My anesthetic career began in 1952, between my first and second years of medical school. This coincided with the introduction of the first modern inhaled anesthetics (those halogenated with fluorine). The earliest of these was fluroxene, an ethyl vinyl ether released for use in 1953. The primary advantage of fluroxene was that it didn’t explode, a considerable clinical advantage over the earlier anesthetics with the potential to blow up the operating room. Fluroxene was eclipsed in the mid-1950s by halothane, an ethane synthesized by Suckling for Imperial Chemical Industries (later renamed ICI). Suckling only made 12 target compounds. By pharmaceutical standards, Suckling was either very clever or very lucky to find a blockbuster new drug from just 12 targets. Most such discoveries require synthesis of a thousand or more compounds!

I first saw halothane when it was introduced at the University of Iowa during my residency (1956-1958) for a clinical trial. The clinical benefits over fluroxene and ether were immediately obvious: halothane was highly potent (MAC = 0.75%), nonpungent, and had more rapid pharmacokinetics because of its lower solubility. Halothane quickly displaced ether at Iowa (and worldwide). In the following decades, halothane became the anesthetic against which every subsequent new anesthetic was to be compared. Halothane was also the exemplar anesthetic for studies of cardiovascular, respiratory, and other basic physiological effects of volatile anesthetics.

As mentioned in Chapter 7, halothane and I became fast friends. Halothane was the anesthetic against which I tested my theories of anesthetic potency, solubility, and the physiology responsible for anesthetic uptake and distribution. Halothane participated in my discovery of MAC, a fundamental property of inhaled anesthetics. Nearly all of what I know about inhaled anesthetics I learned from halothane.

The commercial success of halothane prompted competition for even better inhaled anesthetics. The first candidate was methoxyflurane, introduced in the early 1960s. Methoxyflurane never gained popularity because it was quickly demonstrated that it could injure the kidney. Additionally, the kinetic properties
of methoxyflurane were slower than halothane, and the slower uptake and distribution was not acceptable to clinicians who had become accustomed to the rapid onset and offset of halothane.

However, evidence was also emerging that halothane had rare but potentially life-threatening toxicities. In one of our early clinical studies of MAC,¹ one patient turned yellow a few days after the study. The clinical picture was acute hepatitis. However, there was no reason for this patient to develop acute hepatitis. We speculated on whether halothane might occasionally cause acute liver injury. Similar observations were being made by other clinicians, and occasionally the patients died from fulminant hepatitis after receiving halothane. The common thread was that the patients had always had a previous anesthetic with halothane. This suggested an immune mechanism, with the patient initially developing an immunological response to halothane. In such patients, a subsequent exposure triggered an immunologically mediated hepatotoxicity. As the evidence for “halothane hepatitis” became incontrovertible, a race was on to find something that retained halothane’s desirable pharmacokinetics, but without the hepatotoxicity.

Ohio Medical Products (OMP) was one of several companies competing to find a replacement for halothane. OMP introduced one of the first fluorinated hydrocarbons, fluoroxene, in 1951. Fluoroxene failed commercially, being somewhat flammable, but the company maintained an interest in the field. In the 1960s OMP had hired Jim Vitcha to lead their anesthetic research program. His goal was developing a new inhaled anesthetic, one that would be better and safer than the then dominant halothane. Maybe Jim had followed my short career or maybe he had asked for a recommendation for someone young and knowledgeable about inhaled anesthetics. I never knew. For whatever reason, he approached me, asking if I would like to advise Ohio Chemical Co. in its task. I didn’t realize that he was asking me to be their de facto Medical Director. I said yes, beginning a half-century relationship that drew me into adventures and opportunities I never would otherwise have had.

Jim had the good sense to hire a brilliant and unassuming young fluorine chemist, Ross Terrell, to find a drug that met the high standards set by halothane, but without hepatotoxicity. Ross genius was figuring out how to synthesize peculiar fluorinated compounds. Ross synthesized more than 700 novel compounds in his search for a replacement for halothane.² The first of these to advance beyond laboratory trials was enflurane, an ethyl methyl ether. Enflurane was approved by the FDA in 1972, just as we were completing our basic work into the uptake, distribution, and biological effects of inhaled anesthetics.

I joined others in evaluating the anesthetics Ross made. My colleagues and I arrived too late to make a significant contribution to the study of enflurane. However, Ross had started working on another molecule, 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether (Figure 12.1). This molecule would eventually become known to the anesthesia community as isoflurane.

Ross and his colleagues turned to our laboratory at UCSF to study isoflurane to characterize the potency, solubility, and the rates of uptake and distribution that we had defined for halothane and methoxyflurane. I was thrilled! There had been three reasons I had developed these concepts early in my career. One was that John Severinghaus had posed tough questions, and I needed the mathematics to answer them. A second reason was to guide clinical care. I knew that a patient’s life hung in the balance, based on the clinician’s skill with anesthetic drug administration. Knowledge was power in the hands of the anesthesiologist. My third reason was that I wanted to apply these concepts to develop the next generation of anesthetic drugs. Ross gave me that chance.

We defined many of the properties of isoflurane in humans, including isoflurane’s potency (MAC),³ and its cardiovascular,⁴,⁵ respiratory,⁶,⁷,⁸,⁹ electroencephalographic,¹⁰ and neuromuscular¹¹ effects, including the capacity of isoflurane to augment the paralysis produced by neuromuscular blocking drugs.¹²,¹³ Comparing isoflurane and halothane in humans, we found that isoflurane had advantageous effects on postanesthetic mentation.¹⁴ Unlike halothane, isoflurane did not predispose to ventricular arrhythmias.¹⁵ We showed that isoflurane had more desirable kinetic characteristics, and that the liver of swine minimally metabolized isoflurane.¹⁶ We found little or no toxicity in humans anesthetized with isoflurane versus other inhaled anesthetics for several hours, including hours at deeper levels of anesthesia.¹⁷

Isoflurane demonstrated remarkable chemical stability, with virtually no evidence of metabolism. It had become clear that a trifluoroacetate metabolite mediated halothane’s hepatotoxic effect. Given this, isoflurane’s resistance to metabolism seemed particularly advantageous.

Our repertoire of clinical assessments grew, reflecting the expanding scope of anesthesia practice. We studied the effects of isoflurane on uterine tone, demonstrating that it increased uterine bleeding during abortions.¹⁸ In vitro tests of Staphylococcus aureus demonstrated that modern potent inhaled anesthetics (including isoflurane and halothane) were lethal to S aureus at test vapor pressures that exceeded 35 times MAC.¹⁹ At least some bacterial pathogens were unlikely to survive in a vaporizer charged with liquid isoflurane.