance, the tail flick response of the rat. In other species, radiant heat applied to the skin, leading to a withdrawal response, has been used with more or less success. These and other techniques for the quantitative assess- ment of pain responses may be employed to determine. the effects of acupuncture as a pre- liminary step to establishing whether analgesia is produced in a given species. If con- sistent results can be obtained in this way, subsequent objectives should include: e Studies to determine whether certain acupuncture sites are more effective than others or whether the effect is a general nonspecific one, in which case the classical acupuncture points would cease to have any further relevance; Establishment of optimal stimulus parameters; determination of the route by which acupuncture effects are mediated peripherally and centrally; If peripheral mechanisms are involved, are acupuncture effects elicited by acti- vation of specific types of receptors or nerve fibers, and is stimulation of deep neural or muscular structures more ef- fective than cutaneous ones? If central mechanisms are involved, are there selective inhibitory effects on neurons concerned with nociceptive relay and, if so, at what presynaptic or postsynaptic level do they occur and at what levels (segmental, suprasegmen- tal) do these effects take place? When some or all of the preceding issues have been resolved, one of the important ob- jectives would be to try to enhance the effec- 93 tiveness of acupuncture hypalgesia since, as noted earlier, it is recognized that analgesia is rarely if ever achieved. Potentiation of the acupuncture effect might be achieved by im- proved stimulus parameters (frequency, waveform and/or current delivered), by im- proved combinations of points selected or, pos- sibly, by enhancing the effect by combining acupuncture with drugs. With regard to vis- ceral pain which is poorly controlled, this may well be an inherent defect of the method and thus not subject to modification; however, we do not have evidence on this point and similar efforts to improve the effectiveness of acupuncture stimulation could be considered. Similarly, if adequate abdominal explora- tion is to be achieved under acupuncture analgesia, improved muscular relaxation should be an objective. Again, this may be an illusive goal; there is little to suggest that re- laxation should occur as a result of acupuncture stimulation and few if any clues to suggest how this defect can be minimized or eliminated. At the present time, acupuncture hypalgesia is a provocative issue mainly be- cause it introduces the possibility that pain mechanisms exist about which we know noth- ing and, concurrently, suggests the possibility of controlling pain by a relatively simple and innocuous means. For these reasons an effort to clarify the responsible mechanism is timely, and some suggestions regarding research ob- jectives have been made. As a technique for controlling operative pain, acupuncture is as yet in an experimental stage and for reasons stated appears to have more shortcomings than virtues in its present form, at least for application in our own envi- ronment. RESEARCH IN OBSTETRICAL ANESTHESIA DR. SHNIDER: There are a number of problem-solving projects that should be given high priority in obstetrical anesthesia re- search. First, in addition to the well-known nar- cotizing effects of drugs on the neonate, what is the impact of anesthesia on the fetus in ut- ero? Is any well-administered, uncomplicated general or regional anesthetic necessarily safe for the fetus? Are some anesthetic agents or techniques beneficial to the fetus? Do some agents increase while others decrease blood flow to the placenta? To cite an example, it is widely assumed and taught that the uterine vasculature at term is maximally dilated and can only respond to a drug or stress by vas- oconstriction. However, very recent data from our laboratory indicate that low doses of halogenated agents such as halothane or isof- lurane, administered with oxygen, increase uterine vascular conductance and uterine blood flow. Questions remain as to whether nitrous oxide or barbiturates added to the halogenated agent modify this response. Another question is whether the increase in uterine blood flow goes to the placenta or the uterine muscle. Another area for needed research, hitherto hardly examined, is a study of obstet- rical anesthesia in the maternal disease state, for example in patients with toxemia of preg- nancy, chronic hypertension, or antepartum hemorrhage. These studies can begin in the laboratory. It is possible, for instance, to de- velop a chronic maternal-fetal sheep or monkey preparation with many of the clinical signs of toxemia of pregnancy. It is also possible to de- velop an experimental model of fetal hypoxia and intrauterine growth retardation. We then could administer anesthesia or other drugs to see if there was improvement or deterioration in fetal oxygenation. Finally, a relatively new area for investi- gation is the effect of fetal medication on sub- sequent neonatal brain damage. This is really an extension of the work on barbiturates in treatment of stroke. Our question is, can we stop brain damage due to fetal hypoxia by ad- ministering large doses of barbiturates or some other anesthetic drugs to the mother, thereby causing decreased oxygen require- ment in the fetal brain? Should we always strive for an Apgar score of 10 at one minute in the infant by avoiding medication when it may be possible to decrease the incidence of cere- bral palsy by medicating asphyxiated babies in utero? DISCUSSION DR. WOLLMAN: We have heard that we don’t know precisely either the morbidity or 94 the mortality resulting from anesthetic techniques. Would Dr. Steinhaus like to com- ment on this? DR. STEINHAUS: We have heard refer- ences to the fact that the greatest advances in health care have come out of the general area of preventive medicine in contrast to the actual care of the sick patient. This does suggest that we need to know more about what is happening to large numbers of patients, in order to draw useful conclusions. Postoperative follow-up care is our weakest area. Usual information is not recorded due to the demands of the anesthetic schedule and other medical neces- sities more pressing at the time. We need bet- ter collecting systems. If we are to make judgments and demonstrate needs in anes- thesia, we must have data to support our be- liefs. DR. WOLLMAN: The next question, di- rected to Dr. Brunner, is what are the practi- cal results from the last decade of anesthesia research? DR. BRUNNER: In the early 1960's when I was a resident with Dr. Dripps, the principle taught was that a patient must be hospitalized if he was to be anesthetized. At that time, the research planner for the next decade included respiration, circulation and metabolism. Yes- terday, we heard the end results, the current state of the art in the areas of circulation, res- piration, metabolism and other areas. The ap- plication of this accrued knowledge now allows us to say that some patients, when anes- thetized, need not be hospitalized but can be allowed to go home in the afternoon. We can safely do this now with our knowledge about the toxicity of anesthetics and their duration and side effects. If we can move from 0.5% outpatient anesthesia to 20% outpatient anes- thesia, we will have gone to approximately four million outpatient anesthetics a year at a savings of perhaps $400 million dollars a year in health care delivery costs. One may say that is an overestimation of what is possible. How- ever, last year at Wesley Hospital, 16% of our anesthetics were done on an outpatient basis. While this speaks only to one institution, I be- lieve it demonstrates how research results have permitted us to change techniques of practice and produce significant results. DR. BRUCE: There is no doubt that surgery done on an outpatient basis will save millions of dollars yearly in the cost of patient care. There is, however, one unknown factor which tempers my enthusiasm for this trend. That is the length of time taken to recover completely from general anesthesia. Our studies with volunteers have shown that when they have been exposed to traces of nitrous oxide, halothane or enflurane they perform poorly on a complex psychomotor task as com- pared to themselves in the control condition. At the time of these tests, their expired air 95 content of halothane was about the amount found on the sixth postoperative day after gen- eral anesthesia. To me, this means simply that we know very little about the time to complete recovery from anesthesia. There are means available to study the recovery process and I feel this deserves high priority and must be done very soon, if we are to have any real basis for recommendations regarding resumption of normal activities following outpatient general anesthesia. PANEL DISCUSSION: RELATIONSHIP OF ANESTHESIOLOGY TO OTHER NIGMS PROGRAMS Links to Trauma Research, Bioengineering, Genetics, Cellular and Molecular Basis of Disease, and the Pharmacology-Toxicology Programs JOHN J. BONICA, Moderator John M. Kinney, Wen H. Ko, Nancy Simpson, David Bruce, Frank J. Standaert, Panelists DR. BONICA: I have long felt that anes- thesiology should interact with the basic sci- ences and surgery. Unfortunately in the past, this type of direction has been inadequate in most American universities due to a variety of reasons, not the least important being the fact that anesthesiology has not had the scientific base to develop a meaningful direction. Insuf- ficient funds, heavy clinical load, and, most important, insufficient anesthesiologists- scientists have contributed to this lag. These may be improved with development of the pro- grams we have talked about, but we have a long way to go. I strongly believe that in the future we must build sturdier bridges between basic scientists and clinicians. This will not only enhance the research effort but elevate its quality. Obviously, one of the first and most logical interactions should be between anesthesiology and surgery. As you know, NIGMS has an im- portant program on trauma research. With the serious impact that anesthesia has on the sur- gical management of injured patients and in- jury has on the anesthetic management, it is surprising that there is very little interaction between the two programs. Therefore, to explore common areas of interest and oppor- tunities for needed collaboration, we have in- vited Dr. John Kinney, Director of the Trauma Research Center at Columbia University Col- lege of Physicians and Surgeons, to review the trauma program. TRAUMA RESEARCH DR. KINNEY: I would like to show similarities of the trauma and anesthesiology research programs, touching briefly on four areas: the background and support of the pro- gram, certain challenges and opportunities of trauma centers, the major areas of current re- 97 search, and some areas of future promise. These quotations from the NIH Almanac, 1971, emphasize why trauma and anesthesia research found their home most logically in the Institute of General Medical Sciences: “The mission of NIGMS is to support re- search and training in sciences basic to medicine and in certain disciplines central to the nation’s total health efforts. ...” “Research programs involve selective support of various combinations of basic and applied research organized so as to meet acute needs in specific areas of health care.” NIGMS has supported these research pro- grams through three interrelated mechanisms: research grants, fellowships and training grants. You heard yesterday the general situa- tion regarding fellowships and training grants. Trauma research like anesthesiology has had budget cuts. The Trauma Research Program prior to 1966 was limited to selected research projects totalling less than one million dollars per year. During the period 1966 to 1968 the Institute more than tripled its support, which included the funding of six centers for trauma research. Dr. Black has discussed how, during the past six years, the trauma budget growth was simi- lar to that in anesthesiology research. Cur- rently, nine trauma research centers are funded at levels requiring approximately two- thirds of the trauma budget. In addition, there are 31 trauma research projects and two pro- gram projects. Foci for Research: Each center has a gen- eral research theme; areas of investigation in- clude shock, surgical infection, blood clotting, ventilatory failure, metabolism and endo- crinology, not uncommon in anesthesiology re- search. The research centers highlight certain special problems. Excellence in patient care, associated with the research center, is the only truly acceptable justification to the patient, his family or to other professional staff within the institution. Responsibility for application of research to patient care rests with the inves- tigators in both programs. The trauma patient may never present the desired “steady state” for optimum experimental design; hence more data will be needed to conduct meaningful ex- periments in a changing clinical condition. Trauma is a “disease of nights and weekends” which may dampen the enthusiasm of an otherwise interested basic scientist. But even if this handicap is overcome, more attention is needed to establish in the clinical setting, an intellectual environment where the basic sci- entist may feel at home. Let us take a straightforward example of trauma—the previously well, adult male who is struck by an auto and brought to the hospital in shock with skeletal and soft tissue injury. The patient’s course may be arbitrarily divided into resuscitation, operation if needed, the im- mediate postanesthetic recovery, a catabolic phase lasting days to weeks, and finally an anabolic phase of weeks to months. The more severe the trauma, or if complications occur such as organ failure or infection, the longer the time course. The integration of different scientific disciplines is obvious even for the study of one phase of the changes which occur. There is a special opportunity to exchange and compare research findings at all levels of biological organization: from the whole body and organs, to cells and ultimately to molecular pathways. There has been some very provocative discussion here on the metabolic changes in re- lation to the use of various anesthetic agents. One wonders whether some of the events dur- ing anesthesia might possibly predispose to the ensuing catabolic changes which we observe long after the patient has recovered from anes- thesia and assume to be the result of unrelated influences. Rates of transport: We are seeking to measure rates of transport in addition to con- centrations in both blood and tissue specimens, whether we are looking at the movement of ions, the transport of substrate or the turnover of specific proteins. Our ability to relate these changes to tissue and organ function is pre- liminary at best, but promises an exciting fu- ture. We are somewhat shocked to realize the extent of tissue depletion we allow to occur during our relatively sophisticated support of ventilation and circulation—particularly in protein and calories. It seems reasonable to expect that such findings would come from the environment of a research center. Perhaps the most striking change in in- stitutional medical care during the decade of the 1960's was the growth and proliferation of intensive care units. This relatively unstruec- tured growth could not continue in the present decade because of financial restraints. But as there is more information available for guid- ance in planning and operating intensive care units, those interested in clinical research must constantly bear in mind that the ICU probably represents the greatest under- utilized facility for research that is commonly available. Unfortunately, the trauma research centers have not developed extensive joint re- search efforts with the anesthesiology pro- gram as of now. However, there are promising beginnings in certain institutions and oppor- tunities for joint research are greatly in- creased by the interest of both disciplines in the advent of intensive care units for surgical patients. The NIGMS has five major research pro- grams: Cellular and Molecular Basis of Dis- ease, Genetics, Bioengineering which includes Diagnostic Radiology and the Automated Clin- ical Laboratory, Pharmacology/Toxicology, and the Clinical and Physiological Sciences Program. The latter supports research in trauma, anesthesiology, and the behavioral sciences, each of which is directly or indirectly related to the other programs. One example will suffice: the “GemSaec” automated cen- trifugal analyzer promises to open a new era in rapid, simultaneous chemical analyses on biological fluids, allowing automation of meas- urements such as enzyme determinations .which change with time. This principle de- 98 veloped jointly with NIGMS and Atomic Energy Commission support, is currently in commercial production and is one of the exam- ples where a technological advance in another Institute-supported area may expand our re- search horizons. BIOENGINEERING DR. KO: In your discussions many exam- ples have been cited of the relationship be- tween anesthesiology and bioengineering. This area arbitrarily can be divided into three major fields: instrumentation, computer application and modeling of physiological systems. All of these have use in anesthesiology: instrumenta- tion is involved in gathering data on blood pressure, peripheral flow and perfusion of every patient monitored; a computer is needed to analyze these data and reduce the informa- tion for physician availability; and certain models—either respiratory or cardiovascular system models—are needed to interpret the patient’s state. The need for non-invasive measurement devices was also mentioned. A very promising one is being developed by the medical en- gineering group at Stanford University; using ultrasonic imaging technique with a matrix of transducers, one can visualize the soft tissue structure at real time. Possibly in a few years, we will be able to use ultrasonic imaging de- vices to see how the heart beats, how the blood flows through the arteries and so on. Instrumentation: I now would like to talk about what is within the reach of biomedical engineering. From the technologies and skills developed in the engineering area, particularly in the electronics area, many things will flow if enough effort and funding are available. Dr. Smith showed you this morning how the mi- croprocessor can be used to analyze EEG re- cordings and provide some understanding of a patient’s state. Instrumentation of this type has become possible within the last three years. Basically, a small desk computer now can be reduced to the size of a cubic centime- ter. To illustrate further, our microelectronics laboratory is working on implant telemetry, implant stimulation, and implant control sys- tems to study basic problems of design technique and how to solve them. One example is a small, ingestible single channel unit for temperature telemetry. The battery is also in- 99 cluded, and it can operate continuously for two months. If not used continuously, it can be put in the refrigerator, which extends its life from six months to one year. Although designed for animal studies, it can be used ingestibly in man for core temperature, and there is also work underway using it to study human fertility. If some of you wish to use it for monitoring body temperature during surgery, write me and I will gladly provide the instrumentation. The output can be picked up by a very simple re- ceiver, and recorded or processed by compu- ter. Our research results also include a single channel telemetry unit with dry electrodes, which do not require paste. The 1%-x Y%-inch size package can be used for monitoring chil- dren or infants over a long period. Interdisciplinary Bridges: Each of the biomedical engineering groups is sponsored to pursue certain research directions. On the other hand, I believe all are very anxious to know the significant medical problems today so that in planning they can tailor their efforts to solve these problems. Biomedical engineering is a discipline whose major function is to pro- vide bridges between medical sciences, clinical care, physical sciences and engineering. Finally, let me discuss briefly the question of collaboration and specialization. 1 feel we need a certain type of center where collabora- tion between different disciplines extends be- yond the campus. Within the campus there should be collaboration between the depart- ments, but I think the cooperation should ex- tend beyond a physical location. I am suggest- ing that the national community should stimu- late collaboration not only in research but also in application, so that a discovery at one in- stitution can be quickly transferred to another institution for use and evaluation. Biomedical engineering groups, particu- larly our group, are very willing to stimulate such collaboration. In essence, we would like to offer our electronic facility, including equipment and skills, to make integrated cir- cuitry for other groups expressing such a need. Most recently, a Biomedical Electronics Re- source was set up to see how we can collabo- rate with groups which have need for this type of work. GENETICALLY CONTROLLED RESPONSES TO ANESTHESIA DR. SIMPSON: I shall use two models to illustrate collaboration between the geneticist, the anesthetist and the pharmacologist. Al- though the first model may not have practical implications in all of your minds, it is a “geneti- cist’s dream” for answering the question “how does the gene produce its effect.” The gene is that segment of DNA which codes for a polypeptide, and all it needs is one alteration in the base sequence of the DNA to alter the amino acid sequence of the polypeptide. Such a change, for example, can diminish the effective function of a protein or enzyme of which the polypeptide is a part. And if that enzyme or protein is concerned with drug metabolism, a profound difference may result in the efficacy of the drug in a patient who has the altered protein. In practice, this sort of problem is ap- proached by starting with the result. The anes- thetist starts with an unexpected response to an anesthetic, or drug used with the anesthet- ic, and attempts to ascertain the reason for the unexpected response; and the pharmacologist and geneticist subsequently may be involved in solving the problem. The first model is the classical example of prolonged apnea after a standard dose of suc- cinylcholine. The unraveling of this phenome- non started with knowledge that cholines- terase in human plasma or serum was respon- sible for hydrolyzing succinyldicholine, first to succinylmonocholine and choline and then to choline and succinic acid. Next it was noted that two psychiatric patients receiving suc- cinylcholine during repeated electric shock treatments always had prolonged apnea (Kalow, 1959). Thus, comparison was made of the kinetics of cholinesterase from these pa- tients and those which did not experience pro- longed apnea. This showed that the cholines- terase from the apneic patients had a reduced affinity for succinyldicholine (Kalow, 1962), and in fact had a reduced activity, on the aver- age, when the enzyme activity was measured towards benzylcholine in vitro. Furthermore, dibucane was found to inhibit the enzyme’s ac- tivity less in the patients (around 20%) com- pared to that in the controls (around 80%) when the family members of the apneic pa- tients were studied. Kalow and Staron (1957) found a third group of individuals whose en- zyme activity and dibucaine inhibition were in- termediate to those of the patients and con- trols. Moreover, genetic analysis of the family data supported the hypothesis that the pa- tients were homozygous for a gene which codes for the so-called atypical enzyme; the controls were homozygous for a gene coding for the usual enzyme, and the intermediates were heterozygous for the two genes. If the enzyme activity alone is measured, the distributions for the three types overlap; but if the percent of dibucaine inhibition—now known as the di- bucaine number (DN)—is measured, the dis- tribution becomes trimodal (see Simpson, 1971). Thus, by measuring the DN, it is possi- ble to predict the adverse reaction before the individual has been given the drug. Subsequently, two additional genes were found which code for altered cholinesterase. The genetic evidence indicates that these mu- tations involve the same piece of DNA and are, therefore, known as alleles of the first two genes, and the four are known as alleles at the first locus. They are designated Eu. for usual, Ea for atypical, Es for silent, which is an al- lele for almost no detectible activity and which in the homozygote results in prolonged apnea of a similar duration to that of E,. (Simpson, 1968). The fourth allele is E,r, which in the homozygotes results in apnea not as prolonged as that from the atypical and silent forms of the enzyme (Liddell et al, 1963 and Simpson, 1967). The model has reached the stage in which the drug reaction can be predicted from a blood test; although it is impractical to screen the entire population who will receive the drug, it is warranted to screen relatives of a “reactor” once found. This is because the frequency of prolonged apnea will occur in about 1 in 2000 anesthetic procedures. The reaction is not fatal or harmful to the patient but selected relatives have usually 25% and as much as a 50% risk of also being “reactors” and it is practical to test, predict and prevent the reaction in this high risk group. Thus we have one drug, one reac- tion and three known mutant genes, any one of which can contribute to the reaction, either in homozygous or heterozygous form with each other but not with the usual gene. The second model is not as clearly worked out and has been termed the “anesthetist’s 100 nightmare.” Although someone yesterday said no further research is needed in malignant hyperthermia, I do not believe that the ulti- mate answer for the efficient handling of these cases has been found. Genetic studies (King et al, 1972 and Britt, 1974) have shown that about half of the families have a dominantly inherited susceptibility and it has been shown that mus- cle disease or muscle bulk, raised CPK (creatinine phosphokinase) levels in serum, and the clinical features suggestive of Noonan’s syndrome may all be predictors of the reaction (King et al, 1972, and Pinsky and Levy, 1973); not all reactors, however, have one or more of these signs (Britt, 1974). Some have only a family history of an anesthetic de- ath. The other half of the patients are sporadic in their families. While it is probably not reasonable to screen every patient for CPK levels to find one reactor in about 15,000 anesthetics (Britt and Kalow, 1970), it is reasonable to: 1) inquire about previous anesthetics and family history, 2) clinically examine the patient for muscle bulk and other warning signs, and if suspicious do a CPK determination. Even so, some sus- ceptible patients will be missed. Some will even have had a previous uneventful anesthe- tic exposure. Muscle fibers seen by microscopy of muscle biopsy show abnormalities (Britt et al., 1973, Isaacs et al., 1973, and Harriman et al., 1973) and muscle from susceptible patients show a greater than normal contracture in vitro in the presence of caffeine, a situation which is potentiated even more in the presence of halothane (Britt et al., 1973, and Ellis and Harriman, 1973). Muscle biopsy, however, is not a practical test for predicting the reaction as a general screening procedure, except perhaps in an individual with a known positive family history. The anesthetist has improved treatment of the reaction when it occurs by first noting early warning signs such as muscular fascicula- tion and jaw rigidity if succinylcholine is used and by monitoring temperature and observing tachycardia, arrhythmia, instable blood pres- sure and cyanosis. Successful management is particularly dependent on recognizing the signs early and stopping all of the muscle re- laxants and potent inhalation anesthetics, hyperventilating after a change of tubing, and cooling (Britt, 1974). Pharmacological research has shown that procaine relieves the contracture induced by caffeine or halothane in vitro (Moulds and Denborough, 1972), and the anesthetist has found this useful in humans during a reaction (Britt et al., 1973, and Harrison, 1973). The pharmacologist has told us the basis for the reaction—i.e., that hypermetabolism of the muscle is due to a sudden rise in the myo- plasmic calcium because the sarcoplasmic re- ticulum takes up calcium at a slower than nor- mal rate in the presence of in vivo halothane, which is associated with lowered ATPase in the sarcoplasmic reticulum (Ryan et al., 1974). These series of events result in catabolism and heat production (Britt, 1974). The team ap- proach has brought us a long way in the under- standing of the mechanism of this reaction and in reducing the mortality. We still do not know the nature of the product of the mutant gene, but if we did, perhaps a practical screening measure for recognizing all of the “reactors” could be developed. Thus, we have a variable response to many anesthetics controlled by an unknown number of genes. I believe that the pharmacogenetic ap- proach could be used in other situations. An example is lidocaine, mentioned by Dr. de Jong yesterday, which when given continuously causes convulsions in 1 of 160 patients. As a geneticist I would ask, does this always happen in the same patients? I am not suggesting to try it again, but to ask if it happened before. Has it happened in any close relatives? As the pharmacologist I would ask, do these people metabolize lidocaine differently from normals? If so, perhaps the convulsions could be pre- dicted and hence prevented. Finally, I should like to ask you some questions. Is there any information on the pos- sibility of hepatic toxicity from halothane being under genetic control? The fact that more Mexican-American patients have this side ef- fect than other Americans, as mentioned by Dr. Cohen earlier today, may mean there is genetic control. Again, if the anesthetist can identify the patients, and if the pharmacologist can give us the biochemical steps in degrada- tion of halothane, then the geneticist could look for evidence of an unusual protein involved in the degradation of halothane in persons who have had the side effect and thereby possibly develop a predictive test. Do any patients have an untoward reaction to fluoroxene? If they do, 101 I would be suspicious of genetic control be- cause Dr. Cohen has mentioned that there is interspecies differences in detoxifying the anesthetic; and when this is so, there also are often intraspecies differences. THE NIGMS CELLULAR AND MOLECULAR BASIS OF DISEASE PROGRAM DR. BRUCE: The National Institute of General Medical Sciences has five scientific programs, each of which has a number of sub- sections. Anesthesia research has, by and large, been included as a subsection in the pro- gram called Clinical and Physiological Sci- ences. However, basic studies of anesthesia action also relate closely to other NIGMS sci- entific programs. One of these is termed the “Cellular and Molecular Basis of Disease” program. Many examples of basic studies of anesthetic action fit nicely into one or another areas of this pro- gram. Most of these have come from anesthesia departments and were funded in part by NIGMS grants. A few will be described briefly to illustrate the inter-program relationship. Macromolecular structure and conforma- tional change: In 1961, Featherstone et al showed that cyclopropane solubility increased as the protein content of the solvent solution increased. This suggested a direct interaction between anesthetic molecules and proteins. Five years later, Balasubramanian and Wet- laufer demonstrated directly such an interaction when they showed that halothane altered the optical rotation of bovine albu- min. More recently, Laasberg and Hedley- White demonstrated a decrease in helicity of poly-L-lysine and the beta chain of hemoglobin when these were exposed to halothane. My re- search has shown that halothane increased dye binding by human albumin. Metabolic transformation and bioenerget- ics: Many studies have been reported on the effect of anesthetics on metabolism. To cite a few, Fink et al. reported in 1969 that several volatile anesthetics decreased oxygen uptake and increased glycolysis of cultured mouse heteroploid cells. That same year, Peter Cohen and co-workers reported that halothane blocked oxidation of NAD-linked substrates but not that of succinate, in metachondrial preparations. In 1971, Brunner and Passon- neau reported that several volatile anesthetic agents increased energy stores in mouse brain. A year later, studies by Ko and Paradise suggested that methoxyflurane blocked con- version of glucose-6-phosphate to fructose-6- phosphate in rat atria. There have also been studies of the re- verse relationship, the effect of metabolism on anesthetics. Ellis Cohen described the metabolism of halothane in the mouse, and in 1971 published a review of many studies of metabolism of volatile anesthetics. Strong clin- ical implications of these findings were fur- nished in the report by Mazze on renal toxicity resulting from metabolites of methoxyflurane. Differentiation and specialization; cell life cycle: Prompted by earlier reports of toxic effects of nitrous oxide on bone marrow, I began a series of studies of anesthetic action on bone marrow and published in 1955 an account of halothane inhibition of cell division in the differentiation of rat bone marrow myeloid cells. Recent studies by Cullen and co-workers showed that halothane, dose-dependently, in- hibited the response of human lymphocytes to phytohemagglutinin (PHA), which normally causes these cells to enter the active cycle of events leading to cell division. The end point measured in their studies was DNA synthesis, a relatively late event in the cell cycle. I have since studied earlier consequences of PHA ad- dition to lymphocyte cultures, finding inhibi- tion of RNA and protein synthesis. lon transport; membranes; methods: In 1966, Andersen reported that cyclopropane stimulated, and halothane inhibited, active transport of sodium by toad bladder tissue. Other workers have utilized other modern methods to take fresh approaches to the study of anesthetic action. Hinkley reported on an electron microscopic study in 1972, which showed that halothane caused axonal mi- crotubules to assume enlarged forms. More re- cently he has shown reversible dispersion of microfilaments in halothane-treated neuro- blastoma cells. Trudell et al. have used elec- tron spin resonance methods to study pressure effects on phospholipid membranes, in an at- tempt to explain pressure reversal of anes- thesia. Ueda et al. reported recently a study of 102 anesthetic interaction with a lecithin monolayer model membrane. The studies that I have cited are but a few examples of overlap between anesthesia re- search and the basic science programs. Other areas of study come to mind, some actually in existence and others only potential at the present time. They will be noted with the clear understanding that such a listing is incomplete and reflects the prejudices of this investigator as well as the limit of time available for presen- tation. Mechanism of anesthetic action: The main clinical effect of anesthetics, obviously, is de- pression of brain function. There is a vast area of overlap between anesthesia researchers and basic scientists working on central nervous system structure, function, metabolism, energetics, regulation and coordination, com- partmentalization, and in fact almost every component of the NIGMS Cellular and Molecu- lar Basis of Disease Program. Although that program refers to the cellular and molecular basis of disease it clearly includes normal func- tion since this must be known before disease states can possibly be understood. This is also true for anesthesia which may be viewed as an inatrogenic, reversible pathologic process pro- duced by poisoning the central nervous sys- tem. The euphemism, “putting the patient to sleep,” has a nice ring to it, but it is inaccurate since sleep and general anesthesia are obvi- ously different states. It is common to perform surgery, such as tracheotomy, on unanes- thetized patients in coma; but the normal, sleeping patient would never tolerate this. Almost all basic studies in neuroanatomy, neurophysiology and neurochemistry relate strongly to anesthesia research. Today there is great interest in side effects of anesthesia, which result from anesthetic action on non- neural tissue. Cardiac, renal and hepatic ef- fects of anesthesia may determine the outcome of anesthetic administration to patients who have problems with these functions. Research basic to better understanding of all vital organ functions is therefore basic to the definition of anesthetic effect on these functions. Predictability of drug action: Here the goal is an immediate, practical one. Although desirable it is not necessary to know the pre- cise molecular mode of action of a drug in order to predict its safety and efficacy. New anesthetic agents appear with regularity from pharmaceutical sources, and pharmacologists, anesthesiologists and biochemists are faced with the problem of evaluating these drugs. The tools with which they work are an out- growth of basic studies of the sort cited above. One can easily envision the time when scien- tific sophistication will permit a much faster and more thorough screening of new drugs than is possible presently. This will result only from continuing interaction of workers both in basic and clinical sciences. Relatively recently, great interest has developed in the effect of drug interactions on patients receiving multi- ple drug therapy and then requiring anes- thesia. The same arguments apply to this case; that is, the more knowledge we have about modes of action of all of these agents, the bet- ter the prediction as to their safety in combina- tion. It is even possible that through such studies, “antidotes” may be developed to coun- teract unwanted effects of one agent in the presence of another. Development of research techniques: Around the early 1900’s ether and chloroform were used by many biologists as laboratory tools to suspend cells in various stages of divi- sion, allowing experimental manipulations to be made. If more were known today about molecular mechanisms of anesthetic action, these agents might again be of use to workers in other disciplines. Attractive as this sounds, it is more likely that closer collaboration among scientists would yield immediate gain to anesthesia researchers seeking new techniques to further their studies. One example is the need for a method by which in vivo studies may be made of volatile anesthetics. The literature currently contains abundant studies of the distribution, action and metabolic fate of non-volatile drugs such as digitalis, opioid analgesics and diuretics. By tagging these compounds with radioactive tracers, not only the parent compounds but also their metabolites can be extracted from tissues, separated by column chromatography and studied extensively in many ways. By con- trast, anesthetics are so volatile that they are lost during these procedures, so relatively lit- tle can be done with them. Surely such a di- 103 lemma has a solution. Research conducted in the “methods” component of the cellular and molecular program may offer one. In conclusion, science suffers from frag- mentation. When workers are polarized artifi- cally by funding opportunities requiring their proposals to fit into mutually exclusive “camps,” valuable interplay of ideas, techniques and solutions is stifled. Anesthesia research has, and should continue to develop important areas of overlap with the Cellular and Molecular Basis of Disease Program of the NIGMS. THE PHARMACOLOGY-TOXICOLOGY PROGRAM DR. STANDAERT: I plan to present only an outline of the NIGMS Pharmacology- Toxicology Program, using it as a vehicle to unburden myself of a few personal thoughts about “interdisciplinary” or “collaborative” re- search in anesthesiology. The Pharmacology-Toxicology Program, like the Anesthesiology Program, has been operating about 10 years. It began in 1965 after the thalidomide incident called attention to the need for better study of drugs, and Rachel Carlson’s Silent Spring called attention to the biological effects of non-medicinal chem- icals. Today, the NIGMS Pharmacology- Toxicology Program is considerably larger than the NIGMS Anesthesiology Program. Its 1974 spending level was about $19,300,000 for research and $6,400,000 for training; a total of $25,700,000. This money supported 11 centers, 6 program projects, and 48 individual grants in pharmacology-toxicology. These accounted for about two-thirds of the research budget. The remaining one-third provided funds for 173 projects in bio-related chemistry. Geographic Disbursement: The geo- graphic distribution of the two programs is interesting. There are 11 centers in pharmacology-toxicology and five in anes- thesiology, but there is no overlap among them—i.e., there are no two in the same city. The closest intersect is San Francisco where there is an Anesthesiology Research Center and a Pharmacology-Toxicology Program Project. Clearly the two programs do not op- erate to provide direct day-to-day interaction between the two disciplines. It is informative to look at the areas of research supported by the two programs. Both are broad but each is weighted toward a kind of research. Most of the anesthesiology research is that commonly classified as physiologic— e.g., cardiovascular, pulmonary, central and peripheral nervous systems—with much less emphasis on chemical or biochemical mechanisms. Pharmacology-toxicology is quite the opposite. It is heavily weighted toward chemical and biochemical research with much less emphasis on the physiological aspects of drug action. The two programs may comple- ment each other, but they do not seem to be designed for close collaborative work. One ex- planation, of course, is that the two programs are not intended to coordinate. Each has its own objectives, and they differ. However, the apparent difference may be an aberration. Neither program pretends to support all of the research in its field, and each might, by chance, be supporting different parts of a single research spectrum. Another possible explanation is more heretical: maybe anesthesiology research is not really very closely tied to pharmacology research. I say heretical because we have heard anesthesiology described here as “applied pharmacology.” This term seems very logical; after all, anesthetics are drugs, and pharmacology is the study of drugs. Further- more, about one-half of the anesthesiologists on this program are members of the American Society for Pharmacology and Experimental Therapeutics. This should indicate a close rela- tionship between the two fields. It’s a curious thing, though; I don’t remember seeing many of these members at recent ASPET meetings. Similarly I've been to a few anesthesiology meetings but I don’t recall that they were overrun by people from Departments of Phar- macology. I've noticed another curious thing; the Journal of Pharmacology and Experimental Therapeutics published 146 articles in the last six months, but only six of these were in any way identified as connected with Department of Anesthesiology. “Applied pharmacology” might be another term for clinical pharmacol- ogy; therefore I reviewed Clinical Phar- macology and Therapeutics. In the last six months it published 79 papers, only two of which came from Departments of Anesthesiol- 104 ogy. To approach the matter from the opposite point of view, I reviewed Anesthesiology. It had published 51 papers in the last six months, two of which came from Departments of Phar- macology. In this case, however, there were six others published by groups of anes- thesiologists that included someone with an additional appointment in Pharmacology. In- terestingly, almost all of these were members of Anesthesiology Research Centers. Thus, the differences between the Pharmacology-Toxicology and Anesthesiology Research Programs are not abberations; they are accurately reflecting the habits of their constituencies. In short, anesthesiologists and pharmacologists are not making any real effort to communicate with each other. This lack of communication cannot be due to a lack of com- mon interests. Consider the Pharmacology- Toxicology ~~ Research Program. Drug metabolism and disposition are its priority interests. The kind of work described by Drs. Greene, Van Dyke and Cohen is very close to work being done at some of the Pharmacology-Toxicology Research Centers. Development of new drugs, clinical trials, the incidence of mechanisms of toxicity are also high priority matters in the Pharmacology- Toxicology Program and among phar- macologists in general. We have heard numer- ous descriptions of work in this area of anes- thesiologists. Anesthesiologists and phar- macologists are interested in the same thing, but they don’t seem to be doing very much to- gether. This lack of communication is detrimental to all. A routine question at anesthesiology re- search center site visits is, “How do you relate to basic sciences?” It is not always clear what the questioner has in mind. It usually has to do with help with methods, a greater depth of knowledge in a specific area, or consultation during analysis of data. These are pertinent, but there are better reasons for anes- thesiologists to talk with pharmacologists. For one thing, you are never going to solve all of your problems by yourselves. There are too many problems, too few research anes- thesiologists and too little money. There are pharmacologists who could find working on anesthetics just as challenging as working on another group of drugs. These investigators can and should be recruited to the task. 105 I'd like to diverge from the main theme for a moment, to insert two personal pleas: 1) Yes- terday while discussing aspects of these prob- lems, people were speaking of “guiding” basic scientists. Please find less patronizing words. A good scientist does not want or need to be “guided” by anyone. You'll do better if you'll “point out the problem,” “excite the interest of” or “challenge.” You might even try: “work together with.” 2) Don’t try to increase com- munication with basic scientists by hiring cap- tive basic scientists. Dr. Eckenhoff gave some excellent reasons for avoiding this, and I have another reason. You're not going to get the best basic scientists. They may come to your labs for awhile, but they probably won't stay. They know they won't have the same career opportunities in a department of anesthesiol- ogy as they would in a basic science depart- ment. The other fundamental reason for more communication with basic scientists is to get quality control. Yesterday we debated the quality of research in anesthesia. I submit that you are not going to learn the answers to the questions that were asked until you engage in competition with other scientists doing similar work. I'm an editor of the Journal of Phar- macology and Experimental Therapeutics and occasionally I get a manuscript from an anes- thesiologist. Invariably it goes back for revi- sion and sometimes it is rejected. All too often I don’t get a revised manuscript and there are some authors who, once rejected, never again submit a manuscript. Two explanations come to mind. First, the author doesn’t know the system. Getting a manuscript back is not a dis- grace. In all the years that I have been editing for JPET, I've only seen one or two manu- scripts that did not need revision, and JPET currently is rejecting about 60 percent of the manuscripts submitted. Second, the author has copped-out; he is unwilling to do the work needed to bring his paper up to our standards. This shouldn’t happen, but I think it does. Rigorous Standards: Speaking of cop- outs, yesterday we heard a plea for a special study section for anesthesiology. This proba- bly is a good idea. There are special problems that need special attention. But it shouldn’t be thought of, even subconsciously, as a way of escaping rigorous standards. The research problems we heard described here are ex- tremely important, but the results of this re- search will be important only if the work is done well. If you are going to play in the big leagues you will have to meet the standards of the other players. I’ve been on more pharmacology- toxicology site visits than anesthesiology site visits, but just as many questions are asked. One I've never heard is: “How do you relate to anesthesiology?” I strongly suspect that if it were to be asked it would only confirm the in- vestigators’ worst fears about the mental com- petence of the site visit team. Yet, it should be a legitimate question. Anesthesiology has a lot to offer pharmacologic research. The phar- macologists can be faulted for not knowing this. But the fault is not all theirs and, since they are not here (a significant observation in its own right) there is no point in my berating them. Toga, my captive audience consists al- most entirely of anesthesiologists, and there- fore I'll analyze your faults. I suggest that the basic problem is not so much a lack of communication as a lack of edu- cation. Some of you will find it hard to believe, but I think you are too modest and too timid. One, you haven't done enough to change the image of the old “gas passer.” Two, you haven't let people know about the rapid ad- vance in your scientific competence. The qual- ity of your work and the importance of your problems have changed dramatically in the past 10 years, but you have been reticent about letting others know it. Three, you haven't pointed out to others the advantages of work- ing with your drugs. Four, you haven't pointed out the unique opportunities for clinical re- search that are found in the operating room. There are some things that you should do to close the gap between pharmacology and anesthesiology. Don’t be chauvinistic; there are more problems than you can possibly han- dle, and you're not the only ones who can solve them. Be willing to share them. Become mis- sionaries; do less talking to yourselves and more talking to others. Aggressively seek au- diences; go to national meetings of non- anesthesiology societies; arrange joint sym- posia with the basic sciences; volunteer to give seminars and be insistent about giving them; and publish in non-anesthesiology journals. This kind of proselytizing will add to your al- ready heavy burdens, but I think you have to do it if you are to advance your science and obtain your stated goal of improvement in pa- tient care. If you need more than intellectual induce- ment for this kind of thing, let me remind you that the NIGMS pharmacology-toxicology budget is more than five times bigger than anesthesiology’s budget. That's a nice target for raiding after you've used up all the anes- thesiology money. It is there to be competed for by pharmacologist-toxicologists, be they basic, clinical or “applied.” DISCUSSION DR. WOLLMAN: Dr. Standaert, don’t you think that one way of increasing the con- tact between anesthesia and pharmacology might be an anesthesia representative on one of the pharmacology and toxicology study sec- tions? DR. STANDAERT: In principle, I would not disagree. DR. COHEN: I would like to question Dr. Standaert or take issue with him in terms of opportunities available to basic scientists in the clinical department. I strongly agree that the basic scientist who works in an anesthesia department must maintain his relationship in the basic department from which he came. If he is fortunate enough to be able to get a joint appointment, all the better. In any event, he has to keep up with the developments in his own specialty, otherwise he very quickly re- treats away from the year at which he left his own specialty. But, if we are ever going to do any proselytizing, missionary work of any kind, this is the opportunity to translate these various problems that we have within anes- thesia to those basic scientists who have the background, the knowledge, and the techniques to help us in these considerations. I think it is a step forward to integrate basic scientists into an anesthesia department, again maintaining the relationship to their own basic department. This is a unique opportunity, rather than a lessened opportunity for them. DR. STANDAERT: It depends on what you mean by integration. If a person is coming in to spend two, three, or five years in the anesthesia department, this is a fine thing and should be done. But it is a different matter when you talk about integrating the basic sci- entist into anesthesiology. Why not integrate the anesthesiologist into pharmacology? That is really the heart of it. A bright, ambitious man sooner or later wants to command the show. He knows he will never be Chairman of Anesthesiology. The best he can hope for is to 106 become a research professor who has a re- search group that is under the command of others. This is an inhibiting factor to many people—particularly the ambitious ones. DR. BONICA: But, how many of the young Ph.D. pharmacologists will be chairmen in this country? How many chairs are there? DR. STANDAERT: Some 117-118 chairs are open right now. A good fraction of the young academic pharmacologists have the chairmanship as one objective. This is auto- matically set aside if they make their career in another department, particularly a clinical de- partment. DR. WOLLMAN: I would like to suggest that there are two areas of interface between anesthesia and pharmacology, which don’t show up if you look at publications or at grants. Those are the trainee and the student areas. We have been sending trainees to the phar- macology department. Also, many of us have been lecturing in pharmacology courses for students and the pharmacologists lecturing to our residents. DR. STANDAERT: I agree. But these are small. It’s a nice beginning. As I said, it is the anesthesiology research centers that show these joint appointments, at least in publica- tion, but it is not a widespread phenomenon. DR. EPSTEIN: As to joint appointment, there seems to be movement in the other direc- tion. The department of pharmacology is send- ing graduate students to us for an opportunity to see how drugs work in a compressed time scale in the clinical setting. DR. BONICA: Are there any comments or questions concerning trauma to be addressed to Dr. Kinney? DR. MODELL: Dr. Kinney, you men- tioned that there were no major efforts in the trauma research centers to interact with anes- thesiology. Yet there are a number of areas in this country where anesthesiology is almost in prime control or has responsibility of units that take care of trauma, but are not being funded as trauma units. Can you explain why those places having trauma grants haven't utilized the expertise of anesthesiologists? DR. KINNEY: One can’t help wondering whether or not the same institutions that may have trauma centers also have departments of anesthesia that are funded and busy in their own research programs. DR. BLACK: I would say to Dr. Modell that we do have an inter-relationship, for in- stance, at San Francisco. Several of Dr. Hamilton's people in the anesthesia research center at the University Medical Center are also investigators on Dr. Blaisdell’s trauma re- search center grant at San Francisco General Hospital. Dr. Bonica’s group is certainly in- teracting very early with Dr. Shires’ Univer- sity of Washington trauma research center. Dr. Kitz similarly has one of his investigators working in the burn research center that we recently activated at Harvard. So there is communication. Unfortunately, there simply are too few locations with support from both programs. 107 PROGRAM PROSPECTS: SCIENTIFIC AND MANPOWER ROBERT M. EPSTEIN, JOHN E. STEINHAUS, HENRIK H. BENDIXEN AREAS OF CURRENT THRUST DR. EPSTEIN: After two day’s discus- sion the question remains: where among the suggested very long shopping list shall we find the biggest payoff in future work? I am standing in for Dr. Thomas Hornbein, who as some of you know is in India to partici- pate in a symposium on the neural control of respiration. A survey conducted by Dr. Horn- bein under the sponsorship of the Scientific Advisory Council of the Association of Univer- sity Anesthetists has attempted to determine current research activity in the field of anes- thesiology. I will review with you the findings of this survey and will also explore some of the findings which have been obtained by the analysis of NIH applications in anesthesiology. Hornbein’s study was based on a very open ended questionnaire in which 113 institu- tions were requested to submit information on their current projects in anesthesiology. Ninety-six returned the questionnaire after suitable follow-ups, representing an 85% re- sponse, which probably includes at least 90% of the research being done in anesthesia depart- ments. The goal was to find out the nature of the research being done during the year 1972— 73, how extensive were the studies and at what cost. I say the study was open ended because really all it did was provide a set of data sheets on which the individual could enter the title of his project and a brief description, list the principal investigators, sources and amount of funding, and publications. The limitations are fairly obvious. In regard to projects, the num- bers depend on what individual institutions or investigators called independent projects. In some cases there were broad areas of investi- gation, whereas in others every little change on a common theme seemed to be submitted as a separate project. The funding data were for the most part freely offered and provided total direct costs of the projects. Institutional fa- culty salary contributions were not included nor were institutional cost sharing figures, in terms of space and other support. A number of projects obviously had been performed out of the pocket, using local resources or pig- gybacked onto ongoing research. Individually, these probably represent small investments, but collectively are a significant portion of the total number of projects. There were a total of 658 identifiable proj- ects. In terms of pure numbers of projects, only 20% were from the large programs repre- sented by anesthesia research centers and program grants. This may surprise some of you, but I believe the figures make the funding credible. Data were also obtained showing that research centers and individual grants may be viewed as complementary and not destruc- tively competitive to each other. The key to success in either continues to be quality appro- priate to the opportunities requested. The projects were heavily oriented to- wards pharmacological sciences, in contrast to Dr. Standaert’s survey which suggested that anesthesiologists were not heavily involved in pharmacology. By Dr. Hornbein’s criteria, these accounted for 40% of the total. An addi- tional 32% were divided between physiology and biochemistry, 9% in pathology and mor- phological studies, while other areas together amounted to only 20% of the 658. These in- cluded bioengineering, behavioral sciences, mathematics and computer science, genetics, immunology and clinical sciences. In the light of earlier comments this after- noon, it is interesting to review where the re- search results were published. Anesthesia journals accounted for 46% of the publications and other clinical journals for an additional 32%. The remaining 22% of all the publications reported appeared in basic science journals. This latter proportion seems not unreasonable and testifies to the capability and willingness of anesthesiology to earn its place in the scien- tific community. For the same reasons that basic scientists wish to be identified with their own discipline, anesthesiologists wish to pub- lish primarily in anesthesia journals (46% of the publications) to establish their identity and reputation. Research Orientation: Returning to Dr. Hornbein’s data, considered by organ systems, 109 the pulmonary, cardiovascular and nervous systems accounted for 69% of project studies and were related to physiology and pharmacol- ogy. Multiple organ systems were studied in 11% of the projects. The remaining 20% in- cluded such areas as hepatic, endocrine, hematological, gastrointestinal and musculo- skeletal. Five hundred eighty projects could be identified as applied research. These included general anesthesia, specific diseases, anesthe- tic complications, bio-instrumentation, toxici- ty, and pharmacokinetics and metabolism of drugs. Also included were pain and acupuncture studies, anesthetic systems and techniques, obstetric and perinatology, and studies in regional anesthesia. Of the three hundred eighty-six studies di- rectly concerned with drugs used in anes- thesia, 59% related to inhalation anesthetics, parenterally administered anesthetics, and local anesthetics. Sedatives and barbiturates, analgesics and opioids, and muscle relaxants accounted for 30% of the projects; all other drugs studied came to 12%. Analysis of the FY 73 funding provides an interesting overview of the current status of anesthetic research. Total support was re- ported to be $9.86 million, presumably repre- senting direct costs only. Federal sources ac- counted for 73% of the funds reported, or ap- proximately $7.2 million. Of this, the NIGMS provided $2.49 million, NHLI $1.22 million, and other NIH sources $0.63 million. Other federal programs provided $2.86 million. Center research grants were available in anesthesiology only through NIGMS, and amounted to 69% of NIGMS 1973 funding in anesthesiology. Adding those funds distrib- uted through other NIH institutes and Federal programs, it becomes obvious that consid- erably less than half of the Federal dollars in anesthesiology are being distributed through center grants. Industry, institutional funds and foundations together provide 27% of the funding, or approximately $2.6 million. Interestingly enough, the 73% Federal funding accounted for only 47% of the total numbers of projects identified by the popula- tion survey. Fifty-three percent of the projects for which funding was available was supported by industry, institutional funds and founda- tions. This suggests that the latter groups tend to support small studies requiring minimal equipment or personnel. Many of these repre- sent support for clinical trails or other drug- related studies. Approximately 11% of the total numbers of projects identified were sup- ported from local sources without identifiable funding. Obviously, no estimate can be made of the actual dollar value in this research invest- ment. It is very interesting to compare the $2.49 million figure for NIGMS gained from Dr. Hornbein’s questionnaire with the actual spending in FY 1973. The NIGMS anesthesiol- ogy program was funded at a level of $4.19 mil- lion. I do not have a breakdown into indirect and direct costs, but on average approximately 39% of the direct cost figure may be added for indirect costs. Applying this proportionately, the direct cost spending in 1973 would approx- imate $3.02 million. Our reported values would appear to be approximately 18% low. This may be in part because the core facilities support for centers and program projects was not pro- rated among individual projects in the survey. Despite this difference, the Hornbein figure provides a good check on the completeness of the survey. NIH Review Assignments: We obtained data on the NIH review assignments of appli- cations. From 1972 to March 1974, there were 148 submissions from anesthesia departments or applications with an anesthesia code. Nine research centers and program projects were reviewed by the no-longer-active NIGMS Gen- eral Medical Program Project Committee. The projects were assigned predominantly to the Surgery, Pharmacology, and Cardiovascular study sections, with the remaining being as- signed to Neurology and Pathology Study Sec- tions, of the NIH Division of Research Grants. Forty-seven of the 139, or approximately 33%, were approved and funded by the appropriate granting institutes. A different story appears when one examines only the new applications submitted during the same time interval: 112 applications bore -01 or 01A1 first-year suffixes. Of these, awards were made to only 31% and amounted in dollars to only 24% of the total funds re- quested. These data invite certain interpretations which are admittedly speculative. It appears that funds have continued to support studies 110 on the pulmonary and cardiovascular systems and classic drug studies. The higher percen- tage of renewal applications resulting in awards is not surprising since it is expected that these proposals should present high quality research. There is concern about the assignment of applications to the Neurology and Pathology Study Sections, which appear to lack expertise or familiarity with our field. There is also concern that some of the newly developed areas may not be attracting needed support. Areas of needed research in anesthesia—including biochemical effects of anesthetics, immunology, effects on cell or- ganelles, effects on the nervous system and studies of the mechanism of anesthesia—are difficult to get funded. However, the informa- tion we have is insufficient to draw extensive conclusions. What is to be done now? Where do we go from here? At a time when the total funding available to our discipline will obviously limit the subjects to be studied, it seems vital that we have a clear idea of the best return on the dollar. Also, because there is so much to do and so few of us as yet to do it, we must have a set of priorities. From this meeting must come discussions that will assist in charting the pat- tern of anesthesia research funding and alloca- tion. It may even be desirable to develop a short-term study on a contractual basis for analysis of priorities for the future. It might be a worthwhile investment in terms of maximiz- ing the returns. RFP’s might be appropriate in selected areas of research as well. What of the question posed yesterday about the role of centers. Dr. Eckenhoff raised the question again this morning and stated his conviction that additional centers, probably of smaller individual size, would be of benefit to the field. As one who speaks now from outside the center apparatus, I am impressed by the advantages of collective work, of shared facilities and internal peer review provided by the center. It would be a salutary development both for research and education, if there were a diffusion of the center concept to a few addi- tional institutions geographically located in needed areas. The availability of the manpower nucleus of such centers depends—as does the formida- ble task of meeting our almost overwhelming responsibility for research on the broad range of problems—on continued support of anes- thesiology training grants. Funding of Project Research: The funding of individual projects in anesthesia clearly de- pends on the numbers submitted and their quality. The development of additional re- search centers should not alter the readiness to fund projects of high quality but instead should stimulate additional funding by the NIGMS. It would seem we are far from the saturation point in anesthesiology research at this time. What about the possibility of a DRG Study Section in Anesthesiology? From time to time this proposal has surfaced with concern that anesthesia grants were being distributed to the winds, with indifferent success in funding. However, it seems that the total number of submissions to NIH over a three-year period is relatively small, and would not justify a single review body. Nor in our data is there evidence of any major bias against anesthesia applica- tions of appropriate quality. Even were a specific study section to exist, submissions in certain areas would undoubtedly go, for en- tirely appropriate reasons, to other review groups. Accordingly, I cannot recommend con- sidering the establishment of a study section at this time. It would be useful if some better understanding of the needs and directions of this field could penetrate, by peer representa- tion, the existing study sections which have reviewed anesthesia-related applications. Other functions—e.g., surveillance of the field, and the direction, stimulation and review of progress—have been confined to meetings of this sort, and to the efforts of other groups such as the Scientific Advisory Council of the Association of University Anesthetists. MANPOWER FOR ACADEMIC ANES- THESIOLOGY DR. STEINHAUS: Although research in anesthesiology might be considered an inde- pendent activity, its purpose is drawn from the clinical practice of anesthesiology and the anesthesia faculty. Since patient care require- ments cannot ordinarily be given a second priority, these clinical demands for faculty time and attention have encroached on anes- thesia research and educational activities. A study of academic manpower and its workload 111 provides a good base for assessing and project- ing the manpower needs in anesthesia re- search. An assessment of the manpower situation in academic anesthesiology was approached by means of an extensive questionnaire concern- ing the present and future faculty size of the departments, the clinical and educational workload, and the budgetary support. Replies to this questionnaire regarding anesthesia de- partment staffing and personnel practices were solicited from 109 medical schools in the United States and Puerto Rico. Seven schools reported that they did not currently have de- partments of anesthesiology, 12 schools were classified as “non-respondents,” and replies from four schools were received too late to be tabulated. Therefore, the responses from 86 schools of medicine currently organized to in- clude departments of anesthesiology comprise the basis from which the information for this report was drawn. The university hospitals averaged just over 12 anesthetizing locations and reported 7,590 anesthetics administered each year. In their affiliated hospitals, which varied in number from 0 to 6 per medical school, an av- erage additional 6.7 anesthetizing locations and 5,241 anesthetics are added. Variation in the size of clinical loads at the different schools makes it difficult to provide a simple evalua- tion of anesthesia manpower from the above figures. The extreme differences are illus- trated by comparing one program which re- ported only 5 anesthetizing locations, 2,500 anesthetics and no obstetrical load, to a huge complex program which listed 51 anesthetizing locations and 46,700 surgical anesthetics ad- ministered plus 5,800 obstetrical anesthetics. Nevertheless, the average anesthesia load re- vealed in this study does provide a reasonable estimate for use by medical schools in planning and providing adequate clinical material for education without imposing an undue burden of clinical responsibility on the faculty. Previously applied standards for medical school approval have been based on four hospi- tal beds per clinical student. This would mean 800 beds for a medical school with a class size of 100 students and anticipated classes of 200 students in the clinical years. Such a hospital would probably provide 10,000 anesthetic ad- 112 ministrations yearly, not far from the averages found in this study. The age distribution from the survey indi- cates a young faculty, which substantiates an opinion held by most observers. Over 75% of the professors are under 55 years of age, and the median age of associate professors is 41 years. A total of 1,044 faculty positions were reported from 86 medical schools. Compared to the reported 204 professors and 185 associate professors, the 460 assistant professors seem disproportionately high. Such a distribution is most likely explained by a preponderance of recent additions to the anesthesia faculty. A high loss rate from anesthesia faculty is com- pensated for by the addition of beginners who have not yet had time to advance up the academic ladder. The average academic faculty numbers 12.93 per school and is faced with a clinical workload which includes staffing 19.2 anesthetizing locations as well as being re- sponsible for obstetrical anesthesia, research, teaching, respiratory care, and other duties. This serious disproportion between workload and number of academic faculty limits the qual- ity of patient care as well as the contribution to education and research. Peer review, quality assurance programs, and a serious increase in medical malpractice suits puts into sharp focus the increased demands for elevated standards of patient care. The adoption of vigorous pro- grams would appear amply justified in order to correct these critical deficiencies. Non-physician personnel employed for clinical anesthesia service is largely composed of the 743 Certified Registered Nurse Anes- thetists. This number is approximately 50% that of the residents in training. The combined residents and nurse anesthetists total approx- imately 1,000, which averages over 10 persons per reporting medical school. This latter group includes nurses, technicians, aides, LPN’s, and others. The changing pattern and increased complexity of the modern medical center are indicated by the other full-time personnel now carried on the payroll of the department of anesthesiology. The survey showed these highly trained personnel to include 25 phar- macologists, 23 professional administrators, 16 engineers, and 157 other professional and technical personnel. These data forecast a new dimension within the departments of anes- thesiology. The resident in anesthesiology, like all clinical trainees, provides care of patients but is also an educational obligation for the faculty. Unlike most other personnel, he performs within a wide range of knowledge and skill over his two years of clinical anesthesia train- ing. During his first two or three months, the clinical care which the resident provides is largely non-contributory, but with increasing experience and long hours of call, his clinical workload is considerably greater than that of the non-physician personnel working a 40-hour week. Although surgical anesthesia occupies 70% of the resident’s 24 months of clinical anesthesia training, obstetrical anesthesia, re- covery room, I.C.U., pain therapy and other areas consume a significant portion of this time. Assignment to special services, where education is primary and clinical work sec- ondary, further reduces the resident’s con- tribution to the routine clinical anesthesia load. The survey revealed an average of 16 resi- dents per medical school and affiliated hospi- tals, distributed unevenly over four years. Foreign medical graduates account for almost half of this group but may well decrease with the new proposed regulations. While the postgraduate training program is the academic department’s major obligation, in anesthesiology undergraduate education consumes a sizable proportion of staff time in preparation of educational material, hours spent teaching, and actual clinical instruction. The anesthesia clerkship was available in 100% of the schools reporting, and in 45% of them was required for all students. An average fig- ure of 61.5 medical students per medical school participated in such a clerkship, distributed almost evenly between third and fourth-year students. The reported hours of teaching in- cluded an average 150 class session hours for the third-year students and 185 hours for the fourth. Teaching conference hours for the clin- ical year averaged 340 per school. Anesthesia faculty teaching in other departments included the following percentages of the reporting schools: pharmacology—=82.6, physiology— 46.5, anatomy—18.6, biochemistry—14.0, pathology—>5.8, and community medicine— 4.7. As might be expected, there was a very high participation in pharmacology and a sub- stantial contribution to physiology. Compared to surveys made in 1964, this contribution to interdepartmental teaching has increased. Further increases will probably not be possible unless there are substantial increases in anes- thesia faculty. The sources of professional income include the following average percentages for the med- ical schools reporting: medical school—28.5; teaching hospital—19.2; affiliated hospital salaries—6.6; patient generated income (fee for service)—42.5; grants or foundation monies—2.1; contracts for health services— 1.1. Medical school and teaching hospitals funds cover the major expenses of departmen- tal administration as well as substantial clinical care costs, since many of the teaching hospitals are state and city institutions which provide medical care by means of their teaching pro- grams. The total of funds from these items, plus the 42.5 percent from patient fee indicates that most of the professional income is from patient care. PROGRAM PROSPECTS—NEW AREAS DR. BENDIXEN: I wish to speak for ad- ditional efforts in areas which are relatively new. Osler once said that the desire to take medicine is what separates man from the ani- mals. Cochrane, reviewing Great Britain's Na- tional Health Service in his book, Effectiveness and Efficiency, elaborates on this theme. Cochrane used the phrase, “when the desire to be treated gets together with the desire to treat we have the nicest kind of inflation.” He points to our general failure to establish effec- tiveness and efficiency in what we do, includ- ing our failure to show that drugs, procedures and techniques in fact do work; how efficiently and at what cost. The cost of modern medicine is high, because we do so much and are driven to apply what we can do. The high cost of mod- ern medical care combined with the intellectual urgency of establishing effectiveness and effi- ciency create the need for investigation in these new areas. These are problems which call for scientific rather than political or admin- istrative solutions. Our specialty interacts with almost every other specialty in the modern medical center. Roughly 75% of patients in the medical center are seen by an anesthesiologist, acting in one 113 or another capacity. We occupy a position in the center of activities, which favors investiga- tions of effectiveness and efficiency. I believe this type of investigation to be mandatory, and also potentially very rewarding scientifically. I should emphasize that our central position in the modern medical center makes it likely that the investigation proposed will have signifi- cance, not just for anesthesiology but for every specialty with which we interact. Possible Program Areas: Studies on the medical decision-making process are urgently needed. We need to define in systems analysis terms what the decision-making process is based on; how it works; and what are the end- points. In order to improve the decision- making process we need better indicators of the patient’s condition, as well as predictors of outcome. The principal reason that most monitoring efforts have been less than success- ful is that they aimed to measure and monitor what can be measured and monitored, rather than first asking what is important. Tradition- ally, we have been obsessed with the disease- labeled diagnosis and have given insufficient attention to the study of disease patterns and the recognition of such patterns. As an exam- ple, respiratory failure may be associated with an endless number of disease states. I believe it will be possible to reduce this multitude to a handful of respiratory failure patterns. Differ- ent manpower models have received some at- tention in recent years, but much more needs to be done. In the process we must include an analysis of task and job content as well as motivational studies. It may well be that our current manpower models are far less efficient than they should be. We also should call for studies on the effec- tiveness and efficiency of teaching and train- ing. Difficult as this may be, we have to arrive at quantitative measures. Several groups have started such studies which I view as exceed- ingly important. Use of Simple Models: In anesthesiology we have many opportunities to make fairly simple models which permit the study of qual- ity, morbidity and mortality in relation to pro- cedures, techniques and manpower. Also, in the intensive care unit setting we can use Osler Peterson’s work as the take-off point. He has introduced the term: the cost per live dis- charge. Intensive care invariably is thought to be enormously expensive. In fact, if the cost of intensive care is put in relation to the pro- jected lifespan of the patient, an enormous spread is likely to materialize—with the young patient, having a short hospital stay and a high survival, representing the bargain end of the spectrum; and the costly and lengthy effort to delay death in the critically ill and elderly pa- tient representing the other end of the spec- trum. Without going into details, it is easy to project that at the costly end of the spectrum, sums in excess of $100,000 must be spent on intensive care in the hospital to produce one year of survival for one patient; at the bargain end of the spectrum, a year may be gained at a cost of less than $100. These are the kinds of numbers that need to be determined; and they must lead to a closer examination of what we do, especially our heroic efforts, which we carry out on the margin of the impossible. The increasing knowledge and improving technol- ogy have made the heroic as well as the hope- less effort possible. In the process we must examine the juxtaposition of technology and humanity. I believe that these areas of investi- gation provide an enormous scientific chal- lenge. They also remind us that the greatest strength of the physician is his humanity. In the preceding, I have attempted to give a few examples of untraditional problem areas likely to produce scientific benefits as well as social rewards. There is a great intellectual satisfaction in knowing and in using resources well. The one resource which causes the most concern is highly qualified manpower. Re- cruitment of qualified manpower is enormously important to any specialty, but can succeed only if we use current manpower well. This re- quires the study of effectiveness and efficien- cy. Great care is needed in the design of train- ing programs and in deciding what we want young people to do. As mentioned previously, the anesthesiology research center has con- tributed greatly to an improvement of our manpower situation. We should not ignore the importance of the training grants. The threatened disappearance of the training grants is as serious a setback as any we have received in recent years. I strongly urge the continued support of anesthesiology research centers and an attempt to resuscitate the train- ing grants in one form or another. 114 SUMMARY COMMENTS WILLIAM H. HAMILTON To summarize this two-day meeting, be- cause of the time limitations imposed upon all of us, I will not review each of the individual presentations. Their brevity worked out much better than any of us anticipated. What I say, obviously, represents my own interpretation, subject to my own biases, which are many. As I heard yesterday's discussions, I was a little disappointed to discern an attitude of apology: in a sense, bad-mouthing our own specialty. We need not be apologetic, because we have done a great deal. The evidence pre- sented for this has been overwhelming. If we accept the fact that we should be proud of what we have done, we should stay with and support a winning team. The team to which I refer here is NIH support combined with our own organi- zations. The current system has worked and is working today. It is a productive one. We would be ill-advised to abandon our present system or do anything that would compromise or diminish its effectiveness. I think we have made anesthesia quite safe. Previous contraindications are now indi- cations for the most major surgical interven- tions. We have helped to accomplish that. Also, we have extended our role in such new clinical activities as the intensive care unit, the treatment of respiratory failure, neonatal intensive care, and more recently, activities in pain. Much if not most of this is directly related to our research efforts. It has been pointed out that the NIH has borne a big share of this re- search load and has stimulated us to greater activities. I happened to have participated in some of the meetings of 1965-67 which resulted in the “Papper era.” I recall target areas which were listed at that time. These were the sites of anesthetic action, better methods of anesthetic administration, improved equipment, im- proved anesthetic agents, increased investiga- tion of cardiopulmonary function, improved monitoring and understanding of neuromuscu- lar block, and the observation of visceral fune- tion, especially liver, kidney and brain. We have heard evidence that we have attacked these areas successfully and vigorously and have made real advances therein. In spite of the admonition that we should be proud of what we have done, we obviously cannot be complacent. We must continue to improve. To stand still would be to fall back to the previous state of parasitic existence to which reference was made yesterday. We have heard, without too much supporting data, that anesthesia morbidity and mortality still exists. We all know this and meet weekly in our de- partments to discuss the problems. There is obviously a real need for continual improve- ment in anesthetic care. We have heard at least twice that we are not as safe as the air- lines, and we ought to approach that. We lack data to define and to quantitate the morbidity and mortality, and suffer greatly from that lack. Bigger and better epidemiological studies must be done to define what anesthesia is doing to patient care and patient welfare. Some of the untoward effects we can iden- tify in anesthesia are due to bad equipment and to pilot error. These, I believe, are strong ar- guments, irrefutable arguments, for additional research in bioengineering. Some mishaps are on a genetic basis and there is a real need to explore this area, including metabolism and re- lated fields. Some are due to poor understand- ing on our part. We therefore must have a broader knowledge of the mechanisms of the anesthetic state and the effects of drugs. Cer- tainly we need more studies in the area of pain management. This is the most basic reason for which patients consult physicians. Yet causes, mechanisms and management of this oldest of symptoms are poorly understood. We have been looking at acupuncture. The very fact that it appears indistinguishable from the effects of hypnotism suggests a need for further study. One of my own residents had a palmar fasciectomy under hypnosis and got up from the operating room and rode his bicycle home. He had no needles in his Hoku point, or anywhere else. This tells that anecdotes prove little, and demands that careful research be done in this area. We heard debates yesterday and today on the value of the research center grant concept. Debate on this matter is appropriate, but I was disturbed to see it develop into a “have versus 115 a have-not” argument. My bias, and I think we have some supporting information, is that re- search centers do work. They have been very productive of good research. It is of interest that somewhat in excess of 40% of the papers to be presented at this week's ASA meeting are products of the five NIGMS research cen- ter grants that exist today. There was much evidence reported here this afternoon of avail- able funding for the research project. Re- search centers and projects can exist in some sort of symbiotic arrangement. They are not mutually exclusive or antagonistic. As a logical spinoff, research centers provide academic manpower pools. They have supplied many fa- culty members for other schools, and have helped recruit good students into our field. It is important that it be firmly understood that there would not be a fixed amount of money earmarked for individual anesthesia project grants if the research centers were discon- tinued. Research centers have good quality con- trols, perhaps better than individual projects. They are site visited project-by-project, which does not occur with the individual projects. An intramural control mechanism within the in- stitution is strongly urged by NIH. Certainly, intramurally, if one of our investigators is not doing his work well another will be demanding his equipment and space. Competition is tough. This is the big league. The old easy days are gone for the moment, and probably for the foreseeable future. I believe a rational argument can be made for “mini-grants” for starter grants, or some kind of funding that might help the young in- vestigator get started. It was stated by one of our colleagues that the young kid in Fort Smith, Arkansas, with a bright idea should be as entitled to tax-derived support as the fellow who happens to live in San Francisco or Bos- ton. Don’t force anyone to move to the center, where the supply of academicians is already much better. The training grant picture described here is the gloomiest thing we have heard the past two days. This is not limited to anesthesia. The on-again, off-again practice that has occurred over the past couple of years has certainly been disastrous in its results on recruiting. This year, while we can show a distinct, continuing need for academicians and re- searchers, we've found that the number of re- search trainees is down. That is quite under- standable, because none of us could commit positions until May, at which time most candi- dates had already made their plans for the com- ing year. In light of the need for researchers and academicians, which I believe we can estab- lish, it is unbelievable to me that we were not recognized on the list of critically short areas for institutional fellowships under the National Research Service Award Act. I read the Act’s provisions over three or four times. I saw clini- cal pharmacology, which has minimum clinical responsibilities, listed as a shortage area, yet we are not. We have a severe shortage of academic people. We have the data to prove it, and we must be heard, to make this fact known. We discussed the important problems of the peer review system. This has been under heavy attack from the anesthesia community, and I suspect from other communities, because there are not special study sections in some of these clinical specialties. It is obvious that a number of anesthesia research applications are looked at and reviewed by study sections with no anesthesia experience or representation and little insight. It is inevitable that some in- justice will result from this. The magnitude of the problem is not known. Within a group as small as ours, the unfair treatment of two, three, or four excellent grants may be a signi- ficant fraction of the output of our specialty. To have our own study section is considered a sol- ution to this problem. A more practical alter- native would be a better and broader repre- sentation on existing study sections. The least effective solution would seem to be the in- creased use of ad hoc consultants on commit- tees which do not have anesthesia representa- tion. It is important that we take an honest look at the problem and ask ourselves, “Are the problems we face in funding due to a poor re- view system or due to the quality and effort of program directors and potential inves- tigators?” I have no doubt that there is some of both at present. But it is counter-productive to think that we can blame someone else for all or 116 most of our problems. We should get our own house in order, by putting out greater efforts. Then possibly we will get better results. We needed a special start some years ago, but now we should be considered a mature specialty. One of the most impressive things to me at this gathering was a real lack on reporting good clinical research. This probably results from two things. First it is extremely difficult to do; second, we have a real tendency to downgrade it. If we take a patient to the operating room and keep constant his temper- ature, CO2 tension, and dose of halothane, and then study his neuromuscular transmission, that is clinical research. But if we do this in a pharmacology lab on a chicken leg where respi- ration is not monitored and the leg is perhaps not even attached to the chicken, this is basic research. This emphasizes with appropriate exaggeration the problem that does exist. We, in our own group, look down upon clinical re- search as being of less virtue and of less sanctimony than basic research. I submit that this is an artificial dichotomy. We in anesthesia should do what we are uniquely qualified to do. I try to tell people in our institution that we ought to do what Dr. Julius Comroe can’t do: attack and solve clinical problems. It is cer- tainly an area in which we have a unique oppor- tunity. As examples of the importance of clini- cal research, I would mention two things dis- cussed here. First, Dr. Severinghaus talked yesterday about the cerebral steal, and the Robin Hood effect, and the obvious benefits that would re- sult from those concepts in our clinical treat- ment of patients with occlusive carotid disease. In our own institution, the clinical results in terms of mortality and neurological residual deficit are inseparable, whether they occur from hypo-or hypercapnia. This “obvious” phenomenon that we measured in the labora- tory has not proven itself effective in terms of different results in the clinic. This does not downgrade the observation or the research, but it says the observation of an existing phenomenon must be tested in the actual clini- cal situation. Second, Dr. Laver emphasized problems inherent in evaluating myocardial contractili- ty, in comparison of the morphine versus halothane techniques. At the ASA meeting two years ago, these two quite opposite approaches to cardiovascular system anesthesia were compared, but the postoperative results were no different. Yet when we determine in the laboratory that a myocardial depressant is present, we express concern and look at the eventual results on the patients as we treat them. We do not have hard data to support many of our claims and our needs. I suspect that other groups similar to us are talking about hard data regarding the needs or nutrition of patients or the number of babies that are dying of certain diseases. We do not have such data. We need them badly to support our requests and define our clinical problems. There is so much to do and so few to do it. Must we not make an active effort to define goals and priorities? Dr. Severinghaus pointed out the ineffectiveness of a complete and exhausting list, but he then said, “Let’s look at a small list and pick out a few things that really need doing and attack them.” Developmental grants were suggested by Dr. Modell. There are other and more tradi- tional mechanisms of getting started. The re- search center grant has traditionally evolved from an individual project grant, which ex- panded into two project grants or a program project. The idea of a research center grant starting with a core budget which might pro- vide better and more expensive equipment, not justifiable on an individual project, does have some appeal. Today we were provided with a mountain of research yet to be done. There can be no doubt left in the minds of those listening that attacking these problems will uncover more problems. All speakers gave compelling reasons for further investigative efforts, rang- ing from investigations at the molecular levels to nationwide epidemiological studies. We have discussed research from all aspects and have talked about cooperative efforts with five or six other related disciplines. These, hope- fully, will provide information so that in the future when I have to anesthetize Mrs. Jones for her cholecystectomy, I can make my deci- sion on something other than medicolegal grounds. To those not in anesthesia, it is worth your recalling that the service load to anesthetists is 117 somewhat unique. It is put upon us by others and we have almost no control over the daily requirements for service. One can say this is true of the radiologist and pathologist. How- ever, one can stack up X-rays and read them later according to the schedule. One can also look at microscopic slides and lab results a lit- tle later; but an anxious surgeon and an ill pa- tient require our personal service right now. While a surgeon can look at his own X-rays or lab results, he has to be a little more than am- bidextrous to do his own anesthesia. The crush of service load is a very severe restriction on our research and academic activity. We cer- tainly cannot shun it. It is the basis for our existence. In summary, we have made big advances. We have established that there is a real short- age of academicians, especially those commit- ted to research. However, we are not included in the critically short classification at this time. Closely related in the shortage of high-quality research proposals from our colleagues. Our most severe shortage or gap is in the area of clinical research. It is a difficult job, but neces- sary, for obvious reasons. We need to support projects and we need to continue research centers. These are not mutually exclusive. We need to support facilities, buy space and equipment, and perhaps most importantly we need to train re- search personnel. As a result of the past 48 hours of discussion, the following suggestions are made: 1) It is most important that all efforts be directed to include anesthesiology as a critically short or scientifically deprived area for academic and research personnel, therefore eligible for institutional support. 2) That some form of starter money be considered. I am aware this is not easily done, but its purpose is important. We should protect and aid the young inves- 118 tigator in the small or beginning depart- ment, so he will not be forced to join the already well supplied center to get his in- vestigative work underway. 3) That we as a specialty and the NIH as a granting agency do our best to avoid downgrading clinical research; that we give it the respect it deserves. 4) That we thoroughly examine the serious handicaps imposed upon us in some areas by restrictions on human investigation. Perhaps a conference is needed to discuss the effects of these restrictions. Are the effects real or merely imaginative? They seem extremely real to me. We cannot look at the effects on man without study- ing man in the clinical environment. If the regulations are compromising important research, it should be known to NIH and others. This could be a meaningful sugges- tion by this group. 5) That epidemiologic studies be consid- ered as a most important area which will help us in our priority search. 6) That research centers be continued and, if possible, be increased in number, but not at the expense of individual projects. Clearly, there is no surplus of unfunded approved grants. Nonetheless, potential investigators should not withdraw or re- tract themselves completely from the ap- plication field; rather, realizing that the competition is tough, they should be en- couraged to get in and do a good job. 7) Lastly, I would strongly urge that the NIH ascertain, to the best of its ability, that the anesthesia grant applications get reviewed by groups having real insight into the problems and priorities of the spe- cialty. We are not asking for an easy way out. Merely a realistic peer review. U.C. lil LIBRARIES (029455601 U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service National Institutes of Health DHEW Publication No. (NIH) 76-918