As the 1960s began, anesthesiology worldwide was a specialty short of trained physicians. In the US, fewer than 2500 board-certified anesthesiologists served a country of 180 million or approximately 1.4/100,000 population. Many US medical schools had anesthesia divisions rather than departments, divisions housed within departments of surgery. Most were consumed by large clinical responsibilities. Only a handful of academic departments (e.g., Harvard, Columbia, Pennsylvania, Iowa, Wisconsin, UCSF, University of Washington) supported research activities with mature trained investigators. Fewer yet had NIH-supported research grants. There were hardly any trained subspecialists. This began to change in the 1960s, starting a transformation of the specialty in the US from one dominated by empiricism to one employing the tools of modern science, spreading its clinical involvement from the operating room to the delivery suite, intensive care unit, post anesthetic care unit, ambulatory surgery suite and acute and chronic pain management departments.

Between 1960 and 1971, 15 new university departments headed by chairs, were established in GB. While clinical anesthesia was their primary responsibility, several of these became the spearheads of research, encouraging higher academic qualifications. In 1968, the Anaesthetic Research Society was formally established out of a less formal group that had begun in 1958.

In the 1960s, research in anesthesiology was largely “phenomenological” (a term now considered pejorative), observational studies lacking a mechanism explaining the cause of the observation. The titles of typical research papers began with “The effect of” rather than “Here is the reason for the effect of”. But “we needed to walk before we could run”. We first needed to provide observations. These would lead to questions such as why and how.

A confluence of factors was needed to enable the first steps. These included devices capable of accurately and rapidly measuring small amounts of anesthetic drugs, research funds sufficient to support talented but unproved academics who were freed from clinical responsibilities, and prescient department leaders in and out of the specialty who recognized the need to develop a scientific base leading to important questions. IS Ravdin, a surgeon at the University of Pennsylvania, had addressed this issue nearly 20 years earlier. stating that “While the importance of the technical advances in a young field is not to be minimized, it is the fundamental contributions which lead to a better understanding of anesthesia that will mark the real maturity of anesthesiologists [9].” Robert Dripps, Chairman of Anesthesia also at the University of Pennsylvania, stated in 1949 that “Talented young men in the specialty of anesthesiology must be encouraged and supported if their inclinations are toward investigation” and “once trained, these young scientists will require budgets, laboratories, and time free from clinical responsibilities [10]”. Finally, in an editorial in 1950, Salter (a non-anesthesiologist) stated:

“There must be trained a group of so-called academic anesthesiologists. They must have the special training and sufficient leisure to advance the basic concepts of applied science. They must not be run ragged with routine assignments but must be protected from the irate surgeon who demands “service now” in the name of all humanity and the trustees”. [11]

Although several factors accounted for the delayed development of anesthesiology as a specialty in Asia and much of Europe, the factor that was undeniably of greatest importance was World War II, with its horrific devastation, millions killed, destruction of physical and governmental infrastructure, and the resulting revisions of social order and scientific institutions’a complete reordering of society. With democracy replacing authoritarianism in Japan and German speaking countries, virtually every institution required restructuring. Combined with the fact that the specialty had been slow to develop before the war, these factors delayed its development until nearly the 1960s. For example and as nicely described by Goerig in Chapter29, up to the 1950s, tracheal intubation was still performed digitally and under topical anesthesia and it was not until the clinical use of muscle relaxants well into the 1950s that laryngoscopes were used. Goerig observed that in 1959, German nursing authorities officially refused to perform “intravenous anaesthesia methods, intubation procedures, controlled ventilation or use of curare”.

In Japan, the specialty was slow to develop, partly because of the impact of World War II and partly because anesthesia even by the middle 1950s was not considered a recognized specialty. Of importance was the number of leaders trained in the US in the 1950s, returning to Japan as professors in key universities. Suwa notes (Chapter31) that this system initially allowed permanent qualification as a specialist following two years of training and/or experience administering general anesthesia to 300 patients. This has changed to a far more demanding system today.

In the 1920s, Haggard investigated the absorption, distribution, and elimination of diethyl ether in dogs [12,13], and 30 years later Severinghaus measured nitrous oxide uptake in humans [14]. Those were the sum of the pharmacokinetic work up to the 1960s, work that dominated much of research in anesthesia in that decade. Some might add that the great Seymour Kety supplied the first paper explaining the pharmacokinetics of inhaled anesthetics [15], but he missed the importance of the differential distribution of tissue blood flow. In 1960, Henry Price published the first pharmacokinetic paper providing insight into why drugs distribute as they do, using a physiological-anatomical model. Price described the distribution of thiopental in humans (Fig. 9.3) [16], in the process correcting Kety’s error.

Now go back two decades. The attack upon Pearl Harbor in 1941 killed thousands of Americans. It was asserted (apocryphally) that more deaths resulted from intravenous thiopental than from bombs or other projectiles. The simulation provided by Price explained this statement. Traumatic injury and blood loss decreased the volume of the central blood compartment. Thiopental injected into this smaller volume would produce a greater concentration which, when delivered to highly perfused tissues (viscera such as the heart and brain) would result in greater anesthetic depth, cardiac depression, hypotension…and death. This simple explanation would apply to any intravenous medication and was a cornerstone of non-inhaled PK principals over the remainder of the decade. Obviously, this effect could be mitigated by decreasing the dose, and or restoring blood volume with blood transfusion and or intravenous fluid.

However, while the theory may have been convincing and the explanation logical, it appears that the facts conflicted with both. In Chapter47, Paul White comments that: “…an analysis by FE Bennetts suggested that…despite shortages of oxygen and transfusion supplies, thiopental caused few deaths [17].”

Early in the 1960s, interest in pharmacokinetics flourished. The 1962 symposium on this topic sponsored by the New York Academy of Medicine and the National Research Council-National Academy of Sciences, illustrates the intense focus. Thirty five scientists from around the world (four from the UK, one from Canada, and the remainder from the US) presented the results of largely unpublished research, using measurements and simulations to define what was then known about the pharmacokinetics of inhaled and intravenous agents [18]. The simulations might apply electrical analogs or complicated mathematical models. The contributors speculated on and provided indirect evidence for the inter-tissue diffusion of inhaled anesthetics. They set the stage for further measurements and simulations that continued for the next four decades. For the inhaled anesthetics, research was initially dominated by researchers at UCSF led by Edmond Eger and his many colleagues and trainees in the US, Europe, and Asia. The results from these studies informed our understanding of clinical pharmacokinetics for the subsequent 40 years. Many of the ideas were gathered in Eger’s 1974 book, Anesthetic Uptake and Action [19].

Before the 60s, empiricism ruled both practice and research in the specialty. Little could be measured accurately, and clinical experience rather than evidence based medicine drove clinical care. A typical anesthetic, reflecting the changing nature of the specialty between 1950 and 2013, for an adult in the US, undergoing major abdominal or thoracic surgery is described in Chapter7. The amount of inhaled agent delivered was driven by the vital signs and surgical requirements such as control of blood loss or the relaxation required to perform surgery. But what was the needed dose/concentration, and how did one define “needed”? How did altered physical status, associated co-morbidities, and physiological changes (e.g., body temperature or blood gases) influence this dose? Up to the late 1950s, the volatile anesthetic dose could not easily be measured, and an agreed upon response was not available. Should it be a change in blood pressure or pulse rate or respiratory rate? Of course, patient condition and surgical circumstances would affect these responses. On the other hand, how about an end point that everyone could agree upon, one that made clinical sense? And thus was born MAC’the minimum alveolar concentration preventing movement in response to a noxious (surgical incision) stimulus’perhaps the most utilized metric of anesthetic dose ever! A bit of irony’the study first describing MAC used both halothane and halopropane’the latter an anestheticnever released for clinical use [20].

Edmond (Ted) Eger trained in anesthesia at the University of Iowa, and following two years in the US Army stationed at Ft Leavenworth Kansas, joined Stuart Cullen and John Severinghaus in the anesthesia department at the University of California San Francisco (UCSF). Eger’s interest in pharmacokinetics, and ultimately MAC, began in 1957 while he was a first year resident. Severinghaus (then a second-year resident at Iowa) lectured on the uptake of inhaled anesthetics, using Kety’s ideas and Severinghaus’ results from his study of nitrous oxide uptake. He said that uptake of greater amounts of anesthetic (as with the highly soluble anesthetic ether) would slow the induction of anesthesia. To Eger (and most anesthesia residents yet today hearing this for the first time) it seemed obviously incorrect. A greater uptake would deliver more anesthetic to the blood and brain, so how could Severinghaus be right? Eger argued with Severinghaus for an hour after the lecture, but Severinghaus wouldn’t budge. Higher solubility, greater uptake, slower onset of action. It just didn’t seem correct…but it was. Severinghaus was always correct.

And now Eger was hooked. The more he thought about the reason that ether acted slowly, the more he was drawn to the beauty of the relationships that led to that idea. He spent days, weeks, and years dreaming about the relationships. Finally, it was time to put pen to paper. During his two years in the US Army (1958-1960), Eger used algebra and iterations to develop his descriptions of inhaled anesthetic pharmacokinetics. Along with parallel ideas from others in the field, Eger’s thoughts opened a new era of understanding as to why we do what we do, and how to logically conduct inhaled anesthesia taking into account hemodynamic and respiratory perturbations. The ideas and thoughts opened new ways to assess the worth of new inhaled anesthetics prior to FDA approval. The principles elucidated over this decade revised the way in which anesthetics were administered, and more importantly, enhanced understanding of pharmacokinetics by those responsible for delivery of anesthesia.

Equally important and influential was the development of the above-noted MAC by Eger and his colleagues (Fig. 9.4). The two crucial components in the definition of MAC were “alveolar” concentration and “muscular response” to a noxious stimulus such as a skin incision. Alveolar concentration (or its surrogate, partial pressure) was crucial because it approximated the anesthetic partial pressure in arterial blood, that in turn is presumed to approximate the partial pressure at the anesthetic site of action preventing movement in response to surgery. While this site of action was initially opined to be the brain, subsequent findings by Antognini and Schwartz at UC Davis [21] and Rampil et al at UCSF [22] established the spinal cord as the major site of action.

Movement was the second crucial component of MAC because preventing movement is the principal responsibility of the anesthetist to both the patient and to the surgeon. And it was an easily recognized and unambiguous response occurring in every experimental subject and species (avoidance to noxious stimulation), and was thus as applicable in the laboratory as it was in the operating room.

MAC-related research quantified clinically important physiological and physical effects of inhaled anesthetics. In particular, it allowed a comparison of these effects by different agents at multiples of equipotent concentrations, with the reasonable assurance that the results of a study performed at one site anywhere in the world could reasonably be compared with results performed elsewhere, as long as the MAC multiples were the same. Similarly, employing MAC as a measure of anesthetic depth simplified the study of new anesthetics. This meant that when enflurane (late 1960s), isoflurane (1980s), sevoflurane and desflurane (1990s) were released for clinical use, similar studies at similar anesthetic depths had been performed at different institutions with reasonable assurance that nearly identical conditions had been present for each agent.

The first study measuring MAC in humans was conducted at UCSF in 1962-63 using surgical patients anesthetized with halothane with or without nitrous oxide or opiate premedication [23]. In each patient a predetermined alveolar concentration was achieved and held steady for at least 15 minutes prior to the skin incision to allow equilibration of the end-tidal anesthetic concentration to its site of action in the central nervous system. Following incision, the patient was observed for purposeful movement. MAC was based on the combined responses from a group of patients. The investigators decided to validate the accuracy of this measurement by studying the response of four patients, each serving as their own control. In these patients, following induction of anesthesia with halothane and oxygen, needles were inserted subcutaneously in the forearm and attached to a stimulator that could provide a supra-maximal stimulus. Similar to the method described above, once a predetermined alveolar halothane concentration had been achieved, the stimulus was applied and the response’movement or not’was noted. If movement occurred, the alveolar concentration was increased in steps until movement was abolished, and the process repeated in the opposite direction. Thus several “cross-overs” were achieved and the midpoint of the concentrations allowing and preventing movement was designated as MAC.

The first patient studied was an obese (BMI 33) 47 year-old man scheduled for repair of a ventral hernia by a surgeon noted for his insistence on profound muscle relaxation. After completing the MAC study, Saidman and Eger relinquished care of the patient to the resident and staff anesthetist and departed for the lab. However, shortly after, they were recalled to the OR because the patient’s temperature had increased. Temperature was not routinely monitored in 1963, but fortuitously and fortunately it was monitored in this case because of the MAC determination. Although a succinylcholine infusion had been and was being used, the surgeon complained that abdominal rigidity interfered with his work. The patient was sweating and breathing deeply, the color of the carbon dioxide absorbent indicated exhaustion, and the succinylcholine infusion was running rapidly. The temperature of the patient now exceeded 107 F, ultimately increasing to 108.5 F. One of the original blood-gas machines assembled by John Severinghaus and Freeman Bradley [24] was available and an arterial sample revealed a pH of 6.82, a pCO₂ of 179 mmHg, a pO₂ of 143 mmHg and a severe metabolic acidosis (base deficit’14.3 meq/L). Blood pressure decreased from 110/70 mmHg to 40/0 mmHg and was treated with metaraminol. The surgeon was asked to quickly complete the procedure, the patient was packed in ice, 3000 ml of lactated Ringer’s solution were rapidly infused, and bicarbonate was given to correct the metabolic acidosis. Within 30 minutes, the temperature decreased to103 F and in another 30 minutes to 97.2 F. The blood pressure increased to 110/70 without further therapy, and the patient survived without any apparent neurological deficit. Dantrolene, a muscle relaxant presently used in the management of malignant hyperthermia, was not available in 1963.

This case was presented before the anesthesia section of the 1964 AMA meeting held in San Francisco and when the moderator queried the audience if any had experienced a similar case, several replied that they had in patients who, similarly, had also been anesthetized with halothane and paralyzed with succinylcholine. This patient had likely suffered from malignant hyperthermia and provided the first ever determination of the metabolic aberration associated with this syndrome [25]. An earlier paper by Denborough highlighted the fact that a similar syndrome had been noted in many relatives (some of whom had died) within a family. Because the title of the paper did not mention temperature, it escaped notice when the UCSF patient was being reviewed [26].