1 The Development of Concepts of Mechanisms of Anesthesia

Donald Caton and Joseph F. Antognini

INTRODUCTION Even before Morton's demonstration of surgical anesthesia in Boston, on October 16, 1846, phy• sicians and scientists had begun to explore mechanisms by which drugs affect the central nervous system. In large part, this was an outgrowth of a revolution in therapeutics that had begun in wake of the Enlightenment. As philosophers and politicians threw out old patterns of religious, political, and economic thought, so physicians discarded a system of medical practice that had been in place for almost fifteen hundred years. Modem medicine began during this era and with it new disciplines such as physiology, , and biochemistry (1). The discarded system of practice, called "Galenic Medicine", for the early Greek physician who established it, maintained that the body was composed of four elements (earth, air, fire, and water), which combined in various proportions to produce four humours (blood, black bile, yellow bile, and phlegm). Health was a state in which humours stayed in proper balance: disease a condition in which that balance had been upset by some internal or external disturbance. Physicians were to discern the character of the imbalance and institute appropriate restorative measures such as bleeding, purging, or cupping (2,3). In the centuries following Galen's death, physicians modified his original scheme in response to new discoveries in other areas of science. As engineers began to exploit hydraulics, for example, physicians attributed all disease to fluctuations of hydrostatic pressure. After the discovery of elec• tricity, they exchanged hydraulics for energy imbalance to explain disease. Despite changing theory, however, therapy remained the same. Even at the beginning of the nineteenth century, physicians recommended many methods familiar to Galen, modified only in that they used them with less restraint. At the time of the American Revolution, for example, physician Benjamin Rush became known for his propensity to bleed patients to the point of death (4). The movement away from Galenic medicine began with French physicians. Early in the nine• teenth century, they began to question and then discard Galenic concepts of disease and therapy. Coincidentally, they created a new system based on careful clinical observation, supplemented by post mortem dissection and statistical analysis (5). From this, they developed the idea that disrup• tions in the structure of specific organs would induce functional changes recognizable to a clinician as distinctive patterns of signs and symptoms. In the context of this discussion, studies of neurologi• cal disorders proved to be particularly important. The association of localized lesions with specific

From: Contemporary Clinical Neuroscience: Neural Mechanisms of Anesthesia Edited by: Joseph F. Antognini et al. © Humana Press Inc., Totowa, NJ 3 4 Caton and Antognini deficits led them to reject the concept that the central nervous system was a homogenous mass in favor of the concept that it consisted of many components, each with a different function. Physi• ologic data soon confirmed this. Scottish physician Charles Bell showed, and French physiologist Fran~ois Magendie demon• strated, that dorsal and ventral nerve roots of the spinal cord have different functions. Legallois rec• ognized the importance of the cerebellum for the coordination of motor activity. Johannes Muller established the idea that different receptors respond to different stimuli-pain, light touch, or tempera• ture, for example. Coincidentally, anatomists showed the nervous system to be a collection of highly differentiated cells, ganglia, and pathways. These concepts influenced physiologists and physicians who were just beginning their studies of drug action (6). Significant among early studies of drug action was work by French physiologist Fran~ois Magendie (1783-1855). In 1810 he began experiments on the plant upas tieute, a member of the styrchnos family (7,8). Natives of Borneo and Java used a dried extract of the plant, which caused convulsions and cardio-pulmonary arrest, on the points of their arrows to kill small game much as Indians of South America used curare. Magendie showed: • That the poison worked most quickly when placed directly on the spinal cord or brain rather than on a peripheral nerve. • That the onset of action varied directly with the time it took for the drug to reach the brain. For example an intravenous injection killed more rapidly than intra-muscular injection. • That the circulation had to be intact for poison to work. Dogs died quickly after an injection of the poison into a severed limb, but only when he left its arterial and venous connections intact. Magendie's experiments influenced the next generation of physicians when they began to study mechanisms of anesthetic drugs.

EARLY STUDIES IN ANESTHESIA: ATTEMPTS TO ASCERTAIN ITS SITE OF ACTION Important though they were, Magendie's experiments had little impact on the practical American physicians who first demonstrated the anesthetic effects of nitrous oxide and ether. Crawford Long, Horace Wells, and William Thomas Greene Morton simply wanted to relieve pain. They showed no particular interest in the mechanisms that brought this about. Their pragmatic approach was typical of early nineteenth century American physicians and scientists, who distrusted theory and had little interest in any innovation for which they could not find an immediate use. Accordingly, most early studies of mechanisms of anesthesia emerged not from the United States but from Europe among physicians and scientists who were better attuned to theory and scientific inquiry (9,10). At first, physicians appeared to be most concerned about establishing the site of action of anesthe• sia. They attacked this problem in much the same way that Magendie had dealt with strychnine. Here the influence of clinical and pathological studies of neurological disorders becomes apparent. As physicians used ether, for example, they recognized that anesthetized patients exhibit an orderly sequence of clinical signs, starting with a disturbance of consciousness, followed by a loss reflex activity, and finally a paralysis of respiratory and cardiac activity. From this they reasoned that some parts of the nervous system were more susceptible than others. In fact, within months of the announcement of Morton's demonstration in Boston, French physiologist Pierre Flourens described anesthesia as a progressive depression of the nervous system beginning with the cortex, followed by the cerebellum, and finally the brain stem and spinal cord (11). Others confirmed his findings, among them Nicolai Pirogoff (12-14). Born in Moscow, Pirogoff (1810-1881) trained there before moving to Dorpat, Estonia to con• tinue his studies. The University in Dorpat, staffed at that time by German speaking physicians, was to have a seminal influence on the development of experimental pharmacology and on early concepts of mechanisms of anesthesia. From Dorpat, Pirogoff moved to Saint Petersburg, where he became Mechanisms of Anesthesia 5

chief surgeon in the medical school. He was teaching there when he first learned about Morton's work with ether (15). Within a year, Pirogoff published a book about anesthesia. In it he describes his use of ether, but he also describes more than forty-five experiments that he performed to elucidate its site and mechanism of action. For example, Pirogoff demonstrated that direct application of ether on a peripheral nerve caused partial anesthesia. He speculated, however, that this response might be due less to the pharmacological action of the drug than to a temperature change in the nerve caused by direct application of the liquid. Pirogoff then proceeded to demonstrate that ether had a more potent effect on the brain than on peripheral nerves, and that it worked better when distributed by the circulation rather than by direct application to the cortex. Pirog off examined individual nerves look• ing for microscopic anatomical changes that might explain how ether blocked the conduction of impulses (14). He suggested two possibilities. First, that ether might have some "chemical action on nervous tissue." Second, he thought that "ether vapor in the capillary system surrounding nervous tissue" might exert a "greater or lesser degree of compression on the component fibers of the brain and nerves, partly by the force of expansion or partly by passage into the cerebrospinal fluid." In fact, neither of Pirog off's suggestions was particularly new. Pharmacology textbooks from the eighteenth century had speculated that morphine induced some physical change in nerve fibers, thereby inhibit• ing function (16). Similarly, surgeons had long known that pressure on a nerve could render a limb anesthetic. In fact, one English surgeon, James Moore, tried to popularize this method for painless amputations (17,18). In effect, Pirogoff simply substituted gaseous pressure for the mechanical force that Moore had used (19). Establishing the central nervous system as the primary target of anesthesia was no small achieve• ment. Even after Magendie's work with strychnine, physicians continued to debate the primary site of action of morphine. Most believed that it affected the brain, but others believed that morphine had its most profound effect on peripheral nerves. For this reason, textbooks recommended that morphine be administered as close as possible to an injured part. In fact, it was for this purpose that Alexander Wood introduced hypodermic injections in 1855 (20). Perhaps the most extensive and sustained series of studies, during this early period, came from the laboratory of Claude Bernard. Bernard, who had been a student of Magendie, summarized his work in the book, "Lectures on Anesthetics and on Asphyxia"(21). In the book, Bernard made several points. First, he defined anesthesia and distinguished it from narcotism, a state that he associated with morphine. Second, he sought to explain anesthesia in precise anatomical and physiological terms (22). Third, he, too, sought to establish the primary site of action of anesthetic drugs. Towards this end, he performed a series of experiments on frogs not dissimilar from those used by Magendie in his studies of strychnine. Like Magendie and Pirogoff, Bernard concluded that anesthetics act on the brain rather than peripheral nerves. He also recognized, however, that anesthetic drugs suppress not just neurological activity of higher animals, but basic functions of many different kinds of cells, even those of plants. This led him, and others, to speculate that anesthetics may work by altering mecha• nisms common to the cells of many different tissues and species. Lastly, Bernard distinguished anes• thesia from asphyxia, an important point about which more will be said in the Early Studies Section. Among early contributors to studies of mechanisms of anesthesia, English physician John Snow also warrants mention. Snow also described clinical signs associated with different depths of anes• thesia, but he went one step further. Whereas, experiments by Flourens, Bernard, and Pirogoff had largely been descriptive, Snow was among the first to establish a quantitative relationship between the concentration of inspired gas and the clinical response-a nineteenth century forerunner of the concept of minimum alveolar concentration (MAC). He did this by placing small animals in an enclosed chamber filled with air containing different concentrations of anesthetic. Snow made the gas mixtures himself by adding measured amounts of liquid to containers of known volume. After allowing time for the liquid anesthetic to vaporize, he placed animals in the container so that he could observe clinical signs associated with different concentrations of inspired gas. Snow 6 Caton and Antognini used these data to argue for more precise control over concentrations of ether administered to patients, and even designed a temperature-controlled vaporizer to achieve this. His experiments demonstrate a remarkable understanding of the gas laws, which had only recently been described, but also an appre• ciation of the significance of these laws to theory and practice. Most important, by describing and measuring a dose-response relationship, he developed an approach that would become important for later studies (23).

THE EMERGENCE OF MODERN PHARMACOLOGY Coincident with the studies of the site of action of anesthesia, scientists also began to study mecha• nisms. An important stimulus for this work was the emergence of experimental pharmacology. In part this was an outgrowth of Magendie's work with strychnine, but there were other factors. By 1850, for example, chemists had identified nitrogen, carbon dioxide, oxygen, and nitrous oxide. Dalton and Henry had described the gas laws. By 1811, German pharmacist, Sertiirner, had isolated two active principles of opium, morphine and codeine. By 1832, Samuel Guthrie and Justus von Liebig had synthesized chloral hydrate. Simultaneously, biologists began to shift their attention from descriptive to experimental work. For example, after the announcement of the cell theory by Schleiden and Schwann in 1838, pathologists and physiologists began to explore cellular mechanisms of dis• ease. Simultaneously, Felix Hoppe-Seyler and others began to apply chemical analysis to the study of biological phenomena. In short, advances in many branches of science gave physicians tools and concepts that they could use to study drugs. Two men prominent in the emergence of experimental pharmacology were Rudolph Buchheim and Oswald Schmiedeberg. Both had sound training in experimental science. Directly, and indirectly, they shaped early studies of mechanisms of anesthe• sia. Curiously, both had strong ties to the medical school in Dorpat, the institution where Pirogoff once worked. Historians often call Rudolph Buchheim (1820-1879) the founder of modern pharmacology. German by birth, Buchheim studied medicine first in Dresden and then in Leipzig, where he worked under E. H. Weber, a physiological chemist. Soon after completion of his studies, he became known as an editor of Pharmazeutisches Zentralblatt, and as the author of several chapters in Schmidt's lahrbuder der Medizin. Not long thereafter, he won more praise for his translation into German of Pereira's The Elements of Materia Medica. Early in his career, Buchheim spent several productive years at the University of Dorpat, where he worked with Carl Schmidt and Friedrich Bidder. Later he moved to Giessen and finally, after the Franco-Prussian war of 1872, to Strassbourg, where he died (24-27). Buchheim made many contributions to pharmacology, among them the concept that drugs should be classified according to their mode of action. This signified a major departure from an earlier "Galenic" convention that simply classified drugs as stimulants or depressants. As late as 1793, for example, one major textbook included a long discussion about opium, whether it acted more as a stimulant or a depressant, that is to say as "hot" or as a "cold" form of therapy, using eighteenth century terminology (16). To Buchheim, pharmacology meant identifying the effect of a drug on specific physiological processes-on liver metabolism or urine formation, for example. It meant understanding the relationship between a drug's structure and function, and it meant establishing how the body dealt with drugs, how they are metabolized and excreted. Buchheim borrowed experi• mental methods from many branches of science, but he also developed techniques widely used by subsequent generations of pharmacologists. Buchheim's research on chloral hydrate illustrates his approach. Buchheim's interest in chloral hydrate grew from his studies of acid base balance. Noting the alkalinity of blood, he speculated that formic acid, a metabolite of chloral hydrate would "neutralize" blood, an effect that he believed might be clinically advantageous. Chloral hydrate did not have this effect, but Buchheim did observe that it made his subjects somnolent. He attributed their somnolence Mechanisms of Anesthesia 7 to the release of chloroform, another metabolite of the chloral hydrate. Unfortunately, when he failed to demonstrate this mechanism, Buchheim dropped the inquiry thereby missing the opportunity to introduce to clinical medicine the first synthesized . Credit subsequently went to Oscar Lebereich of the University of Berlin, who did recognize the clinical implications of the observation (28). Regardless, the story illustrates the shift in the approach to drug studies that was beginning to take shape. Oswald Schmiedeberg (1838-1921), a student of Buchheim, further developed the systematic study of drug action. Born in Dorpat, Schmiedeberg studied there at the University under Buchheim. Schmiedeberg then moved to Leipzig, where he worked with Carl Ludwig, one of the most influen• tial experimental physiologists of the nineteenth century. Schmiedeberg then returned to Dorpat, to take the chair once held by his mentor. Eventually, he too moved to the Kaiser Wilhelm Institute in Strassburg, where he ended his career (29-30). Schmiedeberg studied and anesthetics at several different times during his career. As a student, he measured chloroform concentrations in blood, thereby making some of the first ever measurements of this kind. Shortly after the synthesis of paraldehyde and urethane, he performed pharmacological studies of these drugs. When Schmiedeberg was director of the pharmacology department in Strassburg, Joseph von Mering, another member of the faculty, introduced barbituric acid to clinical medicine. Like Buchheim, Schmiedeberg trained many students who made their own mark on pharmacology. One of them was H. H. Meyer, co-founder of the Meyer-Overton theory of narcosis (31-33).

EARLY STUDIES OF MECHANISMS OF ANESTHESIA As experimental pharmacology flourished, so did studies of mechanism of anesthesia. Theories also became increasingly sophisticated as clinicians and scientists brought to the problem principles and methods of physiology and biochemistry. Readers interested in a critical analysis of experimen• tal data from this period should read the reviews by V. E. Henderson and G. H. W. Lucas (34,35). In the remaining part of this chapter we will summarize some of the major ideas from this early era. A popular and persistent theory attributed anesthesia to asphyxia. Initially, this concept arose among clinicians that observed the dark blood of anesthetized patients. They assumed a causal rela• tionship. As mentioned earlier, Claude Bernard squelched this idea when he pointed out that patients remain anesthetized even when their blood was not dark. He concluded, therefore, that the asphyxia must be "merely an incident, a complication of anesthesia that arises because of the way in which the anesthetic was administered" (21). Bernard's observation, though correct, did not dispel the idea. It simply reappeared in different forms. Some, noting a decrease in oxygen consumption and a rise in lactic acid and acetone, suggested that anesthesia might block a metabolic pathway. Others, who observed that the surface of the cortex turns pale during anesthesia, suggested that change in perfu• sion might limit the "asphyxia" to the brain. Over time each of these explanations lost favor. Claude Bernard himself attributed anesthesia to a reversible "semi-coagulation" of cellular com• ponents. In support of this idea, he and others pointed to the fact that blood may turn "cloudy" and cells may become opaque and their nucleus indistinct, when they are exposed to solutions of chloro• form, chloral hydrate, and morphine. This theory lost favor because the concentrations of drug needed to produce such changes far exceeded any dose used clinically. Perhaps it was coagulation and mechanical distortion of nerves that Pirogoff hoped to observe in his microscopic studies (35). Other investigators postulated that anesthetics cause cells to lose water, to the point that they shrink and become nonfunctional. Data supporting this idea came mostly from observations of microscopic alterations in protozoa exposed to anesthetics and from measurements of changes in their water content. Some investigators observed an inverse relationship between anesthetic potency and water solubility, although they were unable to suggest how this relationship might account for a loss of neurological activity. 8 Caton and Antognini

The enduring theory of anesthesia to emerge from this period related potency to lipid solubility. An antecedent of the idea actually appeared as early as 1847, when Bibra and Harless suggested a relationship between a tissue's fat content, and its susceptibility to anesthesia. However, it was H. H. Meyer, Schmiedeberg's student, and C. E. Overton who developed the principle independently, and announced it simultaneously in 1899. Like his mentor, Meyer served in Dorpat as professor of pharmacology. He then moved to the University of Marburg, and finally, to the University of Vienna where he became Chair of the Department of Experimental Pharmacology. Meyer developed his theory from work performed by three of his own students. They had been working with various narcotics for several years when he recognized: 1. That all fat soluble chemicals may act as narcotics in so far as they are absorbed; 2. That their effect is greatest in cells with the highest fat content; 3. That the activity of narcotics varies with their affinity to fat like compounds and to other constituents, such as water. Overton arrived at the same conclusion through botanical studies, his original field of work. English by birth, and a distant relative of Charles Darwin, Overton grew up in Switzerland. He trained in botany at the University of Zurich. His interest in anesthesia developed from studies of osmosis. Working with different organic compounds, he observed that many were capable of inducing "narco• sis" and that their potency was related to their lipid solubility, virtually the same conclusion as Meyer. Like Claude Bernard, Overton believed that narcosis was a fundamental biological phenomenon im• portant to plants as well as animals (32). To a large extent, theories of anesthesia that emerged in the 20th century represent an outgrowth of this early work (36). For example, whereas Bernard suggested that anesthetics "coagulated" nerves, a new generation of scientists suggested that they interfered with the movement of ions through "microtubules", or that that they altered surface tension at some critical site such as the extracellular/ cellular interface, e.g., the cell membrane. Later still, Nobel Laureate Linus Pauling postulated that certain anesthetics form microcrystals, or "clathrates," in the central nervous system (37). Mean• while, biochemists rephrased old questions as they discovered new mechanisms by which anesthetics might alter the metabolism of oxygen and other cellular processes. Similarly, anatomists revived Meyer-Overton's original hypothesis when they discovered that, for example, receptors interspersed in the bilipid layer of cell membranes (38), might be a site of action of inhalation anesthetics. The development of the MAC concept stimulated other research, in as much as it permitted investigators to compare equipotent concentrations of anesthetics, and evaluate factors that altered anesthetic requirements (39). Even this approach had pitfalls, however. Some investigators assumed a change in anesthetic requirement as evidence for a mechanism of anesthetic action. For example, some assumed that neuromuscular blocking agents had anesthetic properties because they depressed the muscular response to surgical stimuli.

CONCLUSION Speculation about mechanisms of anesthesia flourished during the last half of the nineteenth century. To a large extent, development of these ideas reflected changes in science and medicine. Starting with descriptive work, scientists progressed rapidly to an analysis of underlying chemical and physical phenomena. Perhaps no one stated the motivation of these early scientists better than Claude Bernard: "What should we think about the action of chloroform or ether on the central nervous cell? Any effect of whatever order on an anatomical unit can take place only through a physical or chemical modification of the unit. Nowadays, it is no longer acceptable to hypothesize about mysterious actions dubbed vital. Use of the word means that nothing precise is known about the phenomenon under discussion. At the present time, the physical or chemical phenomena underlying toxic effects have been precisely delineated in a few cases. As an example, carbon monoxide acts on the red cell Mechanisms of Anesthesia 9

by combining chemically with the hemoglobin. Chemical demonstration of the action is easy in this case, and one can reproduce the reaction with hemato-globin outside as well as inside the organism. We have not advanced as far as that in regard to the action of anesthetics, but arguing from a careful analysis of the facts, we may be able to form a fairly clear idea of the physio-chemical action which they have on nerve units" (21 J. In half a century, scientists did just that. Many current concepts of the mechanism of anesthetic action originated during this period. To a large extent, progress since that time has been shaped by the modification of these original ideas by more complex and sophisticated methods of study. REFERENCES 1. Caton, D. (1985) The secularization of pain. Anesthesiology 62, 493-501. 2. Smith, W. D. (1979) The Hippocratic Tradition. Cornell, Ithaca. 3. King, L. S. (1978) The Philosophy of Medicine: The Early Eighteenth Century. 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