An early illustration of the physician-industry interaction arose in the second half of the nineteenth century. Ether had been discovered by Lully in 1275 CE and Morton in 1846 demonstrated its anesthetizing effect. At the time, Jackson cautioned Morton to use a pure ether [1]. Physician Edward Squibb noted this need for ether and other medicines, leading to the 1858 formation of Squibb Pharmaceutical (see uab.edu/Reynolds/cwfigs/squibb). Squibb’s contribution (so they said) was to make ether more pure “using an improved production method”.

Another early example of a contribution by industry followed progress in the iron and steel industry and the invention of the high pressure gas cylinder in the late nineteenth century. Today, we take for granted the availability of compressed gases for anesthesia, but this was not the case for several decades following the discovery of ether anesthesia. US industrial gas companies were started in the early 1900s, stimulated by the French discovery of new methods of producing various gases at lower cost. Some of these gas companies subsequently developed and manufactured anesthesia equipment and accessories (e.g., Air Products, Puritan Bennett, Airco-Ohio Chemical and Surgical Equipment, and National Cylinder Gas.) In Great Britain, Coxeter and Sons were the first to supply compressed nitrous oxide in steel cylinders. Later, they developed high pressure cylinders for oxygen and until about 1950, were a significant manufacturer of anesthesia equipment of all types.

High-pressure gas cylinders (tanks) solved the problem of storing large amounts of gas in a conveniently small space, but imposed a new problem: how to deal with the huge pressures within the tanks. A full tank of oxygen might have a pressure of 2,200 pounds per square inch, the pressure produced at nearly a mile’s depth in the ocean. The development of the tanks also prompted the development of reducing valves and metering devices. To these, manufacturers added tubing, fittings, and masks, all eventually leading to the anesthesia machine.

Along, the way, manufacturers realized the necessity of standards and regulation to make devices safe, consistent, and interchangeable. Standards associations, and groups such as the National Fire Protection Association (formed in 1896), Food and Drug Administration (1906), US Compressed Gas Association (1913), and American Standards Institute (1918) “fit it all together”. The chaos of World War II galvanized the effort to improve safety via standards. Anesthesia equipment sent to war zones agonizingly illustrated the dangerous incompatibility of equipment provided by different manufacturers. To preclude operating room fires and explosions, the National Fire Protection Association specified guidelines that would prevent sparks and ignition of flammable inhaled anesthetics in 1941. These developments illustrate the inability of industry and the anesthesia profession to separately deal with joint problems, and the need for such associations and regulatory organizations.

On the other hand, the Pin Index Safety System and Diameter Index Safety System, developed in the 1950s, exemplify successful industry-sourced safety efforts. These systems prevented misconnection of gases to equipment. Prior to their introduction, patients had been killed or injured by mistakes such as connection of a tank of nitrous oxide to a fitting intended for oxygen. Wayne Hay and Harold May invented these safety systems while employed at Ohio Medical and Surgical Equipment Company. The patents were donated to the Compressed Gas Association, thereby facilitating universal use by all manufacturers.

The history of nitrous oxide illustrates the early role of industry in the world of anesthesia. We take the availability of this useful anesthetic for granted, but it wasn’t until near the end of the nineteenth century, that industry supplied the wherewithal needed for the practical delivery of nitrous oxide. Large-scale production of nitrous oxide was a daunting task, especially so in the decades prior to sophisticated process control systems. The widely used and economical method involves heating ammonium nitrate to 200°C, a potentially dangerous process because the process is exothermic (generates heat), and at a somewhat greater temperature, the ammonium nitrate explodes. In 1947, the French registered vessel, SS Grandcamp, with approximately 2,300 tons of ammonium nitrate aboard, caught fire in the port of Texas City. The resulting explosion and onshore fires destroyed Texas City, killing nearly 600 people [2].

Similarly, explosions have occurred at nitrous oxide manufacturing facilities, in some cases causing loss of life. In the 1950s, an explosion occurred at an Ohio Chemical and Surgical Equipment-Airco plant in Montreal, fortunately at night’thus sparing loss of life and injury. However, in the 1980s, an explosion occurred at an Air Products nitrous oxide production facility, resulting in a few fatalities. Ohio Chemical had located a nitrous oxide manufacturing facility at the corner of 10th and Mason in San Francisco, but the San Francisco city fathers remembered the great Texas City explosion. No nitrous plants in the city! An abbreviated daily production system was employed, until the facility relocated to an industrial site in the intrepid town of Berkeley.

The commercialization of nitrous oxide manufacturing required industry to manage the cost and deployment of heavy steel cylinders. Fortunately, nitrous oxide compresses to a liquid at moderate pressures. A cousin of Edgar Allen Poe converted this knowledge into a commercial process in the late nineteenth or early twentieth century in Trenton, New Jersey, but a half-century passed before the implementation of bulk delivery/storage of nitrous oxide at large hospitals. Some hospitals used nitrous oxide in such large quantities that it was economical to take it from the production plant in a bulk tank truck, in liquid form, and transfer it to a bulk liquid storage tank at the hospital, much like the liquid oxygen systems used today.

The memoirs of the dentist, Jay Heidbrink, read at the American Dental Society of Anesthesiology in 1957, testify to the challenges of administering nitrous oxide anesthesia to dental patients in the early 1900s. Heidbrink describes patients who fought with him, one for three bouts, before being subdued or anesthetized! Stimulated by such events he tinkered with an anesthesia machine purchased from Charles Teter in Cleveland, in 1903. The machine apparently provided an inaccurate mixture of oxygen and nitrous oxide, and Heidbrink made improvements to correct the problem. Local Minneapolis physicians and dentists asked him to make machines for their practices. A local machine shop quoted a price of $600 per unit for Heidbrink’s device. A second shop asked for $1.00 per pound or $32.00 total. This machine was called the “Model A,” and the Heidbrink company was “off and running.” His company later became part of “Ohio Chemical and Surgical equipment,” with numerous company names to follow.

Of note was the contribution of Elmer McKesson, an anesthesiologist who in the 1910s developed the “McKesson” anesthetic machines, machines particularly devoted to administration of high concentrations of nitrous oxide [3]. McKesson advocated induction of anesthesia with 100% nitrous oxide. When cyanosis became profound, McKesson machines allowed use of a flush valve that would add enough oxygen to prevent death. The combination of nitrous oxide and transient hypoxia was sufficient to anesthetize patients for brief procedures (e.g., dental extractions). The flush valve was McKesson’s lasting contribution to anesthesia. McKesson is an example of the physician-industrialist of a different era. McKesson ran courses for visiting anesthetists, to teach them how to use his machines and learn basic engineering skills, so that they could repair the machines.

In 1951, Charles Suckling, a chemist at Imperial Chemical Industries (ICI) in Cheshire, England, began work leading to the synthesis of halothane and the world of modern inhaled anesthetics [4]. Pharmacologist James Raventos (1905–1982; Fig. 66.2) tested halothane in animals, finding that it had the desirable properties needed for an inhaled anesthetic’absence of flammability, absence of pungency, high potency, and no obvious toxicity (unlike chloroform, its nonflammable competitor) [5]. Halothane became a smash hit, making millions for ICI, and changing the face of anesthesia from the late 1950s. It wasn’t perfect however, as suggested by increasing numbers of reports of hepatotoxicity, starting in the 1960s [6]. The story goes back now to Ohio Chemical.

In 1906, Justin Scholes founded Ohio Chemical Corp in Cleveland, Ohio. The company developed or manufactured ether and other anesthetic compounds for several decades, with cyclopropane and nitrous oxide being the mainstays for much of its early history. Research at Ohio Medical led to the discovery of several widely used inhaled anesthetics. Around the time of World War II, Airco bought both the Heidbrink Company and Ohio Chemical. The combined entity, Ohio Chemical and Surgical Equipment, continued the development of anesthesia apparatus and inhalation products. Today, GE Medical owns much of the equipment portion of Ohio Medical.

Julius Shukys, at Ohio Chemical, synthesized fluroxene, an ethyl vinyl ether in the late 1940s. It was released commercially in 1953, before the introduction of halothane [7]. Another early fluorinated ether discovered by Ohio Chemical, was Indoklon, a convulsant hexafluorodiethyl ether, marketed in the late 1950s as a substitute for electro-shock therapy. However, a convulsant anesthetic is hardly saleable to most anesthetists, and fluroxene couldn’t compete with halothane. Other fluorinated ethers had more promising characteristics. These were developed in the 1960s by fluorine chemist Ross Terrell and his small group of colleagues working in Airco’s Central Research Laboratories in Murray Hill, New Jersey, rather than at the Ohio Chemical facilities in Cleveland. Terrell et al. would synthesize more than 700 compounds in their search for the perfect inhaled anesthetic. They never found that, but they came close enough, producing the dominant inhaled anesthetics from 1970 to the present [8–10].

A key element in Terrell’s program was the establishment of a means to measure the quality of the anesthetic effects produced by his compounds. Accordingly, Ohio Chemical developed a relationship with John Krantz, the chair of Pharmacology at the University of Maryland. One of his graduate students, Freida Rudo (1924–1996) became expert in “screening” the experimental compounds discovered by Terrell and his team. Terrell’s program was small in staff and budget, so having an economical means of preliminary animal testing was critical to success. Great expertise at bargain basement price was needed. Each mouse tested was a noted budget expense, and did double duty by serving as a meal for the University of Maryland’s snake collection.

Rudo was a favorite with her University and Industry colleagues. She had reportedly won first place in a Miss Puerto Rico beauty contest. Add her personal presence, her statesmanship and her pipe smoking, and she was a memorable personality. She evaluated each new putative anesthetic by placing a few drops of the compound in a one quart Mason jar containing one scrambling mouse. She then observed respiratory and cardiovascular responses (Did the mouse stop breathing? Did it die?), the ease and rate of induction, rigidity and convulsions. She recorded her data on 3×5 note cards, an effective if now antiquated data and lab notes management system.

Terrell became an industry legend for his record of successes in inhalation anesthetic discoveries. He synthesized, and Rudo tested, enflurane, isoflurane, sevoflurane and desflurane, in addition to several hundred undeserving compounds. A success rate this great is rare in the pharmaceutical world.

Ohio Medical’s clinical and regulatory expertise was modest, especially at the time of the development of their first anesthetic, enflurane. At the outset, Ohio looked for guidance from members of the anesthetic community. In the 1960s, James Vitcha (see below) sought out a surprised Edmond Eger, asking him if he wanted to be involved in Ohio’s studies of new anesthetics. Eger remembers that he (Eger) quickly wrote a stellar grant for several hundred thousand dollars and was rewarded with a dinner at Toots Shor’s, where Vitcha diplomatically told him that his application was rejected. Eger got it anyway; it just took much longer than he had expected. Eger became involved in the clinical trials for all of the anesthetics that Ohio brought to the market. He was especially effective in arguing for the development of desflurane, noting the need for faster acting anesthetics in a world increasingly focused on ambulatory anesthesia/surgery. The anesthesia community, and especially Eger, played the role of “Medical Director.” This was possible in the regulatory world of the last half of the twentieth century, again illustrating the effective relationship between industry and physicians and academia in that era.

James Vitcha had long worked for Ohio Medical, in various capacities in the anesthetics programs, and took on the role of coordinating the clinical studies and preparing in large part, the New Drug Applications for enflurane and isoflurane. He organized clinical anesthesia researchers effectively, created a strong information base for the products upon market introduction, and provided the FDA with information needed for approval reviews.

Vitcha’s real role at Ohio Medical/Ohio Chemical/Anaquest, was that of the grain of sand in the oyster leading to the formation of a pearl. Ohio Chemical was poorly equipped in both technical and business experience, to deal with the pharmaceutical world. Jim often threw caution and career future to the wind in arguing for the inhaled anesthetic program, persuading many doubters within the Ohio Medical management team. He followed that with a clinical studies program and FDA submissions effort that was impossible by later standards. Were it not for his unique persistence internally, important inventions might never have seen the market place, or would at least have been delayed for several years.

Although the road from laboratory to marketplace for new compounds was shorter in the 1970s than in the twenty-first century, some unanticipated obstacles impeded progress. The obstacle with halothane was its rare capacity to injure the liver [6]. Enflurane, the 347th compound made by Terrell, had minimal hepatotoxic effects [11], and that advantage gave it a competitive edge over halothane. By 1970, enflurane had largely replaced halothane in the US. However, enflurane had its own problem, the capacity to produce seizures [12]. The incidence of seizure activity with enflurane was low and the number of patients exhibiting seizures was small. Moreover, there were no reports of residual damage from the seizures. The FDA chose a middle of the road solution to this situation. They approved enflurane for sale, on the condition that the package literature fully describe the risk, and that a “ phase 4” study comprising a complaint form be included in the package literature, to be used by anesthesiologists for reporting seizure incidence.

It was clear that the FDA was anxious to have an alternative to halothane, and apparent that they had confidence in the physician’s ability to observe and report the condition, to the extent that it was a limitation. This study did not provide alarming findings, and enflurane continued to be widely used.

As indicated above, enflurane largely replaced halothane in the US and some other developed countries (except for anesthesia in children) because enflurane had fewer effects than halothane on the liver. But enflurane was also attacked for its capacity to injure the liver, albeit with a much lower incidence than occurring with halothane [11]. Isoflurane was also tarred with this brush [13]. Anaquest asked Eger to examine each of the rare reported cases of hepatic injury, finding in some patients, that the injury resulted from an infection by a herpes virus [14,15]. Overall, we were impressed with the small degree of metabolism of isoflurane, and therefore decided to fully investigate and resolve reports of ‘toxicity’ in patients as they arose, thinking that other causes would most likely be ruled in and isoflurane toxicity ruled out. At worst, no specific cause would be proven or found, and as such, the overall results would keep the product in good stead in the eyes of clinicians. I suppose we were thinking that one patient did not a side effect make.

Sebastian Reiz’s 1983 suggestion that isoflurane caused “coronary steal” was a larger concern [16]. This issue had been studied by prominent investigators and was added to the package label. We asked Eger and Cahalan to visit Reiz in Umea, Sweden. Eger remembers it being one of the coldest places he’d ever been, and that Reiz offered him some wild mushrooms to eat (Eger declined). My recollection is that “steal,” while not completely irrelevant, did not significantly influence isoflurane usage. The millions of patients, seemingly safely given isoflurane, continued to pile up and significant side effects from any one cause became statistically more remote.

But we’ve gotten ahead of our story in telling of isoflurane’s development. Enflurane was good, but far from perfect, and Terrell and his group searched for something better. In initial trials with compound 469 (isoflurane), made by preparatory chromatograph (personal communication, John Wynne), Rudo found that isoflurane seemed superior in its overall properties. However, a problem in its manufacture nearly killed it. Several hundred pounds were required for additional animal testing, toxicology, and eventually human trials. Wynne was assigned to the process and scale-up work, but was unable to purify the crude final isoflurane to more than 97% by normal distillation. The problem was the boiling point of a contaminant compound, 1-chloro-2,2,2,-trifluoroethyl monochloro difluoromethyl ether, which at 53°C was too close to that of isoflurane at 48.5°C, to enable separation by simple distillation. Louise Speers saved the day, finding that isoflurane forms a high boiling azeotrope with acetone and has a lower volatility, while 1-chloro-2,2,2,-trifluoroethyl monochloro difluoromethyl ether forms a low boiling azeotrope with acetone which can be distilled from isoflurane. As an aside, note that two women, Rudo and Speers, led the way forward in this history of inhaled anesthetics, doing so during an era when female scientists were much less prominent.

Spears took pleasure telling of her interviews for jobs after completion of her PhD in chemistry at Columbia University. During that era, young single women needed a proper escort for their interview travels. Spears’ mother filled that role as best she could (I don’t think she attended the interviews, themselves). Fortunately for the anesthesia world, her trip from Columbia University to Murray Hill, New Jersey to be interviewed by Terrell was less than 50 miles, causing her to choose a career in anesthetic synthesis and azeotrope distillations!

The submission of the New Drug Application, for approval of isoflurane for clinical use, was a family business. Eger remembers Vitcha proudly talking about several feet of documents on his dining room table, he and his wife sorting and stacking. Isoflurane was his baby.

Towards the mid 1970s, it looked like clear sailing to an approval of isoflurane by the FDA, which had provided a preliminary “approvable” status letter. The celebrations inside Ohio Medical began. Human clinical testing had been well orchestrated by Vitcha and Eger (the shadow Medical Director-Consultant). Vitcha was a friend to numerous investigators in the anesthesia world, investigators providing input to the inhalation anesthetics program. His vigor outside the company was also used inside the company, to argue fiercely for additional funding for the anesthetics program. He usually got what he asked for (although complaining that it never was enough).

And then, isoflurane had an enormous setback. Tom Corbett, at the University of Michigan, had studied the potential of various compounds, particularly alpha chloro ethers to cause cancer [17]. Prompted by this, by considerable intelligence, and by a crusader’s zeal, Corbett had conducted a small test on mice which suggested that isoflurane (an alpha chloro ether) had carcinogenic properties [18]. Vitcha, Terrell, and Eger visited Corbett at his laboratory. Convinced that although Corbett’s study was fatally flawed (insufficient controls, absence of blinding, inadequate statistical analysis, and failure to use a comparator anesthetic), Airco had no alternative but to stop the release of isoflurane. Corbett had acted with the best of intentions, and with his findings in print there was naught to do but repeat what he had done, eliminating the flaws. Nonetheless, for a time Airco dithered on whether to challenge Corbett, eventually realizing that they would fight a losing battle. In the meantime (and unknown to us), Eger and Wendell Stevens’with Corbett’s help’set about duplicating Corbett’s study but correcting the flaws in that study. After several months of indecision, and discussions with the FDA, Airco finally asked Eger and Stevens to conduct the study that they had already set in motion.

So on went the experiment, while Airco and the FDA mused a bit more. And then Eger wryly remembered trouble. Vitcha called and said that the FDA and Anaquest would like to make a minor modification to the protocol’to extend the survival period after anesthetic exposure from 15 to 18 months. However, modification was not possible. The mice were in formaldehyde. There was no way they could grow for an additional three months. It was mea culpa time. So Eger and Stevens met with us and confessed their sins, adding that the data seemed to indicate that no inhaled anesthetic caused cancer. Eger remembers being embarrassed at having deceived me but tickled that he had gotten away with it until we asked for the modification. The final answer came after two years of study; isoflurane was exonerated [19].

A few interesting things resulted from this saga. The FDA enacted and then rescinded a rule specific to isoflurane’to withhold approval based on a flawed study. It was probably a stretch of their authority at that time to enact such rules, and it was discriminatory to isoflurane, relative to rules applied to inhaled anesthetics that followed. Faced with this rule stretching, and its effect to delay the release of isoflurane, we acted to extend isoflurane’s patent life. We engaged in lobbying, and I (RL) testified at a congressional hearing conducted by Congressman Kastenmeyer’s sub-committee on intellectual property. The life of only 2 patents had previously been extended. One was Ronson lighters; a bribed judge had ruled against their patent. Imagine this, he was in New Jersey! That happened in the first half of the twentieth century. The other patent extension applied to a sweetener that, like isoflurane, had been accused of causing cancer. Legislation extending the isoflurane patent life eventually was bundled into the legislation by Waxman and Hatch, restoring patent life of pharmaceuticals for the amount of time they spent in regulatory review. There was a quid pro quo for that legislation, making it legal for generic manufacturers to use patented processes in preparation for the generic production of products ahead of patent expiration. Prior to that, it was not legal for generic manufacturers to use a patented process ahead of its expiration. Waxman was anxious to have generic competition as early as possible, and manufacturers were anxious to have patent extension for testing period delays.

In 1981, the Ohio Medical Division of BOC placed its anesthetics business in a new division called Anaquest. Anaquest/Ohio Medical had one considerable success, enflurane, and another about-to-be success, isoflurane. These scientific, clinical, and financial achievements prompted and supported the 1983 commitment of BOC, to enormously expand the Research and Development arm of the general anesthetic business, then headed by Ross Terrell, a pioneer in the development of volatile anesthetics. The vision was to become the resource for all the major drugs used to provide the anesthetic state, specifically to invent premier opioids, local anesthetics, neuromuscular blockers and reversal agents. These would compliment Anaquest’s inhaled anesthetic offerings, meet the increasing demands of ambulatory surgery, and improve the care of anesthetized patients. It was an extraordinarily ambitious goal.

This goal radically changed Anaquest’s drug development program. The small, extremely productive activities of Terrell’s team of Speers, Halpern and a few others would be expanded several fold. Experts in pharmacology and toxicology would occupy a wing of rooms at BOC’s Murray Hill site in New Jersey. By 1984, it housed fifty scientists plus an accredited animal facility to evaluate new chemical entities (NCEs), including new volatile anesthetics. Ted Spaulding, from Hoechst-Roussel Pharmaceuticals joined with Terrell to head this endeavor, particularly to perform in house validation of the efficacy and safety of intravenous therapeutics. It was thought important to bring biology in close proximity to the expanded synthetic chemistry program. Even with this expansion, Richard Wynn, Frieda Rudo, and Paul Thut continued to test some NCEs in the Pharmacology Department of the School of Dentistry at the University of Maryland. Their experience with inhalation anesthetic and muscle relaxant pharmacology, their enthusiasm for the expanded program, and their role as “biology” teammates were crucial to the advancement of the program.

A parallel move was afoot. In 1984, Eger was asked to review the 700+ compounds that Terrell had made in the 1960s, to see if any might have desirable anesthetic qualities that had been overlooked. Consulting with Terrell (who had no memory of their discussions), Eger searched among a subgroup of ether molecules that were halogenated solely with fluorine atoms, believing that these would have the requisite properties of stability, low solubility, and good anesthetic profile as suggested by the tests performed by Rudo. He found 4 molecules worthy of further testing, but only one passed the test of stability. Desflurane. Desflurane had been set aside because it had been dangerous to make, had a relatively low potency, and had a saturated vapor pressure near one atmosphere, making its delivery difficult. Fortunately, Anaquest had thought so little of desflurane that they had not published on its properties, or attempted to patent it. That meant that a new patent and exclusivity for 17 years were possible. Terrell gave Eger all the desflurane that Anaquest had kept on the shelf for 2 decades, approximately 10 ml. Because of the limited availability of compound, Eger recaptured the desflurane at the end of each experiment by condensing the gas phase with liquid nitrogen. With careful use, Eger and colleagues conducted several experiments in 1985 and 1986. Anaquest became aware of the possibility that desflurane might supply a desirable alternative to isoflurane.

By late 1986, the synthetic efforts within Ken Spencer’s chemistry group had resulted in numerous patents, and first-time-in-human testing of intravenous analgesics and a neuromuscular blocking agent. Because of the development time associated with these new chemical entities (NCEs), efforts to in-license¹ both products and newer technologies in drug delivery systems for its small molecule program were also undertaken. It was hoped that these initiatives would rapidly lead to a portfolio of products supplementing the company’s major product isoflurane, whose patent expiry in 1993 was imminent. Times’ winged chariot hurried near.

In 1987, Anaquest had taken a year’s option with Baxter Laboratories for the right to license sevoflurane. At the same time, as noted above, Eger had explored the properties of desflurane. For several months, Anaquest management debated which agent to pursue. Either choice meant a major financial commitment. The decision to develop the next generation of inhaled anesthetics was a difficult and nuanced choice between desflurane and sevoflurane. In retrospect, Paul Thomas (then product manager, later President of Anaquest) summed up the considerations as follows:

“The context of these deliberations included a need to have an anesthetic with a faster recovery than that from isoflurane, ideally with a lower incidence of postoperative nausea and vomiting, and particularly with minimal or no capacity to irritate the airway (especially relevant in children and with the growing popularity of laryngeal mask airways). It was also important to have an anesthetic that could be safely used with lower flow rates (1–2 l/min) because of potential clinical benefits and cost savings. These thoughts informed our analysis of the relative advantages of desflurane and sevoflurane.”

“Desflurane had the lowest’better’blood/gas partition coefficient [20,21], and this plus tests in rats pointed to a recovery that might be faster than with sevoflurane [22]. Desflurane had the edge in safety, its metabolism producing little fluoride ion, and it didn’t break down in soda lime [23] or produce Compound A. Thus desflurane passed muster, but the data for sevoflurane were alarming. And the market’s experiences with halothane and methoxflurane made the Anaquest team gun shy of instability and decomposition issues. We feared that the worst-case sevoflurane decomposition scenario would weigh heavily on clinicians, if not the FDA. The patent life advantage went to desflurane (16 yrs) since sevoflurane had only Waxman Hatch protection (5–7 years). And Anaquest owned desflurane, but not sevoflurane. Initial studies in animals did not reveal evidence of airway irritation, but transfer of such evidence to humans is unreliable. Still, this plus the lower blood/gas partition coefficient gave us hope that induction in humans would be more rapid.”

“But sevoflurane offered counterbalancing advantages. Its lesser MAC [24] meant that sevoflurane would require roughly a third the consumption of desflurane, producing a cost advantage. Sevoflurane could be delivered from a conventional flow vaporizer versus the much more costly vaporizer needed for desflurane. Anaquest would provide vaporizers to anesthetists using either anesthetic, imposing an additional cost with desflurane of tens of millions of dollars. Capital costs’for a plant to manufacture desflurane’were approximately 80 million dollars more than for sevoflurane. And lack of airway irritation in humans was a known fact favoring sevoflurane [25].”

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