Clinical Anesthesia

Chapter 1

The History of Anesthesia

Adam K. Jacob

Sandra L. Kopp

Douglas R. Bacon

Hugh M. Smith

Key Points

1. Anesthesiology is a young specialty historically, especially when compared with surgery or internal medicine.

2. Discoveries in anesthesiology have taken decades to build upon the observations and experiments of many people, and in some instances we are still searching. For example, the ideal volatile anesthetic has yet to be discovered.

3. Regional anesthesia is the direct outgrowth of a chance observation by an intern who would go on to become a successful ophthalmologist.

4. Pain medicine began as an outgrowth of regional anesthesia.

5. Much of our current anesthesia equipment is the direct result of anesthesiologists being unhappy with and needing better tools to properly anesthetize patients.

6. Many safety standards have been established through the work of anesthesiologists who were frustrated by the status quo.

7. Organizations of anesthesia professionals have been critical in establishing high standards in education and proficiency, which in turn has defined the specialty.

8. Respiratory critical care medicine started as the need by anesthesiologists to use positive pressure ventilation to help polio victims.

9. Surgical anesthesia and physician specialization in its administration have allowed for increasingly complex operations to be performed on increasingly ill patients.

Surgery without adequate pain control may seem cruel to the modern reader, and in contemporary practice we are prone to forget the realities of preanesthesia surgery. Fanny Burney, a well-known literary artist from the early 19th century, described a mastectomy she endured after receiving a “wine cordial” as her sole anesthetic. As seven male assistants held her down, the surgery commenced: “When the dreadful steel was plunged into the breast-cutting through veins-arteries-flesh-nerves-I needed no injunction not to restrain my cries. I began a scream that lasted unintermittently during the whole time of the incision—& I almost marvel that it rings not in my Ears still! So excruciating was the agony. Oh Heaven!—I then felt the knife racking against the breast bone—scraping it! This performed while I yet remained in utterly speechless torture.”¹ Burney's description illustrates the difficulty of overstating the impact of anesthesia on the human condition. An epitaph on a monument to William Thomas Green Morton, one of the founders of anesthesia, summarizes the contribution of anesthesia: “BEFORE WHOM in all time Surgery was Agony.”² Although most human civilizations evolved some method for diminishing patient discomfort,anesthesia, in its modern and effective meaning, is a comparatively recent discovery with traceable origins in the mid-19th century. How we have changed perspectives from one in which surgical pain

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was terrible and expected to one in which patients reasonably assume they will be safe, pain-free, and unaware during extensive operations is a fascinating story and the subject of this chapter.

Anesthesiologists are like no other physicians: we are experts at controlling the airway and at emergency resuscitation; we are real-time cardio pulmonologists achieving hemodynamic and respiratory stability for the anesthetized patient; we are pharmacologists and physiologists, calculating appropriate doses and desired responses; we are gurus of postoperative care and patient safety; we are internists performing perianesthetic medical evaluations; we are the pain experts across all medical disciplines and apply specialized techniques in pain clinics and labor wards; we manage the severely sick and injured in critical care units; we are neurologists, selectively blocking sympathetic, sensory, or motor functions with our regional techniques; we are trained researchers exploring scientific mystery and clinical phenomenon.

Anesthesiology is an amalgam of specialized techniques, equipment, drugs, and knowledge that, like the growth rings of a tree, have built up over time. Current anesthesia practice is the summation of individual effort and fortuitous discovery of centuries. Every component of modern anesthesia was at some point a new discovery and reflects the experience, knowledge, and inventiveness of our predecessors. Historical examination enables understanding of how these individual components of anesthesia evolved. Knowledge of the history of anesthesia enhances our appreciation of current practice and intimates where our specialty might be headed.

Anesthesia Before Ether

Physical and Psychological Anesthesia

The Edwin Smith Surgical Papyrus, the oldest known written surgical document, describes 48 cases performed by an Egyptian surgeon from 3000 to 2500 BC. While this remarkable surgical treatise contains no direct mention of measures to lessen patient pain or suffering, Egyptian pictographs from the same era show a surgeon compressing a nerve in a patient's antecubital fossa while operating on the patient's hand. Another image displays a patient compressing his own brachial plexus while a procedure is performed on his palm.³ In the 16th century, military surgeon Ambroise Paré became adept at nerve compression as a means of creating anesthesia.

Medical science has benefited from the natural refrigerating properties of ice and snow as well. For centuries anatomical dissections were performed only in winter because colder temperatures delayed deterioration of the cadaver, and in the Middle Ages the anesthetic effects of cold water and ice were recognized. In the 17th century, Marco Aurelio Severino described the technique of “refrigeration anesthesia” in which snow was placed in parallel lines across the incisional plane such that the surgical site became insensate within minutes. The technique never became widely used, likely because of the challenge of maintaining stores of snow year-round.⁴ Severino is also known to have saved numerous lives during an epidemic of diphtheria by performing tracheostomies and inserting trocars to maintain patency of the airway.⁵

Formal manipulation of the psyche to relieve surgical pain was undertaken by French physicians Charles Dupotet and Jules Cloquet in the late 1820s with hypnosis, then calledmesmerism. Although the work of Anton Mesmer was discredited by the French Academy of Science after formal inquiry several decades earlier, proponents like Dupotet and Cloquet continued with mesmeric experiments and pleaded to the Academie de Medicine to reconsider its utility.⁶ In a well-attended demonstration in 1828, Cloquet removed the breast of a 64-year-old patient while she reportedly remained in a calm, mesmeric sleep. This demonstration made a lasting impression on British physician John Elliotson, who became a leading figure of the mesmeric movement in England in the 1830s and 1840s. Innovative and quick to adopt new advances, Elliotson performed mesmeric demonstrations and in 1843 published Numerous Cases of Surgical Operations without Pain in the Mesmeric State. Support for mesmerism faded when in 1846 renowned surgeon Robert Liston performed the first operation using ether anesthesia in England and remarked, “This Yankee dodge beats mesmerism all hollow.”⁷

Early Analgesics and Soporifics

Dioscorides, a Greek physician from the first century AD, commented on the analgesia of mandragora, a drug prepared from the bark and leaves of the mandrake plant. He observed that the plant substance could be boiled in wine, strained, and used “in the case of persons … about to be cut or cauterized, when they wish to produce anesthesia.”⁸ Mandragora was still being used to benefit patients as late as the 17th century. From the ninth to the thirteenth centuries, the soporific sponge was a dominant mode of providing pain relief during surgery. Mandrake leaves, along with black nightshade, poppies, and other herbs, were boiled together and cooked onto a sponge. The sponge was then reconstituted in hot water and placed under the patient's nose before surgery. Prior to the hypodermic syringe and routine venous access, ingestion and inhalation were the only known routes for administering medicines to gain systemic effects. Prepared as indicated by published reports of the time, the sponge generally contained morphine and scopolamine in varying amounts—drugs used in modern anesthesia.⁹

Alcohol was another element of the pre-ether armamentarium because it was thought to induce stupor and blunt the impact of pain. Although alcohol is a central nervous system depressant, in the amounts administered it produced little analgesia in the setting of true surgical pain. Fanny Burney's account underscores the ineffectiveness of alcohol as an anesthetic. Not only did the alcohol provide minimal pain control, it did nothing to dull her recollection of events. Laudanum was an alcohol-based solution of opium first compounded by Paracelsus in the 16th century. It was wildly popular in the Victorian and Romantic periods, and prescribed for a wide variety of ailments from the common cold to tuberculosis. Although appropriately used as an analgesic in some instances, it was frequently misused and abused. Laudanum was given by nursemaids to quiet wailing infants and abused by many upper-class women, poets, and artists who fell victim to its addictive potential.

Inhaled Anesthetics

Nitrous oxide was known for its ability to induce lightheadedness and was often inhaled by those seeking a thrill. It was not used as frequently as ether because it was more difficult to synthesize and store. It was made by heating ammonium nitrate in the presence of iron filings. The evolved gas was passed through water to eliminate toxic oxides of nitrogen before being stored. Nitrous oxide was first prepared in 1773 by Joseph Priestley, an English clergyman and scientist, who ranks among the great pioneers of chemistry. Without formal scientific training, Priestley prepared and examined several gases, including nitrous oxide, ammonia, sulfur dioxide, oxygen, carbon monoxide, and carbon dioxide.

At the end of the 18th century in England, there was a strong interest in the supposed wholesome effects of mineral

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waters and gases, particularly with regard to treatment of scurvy, tuberculosis, and other diseases. Thomas Beddoes opened his Pneumatic Institute close to the small spa of Hotwells, in the city of Bristol, to study the beneficial effects of inhaled gases. He hired Humphry Davy in 1798 to conduct research projects for the Institute. Davy performed brilliant investigations of several gases but focused much of his attention on nitrous oxide. His human experimental results, combined with research on the physical properties of the gas, were published in Nitrous Oxide, a 580-page book published in 1800. This impressive treatise is now best remembered for a few incidental observations. Davy commented that nitrous oxide transiently relieved a severe headache, obliterated a minor headache, and briefly quenched an aggravating toothache. The most frequently quoted passage was a casual entry: “As nitrous oxide in its extensive operation appears capable of destroying physical pain, it may probably be used with advantage during surgical operations in which no great effusion of blood takes place.”¹⁰ This is perhaps the most famous of the “missed opportunities” to discover surgical anesthesia. Davy's lasting nitrous oxide legacy was coining the phrase “laughing gas” to describe its unique property.

Almost Discovery: Hickman, Clarke, Long, and Wells

As the 19th century progressed, societal attitudes toward pain changed, perhaps best exemplified in the writings of the Romantic poets.¹¹ Thus, efforts to relieve pain were undertaken and several more near-breakthroughs occurred deserve mention. An English surgeon named Henry Hill Hickman searched intentionally for an inhaled anesthetic to relieve pain in his patients.¹² Hickman used high concentrations of carbon dioxide in his studies on mice and dogs. Carbon dioxide has some anesthetic properties, as shown by the absence of response to an incision in the animals of Hickman's study, but it was never determined if the animals were insensate because of hypoxia rather than anesthesia. Hickman's concept was magnificent; his choice of agent was regrettable.

The discovery of surgical anesthetics in the modern era remains linked to inhaled anesthetics. The compound now known as diethyl ether had been known for centuries; it may have been synthesized first by an eighth-century Arabian philosopher Jabir ibn Hayyam, or possibly by Raymond Lully, a 13th century European alchemist. But diethyl ether was certainly known in the 16th century, both to Valerius Cordus and Paracelsus who prepared it by distilling sulfuric acid (oil of vitriol) with fortified wine to produce an oleum vitrioli dulce(sweet oil of vitriol). One of the first “missed” observations on the effects of inhaled agents, Paracelsus observed that ether caused chickens to fall asleep and awaken unharmed. He must have been aware of its analgesic qualities because he reported that it could be recommended for use in painful illnesses.

For three centuries thereafter, this simple compound remained a therapeutic agent with only occasional use. Some of its properties were examined but without sustained interest by distinguished British scientists Robert Boyle, Isaac Newton, and Michael Faraday, none of whom made the conceptual link to surgical anesthesia. Its only routine application came as an inexpensive recreational drug among the poor of Britain and Ireland, who sometimes drank an ounce or two of ether when taxes made gin prohibitively expensive.¹³ An American variation of this practice was conducted by groups of students who held ether-soaked towels to their faces at nocturnal “ether frolics.”

William E. Clarke, a medical student from Rochester, New York, may have given the first ether anesthetic in January 1842. From techniques learned as a chemistry student in 1839, Clarke entertained his companions with nitrous oxide and ether. Emboldened by these experiences, he administered ether, from a towel, to a young woman named Hobbie. One of her teeth was then extracted without pain by a dentist named Elijah Pope.¹⁴ However, it was suggested that the woman's unconsciousness was due to hysteria and Clarke was advised to conduct no further anesthetic experiments.¹⁵

Two months later, on March 30, 1842, Crawford Williamson Long administered ether with a towel for surgical anesthesia in Jefferson, Georgia. His patient, James M. Venable, was a young man who was already familiar with ether's exhilarating effects, for he reported in a certificate that he had previously inhaled it and was fond of its use. Venable had two small tumors on his neck but refused to have them excised because he feared the pain that accompanied surgery. Knowing that Venable was familiar with ether's action, Dr. Long proposed that ether might alleviate pain and gained his patient's consent to proceed. After inhaling ether from the towel and having the procedure successfully completed, Venable reported that he was unaware of the removal of the tumors.¹⁶ In determining the first fee for anesthesia and surgery, Long settled on a charge of $2.00.¹⁷

A common mid-19th century problem facing dentists was that patients refused beneficial treatment of their teeth for fear of the pain of the procedure. From a dentist's perspective, pain was not so much life-threatening as it was livelihood-threatening. One of the first dentists to engender a solution was Horace Wells of Hartford, Connecticut, whose great moment of discovery came on December 10, 1844. He observed a lecture-exhibition on nitrous oxide by an itinerant “scientist,” Gardner Quincy Colton, who encouraged members of the audience to inhale a sample of the gas. Wells observed a young man injure his leg without pain while under the influence of nitrous oxide. Sensing that it might provide pain relief during dental procedures, Wells contacted Colton and boldly proposed an experiment in which Wells was to be the subject. The following day, Colton gave Wells nitrous oxide before a fellow dentist, William Riggs, extracted a tooth.¹⁸ Afterward Wells declared that he had not felt any pain and deemed the experiment a success. Colton taught Wells to prepare nitrous oxide, which the dentist administered with success to patients in his practice. His apparatus probably resembled that used by Colton: a wooden tube placed in the mouth through which nitrous oxide was breathed from a small bag filled with the gas.

Public Demonstration of Ether Anesthesia

Another New Englander, William Thomas Green Morton, briefly shared a dental practice with Wells in Hartford. Wells' daybook shows that he gave Morton a course of instruction in anesthesia, but Morton apparently moved to Boston without paying for the lessons.¹⁹ In Boston, Morton continued his interest in anesthesia and sought instruction from chemist and physician Charles T. Jackson. After learning that ether dropped on the skin provided analgesia, he began experiments with inhaled ether, an agent that proved to be much more versatile than nitrous oxide. Bottles of liquid ether were easily transported, and the volatility of the drug permitted effective inhalation. The concentrations required for surgical anesthesia were so low that patients did not become hypoxic when breathing ether vaporized in air. It also possessed what would later be recognized as a unique property among all inhaled anesthetics: the quality of providing surgical anesthesia without causing respiratory depression. These properties, combined with a slow rate of induction, gave the patient a significant safety margin even in the hands of relatively unskilled anesthetists.²⁰

After anesthetizing a pet dog, Morton became confident of his skills and anesthetized patients in his dental office.

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Encouraged by his success, Morton sought an invitation to give a public demonstration in the Bullfinch amphitheater of the Massachusetts General Hospital, the same site as Wells' failed demonstration. Many details of the October 16, 1846, demonstration are well known. Morton secured permission to provide an anesthetic to Edward Gilbert Abbott, a patient of surgeon John Collins Warren. Warren planned to excise a vascular lesion from the left side of Abbott's neck and was about to proceed when Morton arrived late. He had been delayed because he was obliged to wait for an instrument maker to complete a new inhaler (Fig. 1-1). It consisted of a large glass bulb containing a sponge soaked with colored ether and a spout that was placed in the patient's mouth. An opening on the opposite side of the bulb allowed air to enter and be drawn over the ether-soaked sponge with each breath.²¹

Figure 1-1. Morton's ether inhaler (1846).

The conversations of that morning were not accurately recorded; however, popular accounts state that the surgeon responded testily to Morton's apology for his tardy arrival by remarking, “Sir, your patient is ready.” Morton directed his attention to his patient and first conducted a very abbreviated preoperative evaluation. He inquired, “Are you afraid?” Abbott responded that he was not and took the inhaler in his mouth. After a few minutes, Morton turned to the surgeon and said, “Sir, your patient is ready.” Gilbert Abbott later reported that he was aware of the surgery but experienced no pain. When the procedure ended, Warren immediately turned to his audience and uttered the statement, “Gentlemen, this is no humbug.”²²

What would be recognized as America's greatest contribution to 19th century medicine had occurred. However, Morton, wishing to capitalize on his “discovery,” refused to divulge what agent was in his inhaler. Some weeks passed before Morton admitted that the active component of the colored fluid, which he had called “Letheon,” was simple diethyl ether. Morton, Wells, Jackson, and their supporters soon became drawn into in a contentious, protracted, and fruitless debate over priority for the discovery. This debate has subsequently been termed the ether controversy. In short, Morton had applied for a patent for Letheon, and when it was granted, tried to receive royalties for the use of ether as an anesthetic.

When the details of Morton's anesthetic technique became public knowledge, the information was transmitted by train, stagecoach, and coastal vessels to other North American cities, and by ship to the world. As ether was easy to prepare and administer, anesthetics were performed in Britain, France, Russia, South Africa, Australia, and other countries almost as soon as surgeons heard the welcome news of the extraordinary discovery. Even though surgery could now be performed with “pain put to sleep,” the frequency of operations did not rise rapidly, and several years would pass before anesthesia was universally recommended.

Chloroform and Obstetrics

James Young Simpson was a successful obstetrician of Edinburgh, Scotland, and among the first to use ether for the relief of labor pain. Dissatisfied with ether, Simpson soon sought a more pleasant, rapid-acting anesthetic. He and his junior associates conducted a bold search by inhaling samples of several volatile chemicals collected for Simpson by British apothecaries. David Waldie suggested chloroform, which had first been prepared in 1831. Simpson and his friends inhaled it after dinner at a party in Simpson's home on the evening of November 4, 1847. They promptly fell unconscious and, when they awoke, were delighted with their success. Simpson quickly set about encouraging the use of chloroform. Within 2 weeks, he submitted his first account of its use to The Lancet.

In the 19th century, the relief of obstetric pain had significant social ramifications and made anesthesia during childbirth a controversial subject. Simpson argued against the prevailing view, which held that relieving labor pain opposed God's will. The pain of the parturient was viewed as both a component of punishment and a means of atonement for Original Sin. Less than a year after administering the first anesthesia during childbirth, Simpson addressed these concerns in a pamphlet entitled Answers to the Religious Objections Advanced against the Employment of Anaesthetic Agents in Midwifery and Surgery and Obstetrics. In it, Simpson recognized the Book of Genesis as being the root of this sentiment, and noted that God promised to relieve the descendants of Adam and Eve of the curse. Additionally, Simpson asserted that labor pain was a result of scientific and anatomic causes, and not the result of religious condemnation. He stated that the upright position of humans necessitated strong pelvic muscles to support the abdominal contents. As a result, he argued, the uterus necessarily developed strong musculature to overcome the resistance of the pelvic floor and that great contractile power caused great pain. Simpson's pamphlet probably did not have a significant impact on the prevailing attitudes, but he did articulate many concepts that his contemporaries were debating at the time.²³

Chloroform gained considerable notoriety after John Snow used it to deliver the last two children of Queen Victoria. The Queen's consort, Prince Albert, interviewed John Snow before he was called to Buckingham Palace to administer chloroform at the request of the Queen's obstetrician. During the monarch's labor, Snow gave analgesic doses of chloroform on a folded handkerchief. This technique was soon termed chloroform à la reine. Victoria abhorred the pain of childbirth and enjoyed the relief that chloroform provided. She wrote in her journal, “Dr. Snow gave that blessed chloroform and the effect was soothing, quieting, and delightful beyond measure.”²⁴ When the Queen, as head of the Church of England, endorsed obstetric anesthesia, religious debate over the management of labor pain terminated abruptly.

John Snow, already a respected physician, took an interest in anesthetic practice and was soon invited to work with many leading surgeons of the day. In 1848, Snow introduced a chloroform inhaler. He had recognized the versatility of the new agent and came to prefer it in his practice. At the same time, he initiated what was to become an extraordinary series of experiments that were remarkable in their scope and for anticipating sophisticated research performed a century later. Snow realized that successful anesthetics should abolish pain and unwanted movements. He anesthetized several species of animals with varying strengths of ether and chloroform to determine the concentration required to prevent reflex

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movement from sharp stimuli. This work approximated the modern concept of minimum alveolar concentration.²⁵ Snow assessed the anesthetic action of a large number of potential anesthetics but did not find any to rival chloroform or ether. His studies led him to recognize the relationship between solubility, vapor pressure, and anesthetic potency, which was not fully appreciated until after World War II. Snow published two remarkable books, On the Inhalation of the Vapour of Ether (1847) and On Chloroform and Other Anaesthetics(1858). The latter was almost completed when he died of a stroke at the age of 45.

Anesthesia Principles, Equipment, and Standards

Control of the Airway

Definitive control of the airway, a skill anesthesiologists now consider paramount, developed only after many harrowing and apneic episodes spurred the development of safer airway management techniques. Preceding tracheal intubation, however, several important techniques were proposed toward the end of the 19th century that remain integral to anesthesiology education and practice. Joseph Clover was the first Englishman to urge the now universal practice of thrusting the patient's jaw forward to overcome obstruction of the upper airway by the tongue. Clover also published a landmark case report in 1877 in which he performed a surgical airway. Once his patient was asleep, Clover discovered that his patient had a tumor of the mouth that obstructed the airway completely, despite his trusted jaw-thrust maneuver. He averted disaster by inserting a small curved cannula of his design through the cricothyroid membrane. He continued anesthesia via the cannula until the tumor was excised. Clover, the model of the prepared anesthesiologist, remarked, “I have never used the cannula before although it has been my companion at some thousands of anaesthetic cases.”²⁶

Tracheal Intubation

The development of techniques and instruments for intubation ranks among the major advances in the history of anesthesiology. The first tracheal tubes were developed for the resuscitation of drowning victims, but were not used in anesthesia until 1878. The first use of elective oral intubation for an anesthetic was undertaken by Scottish surgeon William Macewan. He had practiced passing flexible metal tubes through the larynx of a cadaver before attempting the maneuver on an awake patient with an oral tumor at the Glasgow Royal Infirmary on July 5, 1878.²⁷ Because topical anesthesia was not yet known, the experience must have demanded fortitude on the part of Macewan's patient. Once the tube was correctly positioned, an assistant began a chloroform–air anesthetic via the tube. Once anesthetized, the patient soon stopped coughing. Unfortunately, Macewan abandoned the practice following a fatality in which a patient had been successfully intubated while awake but the tube became dislodged once the patient was asleep. After the tube was removed, an attempt to provide chloroform by mask anesthesia was unsuccessful and the patient died.

An American surgeon named Joseph O'Dwyer is remembered for his extraordinary dedication to the advancement of tracheal intubation. In 1885, O'Dwyer designed a series of metal laryngeal tubes, which he inserted blindly between the vocal cords of children suffering a diphtheritic crisis. Three years later, O'Dwyer designed a second rigid tube with a conical tip that occluded the larynx so effectively that it could be used for artificial ventilation when applied with the bellows and T-piece tube designed by George Fell. The Fell-O'Dwyer apparatus, as it came to be known, was used during thoracic surgery by Rudolph Matas of New Orleans. Matas was so pleased with it that he predicted, “The procedure that promises the most benefit in preventing pulmonary collapse in operations on the chest is … the rhythmical maintenance of artificial respiration by a tube in the glottis directly connected with a bellows.”

After O'Dwyer's death, the outstanding pioneer of tracheal intubation was Franz Kuhn, a surgeon of Kassel, Germany. From 1900 until 1912, Kuhn published several articles and a classic monograph, “Die perorale Intubation,” which were not well known in his lifetime but have since become widely appreciated.²⁵ His work might have had a more profound impact if it had been translated into English. Kuhn described techniques of oral and nasal intubation that he performed with flexible metal tubes composed of coiled tubing similar to those now used for the spout of metal gasoline cans. After applying cocaine to the airway, Kuhn introduced his tube over a curved metal stylet that he directed toward the larynx with his left index finger. While he was aware of the subglottic cuffs that had been used briefly by Victor Eisenmenger, Kuhn preferred to seal the larynx by positioning a supralaryngeal flange near the tube's tip before packing the pharynx with gauze. Kuhn even monitored the patient's breath sounds continuously through a monaural earpiece connected to an extension of the tracheal tube by a narrow tube.

Intubation of the trachea by palpation was an uncertain and sometimes traumatic act; surgeons even believed that it would be anatomically impossible to visualize the vocal cords directly. This misapprehension was overcome in 1895 by Alfred Kirstein in Berlin who devised the first direct-vision laryngoscope.²⁸ Kirstein was motivated by a friend's report that a patient's trachea had been accidentally intubated during esophagoscopy. Kirstein promptly fabricated a handheld instrument that at first resembled a shortened cylindrical esophagoscope. He soon substituted a semicircular blade that opened inferiorly. Kirstein could now examine the larynx while standing behind his seated patient, whose head had been placed in an attitude approximating the “sniffing position.” Although Alfred Kirstein's “autoscope” was not used by anesthesiologists, it was the forerunner of all modern laryngoscopes. Endoscopy was refined by Chevalier Jackson in Philadelphia, who designed a U-shaped laryngoscope by adding a handgrip that was parallel to the blade. The Jackson blade has remained a standard instrument for endoscopists but was not favored by anesthesiologists. Two laryngoscopes that closely resembled modern L-shaped instruments were designed in 1910 and 1913 by two American surgeons, Henry Janeway and George Dorrance, but neither instrument achieved lasting use despite their excellent designs.²⁹

Before the introduction of muscle relaxants in the 1940s, intubation of the trachea could be challenging. This challenge was made somewhat easier, however, with the advent of laryngoscope blades specifically designed to increase visualization of the vocal cords. Robert Miller of San Antonio, Texas, and Robert Macintosh of Oxford University created their respectively named blades within an interval of 2 years. In 1941, Miller brought forward the slender, straight blade with a slight curve near the tip to ease the passage of the tube through the larynx. Although Miller's blade was a refinement, the technique of its use was identical to that of earlier models as the epiglottis was lifted to expose the larynx.³⁰

The Macintosh blade, which is placed in the vallecula rather than under the epiglottis, was invented as an incidental result of a tonsillectomy. Sir Robert Macintosh later described the circumstances of its discovery in an appreciation of the

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career of his technician, Mr. Richard Salt, who constructed the blade. As Sir Robert recalled, “A Boyle-Davis gag, a size larger than intended, was inserted for tonsillectomy, and when the mouth was fully opened the cords came into view. This was a surprise since conventional laryngoscopy, at that depth of anaesthesia, would have been impossible in those pre-relaxant days. Within a matter of hours, Salt had modified the blade of the Davis gag and attached a laryngoscope handle to it; and streamlined (after testing several models), the end result came into widespread use.”³¹ Macintosh underestimated the popularity of the blade, as more than 800,000 have been produced and many special-purpose versions have been marketed.

The most distinguished innovator in tracheal intubation was the self-trained British anesthetist Ivan (later, Sir Ivan) Magill.³² In 1919, while serving in the Royal Army as a general medical officer, Magill was assigned to a military hospital near London. Although he had only rudimentary training in anesthesia, Magill was obliged to accept an assignment to the anesthesia service, where he worked with another neophyte, Stanley Rowbotham.³³ Together, Magill and Rowbotham attended casualties disfigured by severe facial injuries who underwent repeated restorative operations. These procedures required that the surgeon, Harold Gillies, have unrestricted access to the face and airway. These patients presented formidable challenges, but both Magill and Rowbotham became adept at tracheal intubation and quickly understood its current limitations. Because they learned from fortuitous observations, they soon extended the scope of tracheal anesthesia.

They gained expertise with blind nasal intubation after they learned to soften semirigid insufflation tubes for passage through the nostril. Even though their original intent was to position the tips of the nasal tubes in the posterior pharynx, the slender tubes frequently ended up in the trachea. Stimulated by this chance experience, they developed techniques of deliberate nasotracheal intubation. In 1920, Magill devised an aid to manipulating the catheter tip, the “Magill angulated forceps,” which continue to be manufactured according to his original design of nearly 90 years ago.

With the war over, Magill entered civilian practice and set out to develop a wide-bore tube that would resist kinking but be conformable to the contours of the upper airway. While in a hardware store, he found mineralized red rubber tubing that he cut, beveled, and smoothed to produce tubes that clinicians around the world would come to call “Magill tubes.” His tubes remained the universal standard for more than 40 years until rubber products were supplanted by inert plastics. Magill also rediscovered the advantage of applying cocaine to the nasal mucosa, a technique that greatly facilitated awake blind nasal intubation.

In 1926, Arthur Guedel began a series of experiments that led to the introduction of the cuffed tube. Guedel transformed the basement of his Indianapolis home into a laboratory where he subjected each step of the preparation and application of his cuffs to a vigorous review.³⁴ He fashioned cuffs from the rubber of dental dams, condoms, and surgical gloves that were glued onto the outer wall of tubes. Using as his model animal tracheas donated by the family butcher, he considered whether the cuff should be positioned above, below, or at the level of the vocal cords. He recommended that the cuff be positioned just below the vocal cords to seal the airway. Waters later recommended that cuffs be constructed of two layers of soft rubber cemented together. These detachable cuffs were first manufactured by Waters' children, who sold them to the Foregger Company.

Guedel sought ways to show the safety and utility of the cuffed tube. He first filled the mouth of an anesthetized and intubated patient with water and showed that the cuff sealed the airway. Even though this exhibition was successful, he searched for a more dramatic technique to capture the attention of those unfamiliar with the advantages of intubation. He reasoned that if the cuff prevented water from entering the trachea of an intubated patient, it should also prevent an animal from drowning, even if it were submerged under water. To encourage physicians attending a medical convention to use his tracheal techniques, Guedel prepared the first of several “dunked dog” demonstrations (Fig. 1-2). An anesthetized and intubated dog, Guedel's own pet, “Airway,” was immersed in an aquarium. After the demonstration was completed, the anesthetic was discontinued before the animal was removed from the water. Airway awoke promptly, shook water over the onlookers, saluted a post, then trotted from the hall to the applause of the audience.

Figure 1-2. The “dunked dog.”

After a patient experienced an accidental endobronchial intubation, Ralph Waters reasoned that a very long cuffed tube could be used to ventilate the dependent lung while the upper lung was being resected.³⁵ On learning of his friend's success with intentional one-lung anesthesia, Arthur Guedel proposed an important modification for chest surgery, the double-cuffed single-lumen tube, which was introduced by Emery Rovenstine. These tubes were easily positioned, an advantage over bronchial blockers that had to be inserted by a skilled bronchoscopist. In 1953, single-lumen tubes were supplanted by double-lumen endobronchial tubes. The double-lumen tube currently most popular was designed by Frank Robertshaw of Manchester, England, and is prepared in both right- and left-sided versions. Robertshaw tubes were first manufactured from mineralized red rubber but are now made of extruded plastic, a technique refined by David Sheridan. Sheridan was also the first person to embed centimeter markings along the side of tracheal tubes, a safety feature that reduced the risk of the tube's being incorrectly positioned.

Advanced Airway Devices

Conventional laryngoscopes proved inadequate for patients with “difficult airways.” A few clinicians credit harrowing intubating experiences as the incentive for invention. In 1928, a rigid bronchoscope was specifically designed for examination of the large airways. Rigid bronchoscopes were refined and used by pulmonologists. Although it was known in 1870 that a thread of glass could transmit light along its length, technological limitations were not overcome until 1964 when Shigeto Ikeda developed the first flexible fiberoptic bronchoscope. Fiberoptic-assisted tracheal intubation has become a common approach in the management of patients with difficult airways having surgery.

Roger Bullard desired a device to simultaneously examine the larynx and intubate the vocal cords. He had been frustrated

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by failed attempts to visualize the larynx of a patient with Pierre-Robin syndrome. In response, he developed the Bullard laryngoscope, whose fiberoptic bundles lie beside a curved blade. Similarly, the Wu-scope was designed by Tzu-Lang Wu in 1994 to combine and facilitate visualization and intubation of the trachea in patients with difficult airways.³⁶

Dr. A. I. J. “Archie” Brain first recognized the principle of the laryngeal mask airway (LMA) in 1981 when, like many British clinicians, he provided dental anesthesia via a Goldman nasal mask. However, unlike any before him, he realized that just as the dental mask could be fitted closely about the nose, a comparable mask attached to a wide-bore tube might be positioned around the larynx. He not only conceived of this radical departure in airway management, which he first described in 1983,³⁷ but also spent years in single-handedly fabricating and testing scores of incremental modifications. Scores of Brain's prototypes are displayed in the Royal Berkshire Hospital, Reading, England, where they provide a detailed record of the evolution of the LMA. He fabricated his first models from Magill tubes and Goldman masks, then refined their shape by performing postmortem studies of the hypopharynx to determine the form of cuff that would be most functional. Before silicone rubber was selected, Brain had even mastered the technique of forming masks from liquid latex. Every detail of the LMA, the number and position of the aperture bars, the shape and the size of the masks, required repeated modification.

Early Anesthesia Delivery Systems

The transition from ether inhalers and chloroform-soaked handkerchiefs to more sophisticated anesthesia delivery equipment occurred gradually, with incremental advances supplanting older methods. One of the earliest anesthesia apparatus designs was that of John Snow, who had realized the inadequacies of ether inhalers through which patients rebreathed via a mouthpiece. After practicing anesthesia for only 2 weeks, Snow created the first of his series of ingenious ether inhalers.³⁸ His best-known apparatus featured unidirectional valves within a malleable, well-fitting mask of his own design, which closely resembles the form of a modern face mask. The face piece was connected to the vaporizer by a breathing tube, which Snow deliberately designed to be wider than the human trachea so that even rapid respirations would not be impeded. A metal coil within the vaporizer ensured that the patient's inspired breath was drawn over a large surface area to promote the uptake of ether. The device also incorporated a warm water bath to maintain the volatility of the agent (Fig. 1-3). Snow did not attempt to capitalize on his creativity, in contrast to William Morton; he closed his account of its preparation with the generous observation, “There is no restriction respecting the making of it.”³⁹

Figure 1-3. John Snow's inhaler (1847). The ether chamber (B) contained a spiral coil so that the air entering through the bross tube (D) was saturated by ether before ascending the flexible tube (F) to the face mask (G). The ether chamber rested in a bath of warm water (A).

Joseph Clover, another British physician, was the first anesthetist to administer chloroform in known concentrations through the “Clover bag.” He obtained a 4.5% concentration of chloroform in air by pumping a measured volume of air with a bellows through a warmed evaporating vessel containing a known volume of liquid chloroform.⁴⁰ Although it was realized that nitrous oxide diluted in air often gave a hypoxic mixture, and that the oxygen-nitrous oxide mixture was safer, Chicago surgeon Edmund Andrews complained about the physical limitations of delivering anesthesia to patients in their homes. The large bag was conspicuous and awkward to carry along busy streets. He observed that, “In city practice, among the higher classes, however, this is no obstacle as the bag can always be taken in a carriage, without attracting attention.”⁴¹ In 1872, Andrews was delighted to report the availability of liquefied nitrous oxide compressed under 750 pounds of pressure, which allowed a supply sufficient for three patients to be carried in a single cylinder.

Critical to increasing patient safety was the development of a machine capable of delivering a calibrated amount of gas and volatile anesthetic. In the late 19th century, demands in dentistry instigated development of the first freestanding anesthesia machines. Three American dentist-entrepreneurs, Samuel S. White, Charles Teter, and Jay Heidbrink, developed the original series of U.S. instruments that used compressed cylinders of nitrous oxide and oxygen. Before 1900, the S. S. White Company modified Frederick Hewitt's apparatus and marketed its continuous-flow machine, which was refined by Teter in 1903. Heidbrink added reducing valves in 1912. In the same year, physicians initiated other important developments. Water-bubble flowmeters, introduced by Frederick Cotton and Walter Boothby of Harvard University, allowed the proportion of gases and their flow rate to be approximated. The Cotton and Boothby apparatus was transformed into a practical portable machine by James Tayloe Gwathmey of New York. The Gwathmey machine caught the attention of a London anesthetist Henry E. G. “Cockie” Boyle, who acknowledged his debt to the American when he incorporated Gwathmey's concepts in the first of the series of “Boyle” machines that were marketed by Coxeter and British Oxygen Corporation. During the same period in Lubeck, Germany, Heinrich Draeger and his son, Bernhaard, adapted compressed-gas technology, which they had originally developed for mine rescue equipment, to manufacture ether and chloroform-oxygen machines.

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In the years after World War I, several U.S. manufacturers continued to bring forward widely admired anesthesia machines. Richard von Foregger was an engineer who was exceptionally receptive to clinicians' suggestions for additional features for his machines. Elmer McKesson became one of the country's first specialists in anesthesiology in 1910 and developed a series of gas machines. In an era of flammable anesthetics, McKesson carried nitrous oxide anesthesia to its therapeutic limit by performing inductions with 100% nitrous oxide and thereafter adding small volumes of oxygen. If the resultant cyanosis became too profound, McKesson depressed a valve on his machine that flushed a small volume of oxygen into the circuit. Even though his techniques of primary and secondary saturation with nitrous oxide are no longer used, the oxygen flush valve is part of McKesson's legacy.

Alternative Circuits

A valveless device, the Ayre's T-piece, has found wide application in the management of intubated patients. Phillip Ayre practiced anesthesia in England when the limitations of equipment for pediatric patients produced what he described as “a protracted and sanguine battle between surgeon and anaesthetist, with the poor unfortunate baby as the battlefield.”⁴² In 1937, Ayre introduced his valveless T-piece to reduce the effort of breathing in neurosurgical patients. The T-piece soon became particularly popular for cleft palate repairs, as the surgeon had free access to the mouth. Positive pressure ventilation could be achieved when the anesthetist obstructed the expiratory limb. In time, this ingenious, lightweight, nonrebreathing device evolved through more than 100 modifications for a variety of special situations. A significant alteration was Gordon Jackson Rees' circuit, which permitted improved control of ventilation by substituting a breathing bag on the outflow limb.⁴³ An alternative method to reduce the amount of equipment near the patient is provided by the coaxial circuit of the Bain-Spoerel apparatus.⁴⁴ This lightweight tube-within-a-tube has served very well in many circumstances since its Canadian innovators described it in 1972.

Ventilators

Mechanical ventilators are now an integral part of the anesthesia machine. Patients are ventilated during general anesthesia by electrical or gas-powered devices that are simple to control yet sophisticated in their function. The history of mechanical positive pressure ventilation began with attempts to resuscitate victims of drowning by a bellows attached to a mask or tracheal tube. These experiments found little role in anesthetic care for many years. At the beginning of the 20th century, however, several modalities were explored before intermittent positive pressure machines evolved.

A series of artificial environments were created in response to the frustration experienced by thoracic surgeons who found that the lung collapsed when they incised the pleura. Between 1900 and 1910, continuous positive or negative pressure devices were created to maintain inflation of the lungs of a spontaneously breathing patient once the chest was opened. Brauer (1904) and Murphy (1905) placed the patient's head and neck in a box in which positive pressure was continually maintained. Sauerbruch (1904) created a negative-pressure operating chamber encompassing both the surgical team and the patient's body and from which only the patient's head projected.⁴⁵

In 1907, the first intermittent positive pressure device, the Draeger “Pulmotor,” was developed to rhythmically inflate the lungs. This instrument and later American models such as the E & J Resuscitator were used almost exclusively by firefighters and mine rescue workers. In 1934 a Swedish team developed the “Spiropulsator,” which C. Crafoord later modified for use during cyclopropane anesthesia.⁴⁶ Its action was controlled by a magnetic control valve called the flasher, a type first used to provide intermittent gas flow for the lights of navigational buoys. When Trier Morch, a Danish anesthesiologist, could not obtain a Spiropulsator during World War II, he fabricated the Morch “Respirator,” which used a piston pump to rhythmically deliver a fixed volume of gas to the patient.⁴⁵

A major stimulus to the development of ventilators came as a consequence of a devastating epidemic of poliomyelitis that struck Copenhagen, Denmark, in 1952. As scores of patients were admitted, the only effective ventilatory support that could be provided to patients with bulbar paralysis was continuous manual ventilation via a tracheostomy employing devices such as Waters' “to-and-fro” circuit. This succeeded only through the dedicated efforts of hundreds of volunteers. Medical students served in relays to ventilate paralyzed patients. The Copenhagen crisis stimulated a broad European interest in the development of portable ventilators in anticipation of another epidemic of poliomyelitis. At this time, the common practice in North American hospitals was to place polio patients with respiratory involvement in “iron lungs,” metal cylinders that encased the body below the neck. Inspiration was caused by intermittent negative pressure created by an electric motor acting on a pistonlike device occupying the foot of the chamber.

Some early American ventilators were adaptations of respiratory-assist machines originally designed for the delivery of aerosolized drugs for respiratory therapy. Two types employed the Bennett or Bird “flow-sensitive” valves. The Bennett valve was designed during World War II when a team of physiologists at the University of Southern California encountered difficulties in separating inspiration from expiration in an experimental apparatus designed to provide positive pressure breathing for aviators at high altitude. An engineer, Ray Bennett, visited their laboratory, observed their problem, and resolved it with a mechanical flow-sensitive automatic valve. A second valving mechanism was later designed by an aeronautical engineer, Forrest Bird.

The use of the Bird and Bennett valves gained an anesthetic application when the gas flow from the valve was directed into a rigid plastic jar containing a breathing bag or bellows as part of an anesthesia circuit. These “bag-in-bottle” devices mimicked the action of the clinician's hand as the gas flow compressed the bag, thereby providing positive pressure inspiration. Passive exhalation was promoted by the descent of a weight on the bag or bellows.

Carbon Dioxide Absorption

Carbon dioxide (CO₂) absorbance is a basic element of modern anesthetic machines. It was initially developed to allow rebreathing of gas and minimize loss of flammable gases into the room, thereby reducing the risk of explosion. In current practice, it permits decreased utilization of anesthetic and reduced cost. The first CO₂ absorber in anesthesia came in 1906 from the work of Franz Kuhn, a German surgeon. His use of canisters developed for mine rescues by Draeger was innovative, but his circuit had unfortunate limitations. The exceptionally narrow breathing tubes and a large dead space explain its very limited use, and Kuhn's device was ignored.

A few years later, the first American machine with a CO₂ absorber was independently fabricated by a pharmacologist named Dennis Jackson. In 1915, Jackson developed an early technique of CO₂ absorption that permitted the use of a closed anesthesia circuit. He used solutions of sodium and calcium

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hydroxide to absorb CO₂. As his laboratory was located in an area of St. Louis, Missouri, heavily laden with coal smoke, Jackson reported that the apparatus allowed him the first breaths of absolutely fresh air he had ever enjoyed in that city. The complexity of Jackson's apparatus limited its use in hospital practice, but his pioneering work in this field encouraged Ralph Waters to introduce a simpler device using soda lime granules 9 years later. Waters positioned a soda lime canister (Fig. 1-4) between a face mask and an adjacent breathing bag to which was attached the fresh gas flow. As long as the mask was held against the face, only small volumes of fresh gas flow were required and no valves were needed.⁴⁷

Figure 1-4. Waters' carbon dioxide absorbance canister.

Waters' device featured awkward positioning of the canister close to the patient's face. Brian Sword overcame this limitation in 1930 with a freestanding machine with unidirectional valves to create a circle system and an in-line CO₂ absorber.⁴⁸ James Elam and his coworkers at the Roswell Park Cancer Institute in Buffalo, New York, further refined the CO₂absorber, increasing the efficiency of CO₂ removal with a minimum of resistance for breathing.⁴⁹ Consequently, the circle system introduced by Sword in the 1930s, with a few refinements, became the standard anesthesia circuit in North America.

Flow Meters

As closed and semiclosed circuits became practical, gas flow could be measured with greater accuracy. Bubble flowmeters were replaced with dry bobbins or ball-bearing flowmeters, which, although they did not leak fluids, could cause inaccurate measurements if they adhered to the glass column. In 1910, M. Neu had been the first to apply rotameters in anesthesia for the administration of nitrous oxide and oxygen, but his machine was not a commercial success, perhaps because of the great cost of nitrous oxide in Germany at that time. Rotameters designed for use in German industry were first employed in Britain in 1937 by Richard Salt; but as World War II approached, the English were denied access to these sophisticated flowmeters. After World War II rotameters became regularly employed in British anesthesia machines, although most American equipment still featured nonrotating floats. The now universal practice of displaying gas flow in liters per minute was not a customary part of all American machines until more than a decade after World War II.

Vaporizers

The art of a smooth induction with a potent anesthetic was a great challenge, particularly if the inspired concentration could not be determined with accuracy. Even the clinical introduction of halothane after 1956 might have been similarly thwarted except for a fortunate coincidence: the prior development of calibrated vaporizers. Two types of calibrated vaporizers designed for other anesthetics had become available in the half decade before halothane was marketed. The prompt acceptance of halothane was in part because of an ability to provide it in carefully titrated concentrations.

The Copper Kettle was the first temperature-compensated, accurate vaporizer. It had been developed by Lucien Morris at the University of Wisconsin in response to Ralph Waters' plan to test chloroform by giving it in controlled concentrations.⁵⁰ Morris achieved this goal by passing a metered flow of oxygen through a vaporizer chamber that contained a sintered bronze disk to separate the oxygen into minute bubbles. The gas became fully saturated with anesthetic vapor as it percolated through the liquid. The concentration of the anesthetic inspired by the patient could be calculated by knowing the vapor pressure of the liquid anesthetic, the volume of oxygen flowing through the liquid, and the total volume of gases from all sources entering the anesthesia circuit. Although experimental models of Morris' vaporizer used a water bath to maintain stability, the excellent thermal conductivity of copper was substituted in later models. When first marketed, the Copper Kettle did not feature a mechanism to indicate changes in the temperature (and vapor pressure) of the liquid. Shuh-Hsun Ngai proposed the incorporation of a thermometer, a suggestion that was later added to all vaporizers of that class.⁵¹ The Copper Kettle (Foregger Company) and the Vernitrol (Ohio Medical Products) were universal vaporizers that could be charged with any anesthetic liquid, and, provided that its vapor pressure and temperature were known, the inspired concentration could be calculated quickly.

When halothane was first marketed in Britain, an effective temperature-compensated, agent-specific vaporizer had recently been placed in clinical use. The TECOTA (TEmperature COmpensated Trichloroethylene Air) vaporizer featured a bimetallic strip composed of brass and a nickel–steel alloy, two metals with different coefficients of expansion. As the anesthetic vapor cooled, the strip bent to move away from the orifice, thereby permitting more fresh gas to enter the vaporizing chamber. This maintained a constant inspired concentration despite changes in temperature and vapor pressure. After their TECOTA vaporizer was accepted into anesthetic practice, the technology was used to create the “Fluotec,” the first of a series of agent-specific “tec” vaporizers for use in the operating room.

Patient Monitors

In many ways, the history of late-nineteenth and early-20th century anesthesiology is the quest for the safest anesthetic. The discovery and widespread use of electrocardiography, pulse oximetry, blood gas analysis, capnography, and neuromuscular blockade monitoring have reduced patient morbidity and mortality and revolutionized anesthesia practice. While safer machines assured clinicians that appropriate gas mixtures were delivered to the patient, monitors provided an early

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warning of acute physiologic deterioration before patients suffered irrevocable damage.

Joseph Clover was one of the first clinicians to routinely perform basic hemodynamic monitoring. Clover developed the habit of monitoring his patients' pulse but surprisingly, this was a contentious issue at the time. Prominent Scottish surgeons scorned Clover's emphasis on the action of chloroform on the heart. Baron Lister and others preferred that senior medical students give anesthetics and urged them to “strictly carry out certain simple instructions, among which is that of never touching the pulse, in order that their attention may not be distracted from the respiration.”⁵² Lister also counseled, “it appears that preliminary examination of the chest, often considered indispensable, is quite unnecessary, and more likely to induce the dreaded syncope, by alarming the patients, than to avert it.”⁵³ Little progress in anesthesia could come from such reactionary statements. In contrast, Clover had observed the effect of chloroform on animals and urged other anesthetists to monitor the pulse at all times and to discontinue the anesthetic temporarily if any irregularity or weakness was observed in the strength of the pulse.

Two American surgeons, George W. Crile and Harvey Cushing, developed a strong interest in measuring blood pressure during anesthesia. Both men wrote thorough and detailed examinations of blood pressure monitoring; however, Cushing's contribution is better remembered because he was the first American to apply the Riva Rocci cuff, which he saw while visiting Italy. Cushing introduced the concept in 1902 and had blood pressure measurements recorded on anesthesia records.⁵⁴ In 1894, Cushing and a fellow student at Harvard Medical School, Charles Codman, initiated a system of recording patients' pulses to assess the course of the anesthetics they administered. In 1902, Cushing continued the practice of monitoring and recording patient blood pressures and pulses. The transition from manual to automated blood pressure devices, which first appeared in 1936 and operate on an oscillometric principle, has been gradual.

The first precordial stethoscope was believed to have been used by S. Griffith Davis at Johns Hopkins University.³⁸ He adapted a technique developed by Harvey Cushing in a laboratory in which dogs with surgically induced valvular lesions had stethoscopes attached to their chest wall so that medical students might listen to bruits characteristic of a specific malformation. Davis' technique was forgotten but was rehabilitated by Dr. Robert Smith, an energetic pioneer of pediatric anesthesiology in Boston in the 1940s. A Canadian contemporary, Albert Codesmith, of the Hospital for Sick Children, Toronto, became frustrated by the repeated dislodging of the chest piece under the surgical drapes and fabricated his first esophageal stethoscope from urethral catheters and Penrose drains. His brief report heralded its clinical role as a monitor of both normal and adventitious respiratory and cardiac sounds.⁵⁵

Electrocardiography, Pulse Oximetry, and Capnography

Clinical electrocardiography began with Willem Einthoven's application of the string galvanometer in 1903. Within two decades, Thomas Lewis had described its role in the diagnosis of disturbances of cardiac rhythm, while James Herrick and Harold Pardee first drew attention to the changes produced by myocardial ischemia. After 1928, cathode ray oscilloscopes were available, but the risk of explosion owing to the presence of flammable anesthetics forestalled the introduction of the electrocardiogram into routine anesthetic practice until after World War II. At that time, the small screen of the heavily shielded “bullet” oscilloscope displayed only 3 seconds of data, but that information was highly prized.

Pulse oximetry, the optical measurement of oxygen saturation in tissues, is one of the more recent additions to the anesthesiologist's array of routine monitors. Although research in this area began in 1932, its first practical application came during World War II. An American physiologist, Glen Millikan, responded to a request from British colleagues in aviation research. Millikan set about preparing a series of devices to improve the supply of oxygen that was provided to pilots flying at high altitude in unpressurized aircraft. To monitor oxygen delivery and to prevent the pilot from succumbing to an unrecognized failure of his oxygen supply, Millikan created an oxygen-sensing monitor worn on the pilot's earlobe, and coined the name oximeter to describe its action. Before his tragic death in a climbing accident in 1947, Millikan had begun to assess anesthetic applications of oximetry. Refinements of oximetry by a Japanese engineer, Takuo Aoyagi, led to the development of pulse oximetry. As John Severinghaus recounted the episode, Aoyagi had attempted to eliminate the changes in a signal caused by pulsatile variations when he realized that this fluctuation could be used to measure both the pulse and oxygen saturation.⁵³

Anesthesiologists have recognized a need for breath-by-breath measurement of respiratory and anesthetic gases. After 1954, infrared absorption techniques gave immediate displays of the exhaled concentration of CO₂. The ability to confirm endotracheal intubation and monitor ventilation, as reflected by concentrations of CO₂ in respired gas, began in 1943. At that time, K. Luft described the principle of infrared absorption by CO₂ and he developed an apparatus for measurement.⁵⁶ Routine application of capnography in anesthesia practice was pioneered by Dr. Bob Smalhout and Dr. Zden Kalenda in the Netherlands. Breath-to-breath continuous monitoring and a waveform display of CO₂ levels help anesthesiologists recognize abnormalities in metabolism, ventilation, and circulation. More recently, infrared analysis has been perfected to enable breath-by-breath measurement of anesthetic gases as well. This technology has largely replaced mass spectrometry, which initially had only industrial applications before Albert Faulconer of the Mayo Clinic first used it to monitor the concentration of an exhaled anesthetic in 1954.

Safety Standards

The introduction of safety features was coordinated by the American National Standards Institute (ANSI) Committee Z79, which was sponsored from 1956 until 1983 by the American Society of Anesthesiologists. Since 1983, representatives from industry, government, and health care professions have met on Committee Z79 of the American Society for Testing and Materials. They establish voluntary goals that may become accepted national standards for the safety of anesthesia equipment.

Ralph Tovell voiced the first call for standards during World War II while he was the U.S. Army Consultant in Anesthesiology for Europe. Tovell found that, as there were four different dimensions for connectors, tubes, masks, and breathing bags, supplies dispatched to field hospitals might not match their anesthesia machines. As Tovell observed, “When a sudden need for accessory equipment arose, nurses and corpsmen were likely to respond to it by bringing parts that would not fit.”⁵⁷ Although Tovell's reports did not gain an immediate response, after the war Vincent Collins and Hamilton Davis took up his concern and formed the ANSI Committee Z79. One of the committee's most active members, Leslie Rendell-Baker, wrote an account of the committee's domestic and international achievements.⁵⁸ He reported that Tovell encouraged all manufacturers

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to select the now uniform orifice of 22 mm for all adult and pediatric face masks and to make every tracheal tube connector 15 mm in diameter. For the first time, a Z79-designed mask-tube elbow adapter would fit every mask and tracheal tube connector.

The Z79 Committee introduced other advances. Tracheal tubes of nontoxic plastic bear a Z79 or IT (Implantation Tested) mark. The committee also mandated touch identification of oxygen flow control at the suggestion of Roderick Calverley,⁵⁹ which reduced the risk that the wrong gas would be selected before internal mechanical controls prevented the selection of an hypoxic mixture. Pin indexing reduced the hazard of attaching a wrong cylinder in the place of oxygen. Diameter indexing of connectors prevented similar errors in high-pressure tubing. For many years, however, errors committed in reassembling hospital oxygen supply lines led to a series of tragedies before polarographic oxygen analyzers were added to the inspiratory limb of the anesthesia circuit.

The History of Anesthetic Agents and Adjuvants

Inhaled Anesthetics

Throughout the second half of the 19th century, other compounds were examined for their anesthetic potential. The pattern of fortuitous discovery that brought nitrous oxide, diethyl ether, and chloroform forward between 1844 and 1847 continued. The next inhaled anesthetics to be used routinely, ethyl chloride and ethylene, were also discovered as a result of unexpected observations. Ethyl chloride and ethylene were first formulated in the 18th century. Ethyl chloride was used as a topical anesthetic and counterirritant; it was so volatile that the skin transiently “froze” after ethyl chloride was sprayed on it. Its rediscovery as an anesthetic came in 1894, when a Swedish dentist named Carlson sprayed ethyl chloride into a patient's mouth to “freeze” a dental abscess. Carlson was surprised to discover that his patient suddenly lost consciousness.

As the mechanisms to deliver drugs were refined, entirely new classes of medications were also developed, with the intention of providing safer, more pleasant pain control. Ethylene gas was the first alternative to ether and chloroform, but it had some major disadvantages. The rediscovery of ethylene in 1923 also came from a serendipitous observation. After it was learned that ethylene gas had been used to inhibit the opening of carnation buds in Chicago greenhouses, it was speculated that a gas that put flowers to sleep might also have an anesthetic action on humans. Arno Luckhardt was the first to publish a clinical study in February 1923. Within a month, Isabella Herb in Chicago and W. Easson Brown in Toronto presented two other independent studies. Ethylene was not a successful anesthetic because high concentrations were required and it was explosive. An additional significant shortcoming was a particularly unpleasant smell, which could only be partially disguised by the use of oil of orange or a cheap perfume. When cyclopropane was introduced, ethylene was abandoned.

The anesthetic action of cyclopropane was inadvertently discovered in 1929.⁶⁰ Brown and Henderson had previously shown that propylene had desirable properties as an anesthetic when freshly prepared, but after storage in a steel cylinder, it deteriorated to create a toxic material that produced nausea and cardiac irregularities in humans. Velyien Henderson, a professor of pharmacology at the University of Toronto, suggested that the toxic product be identified. After a chemist, George Lucas, identified cyclopropane among the chemicals in the tank, he prepared a sample in low concentration with oxygen and administered it to two kittens. The animals fell asleep quietly but quickly recovered unharmed. Rather than being a toxic contaminant, Lucas saw that cyclopropane was a potent anesthetic. After its effects in other animals were studied and cyclopropane proved to be stable after storage, human experimentation began.

Henderson was the first volunteer; Lucas followed. They then arranged a public demonstration in which Frederick Banting, a Nobel laureate for the discovery of insulin, was anesthetized before a group of physicians. Despite this promising beginning, further research was abruptly halted. Several anesthetic deaths in Toronto had been attributed to ethyl chloride, and concern about Canadian clinical trials of cyclopropane prevented human studies from proceeding. Rather than abandon the study, Henderson encouraged an American friend, Ralph Waters, to use cyclopropane at the University of Wisconsin. The Wisconsin group investigated the drug thoroughly and reported their clinical success in 1934.⁶¹

In 1930, Chauncey Leake and MeiYu Chen performed successful laboratory trials of vinethene (divinyl ether) but were thwarted in its further development by a professor of surgery in San Francisco. Ironically, Canadians, who had lost cyclopropane to Wisconsin, learned of vinethene from Leake and Chen in California and conducted the first human study in 1932 at the University of Alberta, Edmonton. International research collaboration enabled early anesthetic use of both cyclopropane and divinyl ether, advances that may not have occurred independently in either the United States or Canada.

All potent anesthetics of this period were explosive save for chloroform, whose hepatic and cardiac toxicity limited use in America. Anesthetic explosions remained a rare but devastating risk to both anesthesiologist and patient. To reduce the danger of explosion during the incendiary days of World War II, British anesthetists turned to trichloroethylene. This nonflammable anesthetic found limited application in America, as it decomposed to release phosgene when warmed in the presence of soda lime. By the end of World War II, however, another class of noninflammable anesthetics was prepared for laboratory trials. Ten years later, fluorinated hydrocarbons revolutionized inhalation anesthesia.

Fluorine, the lightest and most reactive halogen, forms exceptionally stable bonds. These bonds, although sometimes created with explosive force, resist separation by chemical or thermal means. For that reason, many early attempts to fluorinate hydrocarbons in a controlled manner were frustrated by the marked chemical activity of fluorine. In 1930, the first commercial application of fluorine chemistry came in the form of the refrigerant, Freon. This was followed by the first attempt to prepare a fluorinated anesthetic by Harold Booth and E. May Bixby in 1932. Although their drug, monochlorodifluoromethane, was devoid of anesthetic action, as were other drugs studied that decade, their report predicted future developments. “A survey of the properties of 166 known gases suggested that the best possibility of finding a new noncombustible anesthetic gas lay in the field of organic fluoride compounds. Fluorine substitution for other halogens lowers the boiling point, increases stability, and generally decreases toxicity.”⁶²

After the war, a team at the University of Maryland under Professor of Pharmacology John C. Krantz, Jr., investigated the anesthetic properties of dozens of hydrocarbons over a period of several years, but only one, ethyl vinyl ether, entered clinical use in 1947. Because it was flammable, Krantz requested that it be fluorinated. In response, Julius Shukys prepared several fluorinated analogs. One of these, trifluoroethyl vinyl ether, or fluroxene, became the first fluorinated anesthetic. Fluroxene was marketed from 1954 until 1974.

In 1951, Charles Suckling, a British chemist of Imperial Chemical Industries, was asked to create a new anesthetic.

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Suckling, who already had an expert understanding of fluorination, began by asking clinicians to describe the properties of an ideal anesthetic. He learned from this inquiry that his search must consider several limiting factors, including the volatility, inflammability, stability, and potency of the compounds. After 2 years of research and testing, Charles Suckling created halothane. He first determined that halothane possessed anesthetic action by anesthetizing mealworms and houseflies before he forwarded it to pharmacologist James Raventos. Suckling also made accurate predictions as to the concentrations required for anesthesia in higher animals. After Raventos completed a favorable review, halothane was offered to Michael Johnstone, a respected anesthetist of Manchester, England, who recognized its great advantages over other anesthetics available in 1956. After Johnstone's endorsement, halothane use spread quickly and widely within the practice of anesthesia.⁶³

Halothane was followed in 1960 by methoxyflurane, an anesthetic that remained popular for a decade. By 1970, however, it was learned that dose-related nephrotoxicity following protracted methoxyflurane anesthesia was caused by inorganic fluoride. Similarly, because of persisting concern that rare cases of hepatitis following anesthesia might be a result of a metabolite of halothane, the search for newer inhaled anesthetics focused on the resistance to metabolic degradation.

Two fluorinated liquid anesthetics, enflurane and its isomer isoflurane, were results of the search for increased stability. They were synthesized by Ross Terrell in 1963 and 1965, respectively. Because enflurane was easier to create, it preceded isoflurane. Its application was restricted after it was shown to be a marked cardiovascular depressant and to have some convulsant properties. Isoflurane was nearly abandoned because of difficulties in its purification, but after Louise Speers overcame this problem, several successful trials were published in 1971. The release of isoflurane for clinical use was delayed again for more than half a decade by calls for repeated testing in lower animals, owing to an unfounded concern that the drug might be carcinogenic. As a consequence, isoflurane received more thorough testing than any other drug heretofore used in anesthesia. The era when an anesthetic could be introduced following a single fortuitous observation had given way to a cautious program of assessment and reassessment. Remarkably, no anesthetics were introduced into clinical use for another 20 years. Finally, desflurane was released in 1992 and sevoflurane was released in 1994. Xenon, a gas having many properties of the ideal anesthetic, was administered to a few patients in the early 1950s but it never gained popularity because of the extreme costs associated with its removal from air. However, interest in xenon has been renewed now that gas concentrations can be accurately measured when administered at low flows, and devices are available to scavenge and reuse the gas.

Intravenous Anesthetics

Prior to William Harvey's description of a complete and continuous intravascular circuit in De Motu Cordis (1628), it was widely held that blood emanated from the heart and was propelled to the periphery where it was consumed. The idea that substances could be injected intravascularly and travel systemically probably originated with Christopher Wren. In 1657, Wren injected aqueous opium into a dog through a goose quill attached to a pig's bladder, rendering the animal “stupefied.”⁶⁴ Wren similarly injected intravenous crocus metallorum, an impure preparation of antimony, and observed the animals to vomit and then die. Knowledge of a circulatory system and intravascular access spurred investigations in other areas, and Wren's contemporary, Richard Lower, performed the first blood transfusions of lamb's blood into dogs and other animals.

In the mid-19th century, equipment necessary for effective intravascular injections was conceived. Vaccination lancets were used in the 1830s to puncture the skin and force morphine paste subcutaneously for analgesia.⁶⁵ The hollow needle and hypodermic syringe were developed in the following decades but were not initially designed for intravenous use. In 1845, Dublin surgeon Francis Rynd created the hollow needle for injection of morphine into nerves in the treatment of “neuralgias.” Similarly, Charles Gabriel Pravaz designed the first functional syringe in 1853 for perineural injections. Alexander Wood, however, is generally credited with perfecting the hypodermic glass syringe. In 1855, Wood published an article on the injection of opiates into painful spots by use of hollow needle and his glass syringe.⁶⁶

In 1872, Pierre Oré of Lyons performed what is perhaps the first successful intravenous surgical anesthetic by injecting chloral hydrate immediately prior to incision. His 1875 publication describes its use in 36 patients but several postoperative deaths lent little to recommend this method to other practitioners.⁶⁷ In 1909, Ludwig Burkhardt produced surgical anesthesia by intravenous injections of chloroform and ether in Germany. Seven years later, Elisabeth Bredenfeld of Switzerland reported the use of intravenous morphine and scopolamine. The trials failed to show an improvement over inhaled techniques. Intravenous anesthesia found little application or popularity, primarily because of a lack of suitable drugs. In the following decades, this would change.

The first barbiturate, barbital, was synthesized in 1903 by Fischer and von Mering. Phenobarbital and all other successors of barbital had very protracted action and found little use in anesthesia. After 1929, oral pentobarbital was used as a sedative before surgery, but when it was given in anesthetic concentrations, long periods of unconsciousness followed. The first short-acting oxybarbiturate was hexobarbital (Evipal), available clinically in 1932. Hexobarbital was enthusiastically received by the anesthesia communities in Europe and North America because its abbreviated induction time was unrivaled by any other technique. A London anesthetist, Ronald Jarman, found that it had a dramatic advantage over inhalation inductions for minor procedures. Jarman instructed his patients to raise one arm while he injected hexobarbital into a vein of the opposite forearm. When the upraised arm fell, indicating the onset of hypnosis, the surgeon could begin. Patients were also amazed in that many awoke unable to believe they had been anesthetized.⁶⁸

Even though the prompt action of hexobarbital had a dramatic effect on the conduct of anesthesia, it was soon replaced by two thiobarbiturates. In 1932, Donalee Tabern and Ernest H. Volwiler of the Abbott Company synthesized thiopental (Pentothal) and thiamylal (Surital). The sulfated barbiturates proved to be more satisfactory, potent, and rapid acting than were their oxybarbiturate analogs. Thiopental was first administered to a patient at the University of Wisconsin in March 1934, but the successful introduction of thiopental into clinical practice followed a thorough investigation conducted by John Lundy and his colleagues at the Mayo Clinic in June 1934.

When first introduced, thiopental was often given in repeated increments as the primary anesthetic for protracted procedures. Its hazards were soon appreciated. At first, depression of respiration was monitored by the simple expedient of observing the motion of a wisp of cotton placed over the nose. Only a few skilled practitioners were prepared to pass a tracheal tube if the patient stopped breathing. Such practitioners realized that thiopental without supplementation did not suppress airway reflexes, and they therefore encouraged the prophylactic provision of topical anesthesia of the airway

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beforehand. The vasodilatory effects of thiobarbiturates were widely appreciated only when thiopental caused cardiovascular collapse in hypovolemic burned civilian and military patients in World War II. In response, fluid replacement was used more aggressively and thiopental administered with greater caution.

In 1962, ketamine was synthesized by Dr. Calvin Stevens at the Parke Davis Laboratories in Ann Arbor, Michigan. One of the cyclohexylamine compounds that includes phencyclidine, ketamine was the only drug of this group that gained clinical utility. The other compounds produced undesirable postanesthetic delirium and psychomimetic reactions. In 1966, the neologism “dissociative anesthesia” was created by Guenter Corrsen and Edward Domino to describe the trancelike state of profound analgesia produced by ketamine.⁶⁹ It was released for use in 1970, and although it remains primarily an agent for anesthetic induction, its analgesic properties are increasingly studied and used by pain specialists.

Etomidate was first described by Paul Janssen and his colleagues in 1964, and originally given the name Hypnomidate. Its key advantages, minimal hemodynamic depression and lack of histamine release, account for its ongoing utility in clinical practice. It was released for use in 1974 and despite its drawbacks (pain on injection, myoclonus, postoperative nausea and vomiting, and inhibition of adrenal steroidogenesis), etomidate is often the drug of choice for anesthetizing hemodynamically unstable patients.

Propofol, or 2,-6 di-isopropyl phenol, was first synthesized by Imperial Chemical Industries and tested clinically in 1977. Investigators found that it produced hypnosis quickly with minimal excitation and that patients awoke promptly once the drug was discontinued. In addition to its excellent induction characteristics, the antiemetic action of propofol made it an agent of choice in patient populations prone to nausea and emesis. Regrettably, Cremophor EL, the solvent with which it was formulated, produced several severe anaphylactic reactions and it was withdrawn from use. Once propofol was reformulated with egg lecithin, glycerol, and soybean oil, the drug re-entered clinical practice and gained great success. Its popularity in Britain coincided with the introduction of the LMA, and it was soon noted that propofol suppressed pharyngeal reflexes to a degree that permitted the insertion of an LMA without a need for either muscle relaxants or potent inhaled anesthetics.

Local Anesthetics

Centuries after the conquest of Peru, Europeans became aware of the stimulating properties of a local, indigenous plant that the Peruvians called khoka. Khoka, which meant the plant, quickly became known as coca in Europe. In 1860, shortly after the Austrian Carl von Scherzer imported enough coca leaves to allow for analysis, German chemists Albert Niemann and Wilhelm Lossen isolated the main alkaloid and named it cocaine. Twenty-five years later, at the recommendation of his friend Sigmund Freud, Carl Koller became interested in the effects of cocaine. After several animal experiments, Koller successfully demonstrated the analgesic properties of cocaine applied to the eye in a patient with glaucoma.⁷⁰ Unfortunately, nearly simultaneous with the first reports of cocaine use, there were reports of central nervous system and cardiovascular toxicity.^71,72 As the popularity of cocaine grew, so did the frequency of toxic reactions and cocaine addictions.⁷³ Skepticism about the use of cocaine quickly grew within the medical community, forcing the pharmacological industry to develop alternative local anesthetics.

In 1898, Alfred Eihorn synthesized nivaquine, the first amino amide local anesthetic.⁷⁴ Nirvaquine proved to be an irritant to tissues and its use was immediately stopped. Returning his attention toward the development of amino ester local anesthetics, Eihorn synthesized benzocaine in 1900 and procaine (novocaine) shortly after in 1905. Amino esters were commonly used for local infiltration and spinal anesthesia despite their low potency and high likelihood to cause allergic reactions. Tetracaine, the last (and probably safest) amino ester local anesthetic developed, proved to be quite useful for many years.

In 1944, Nils Löfgren and Bengt Lundquist developed lidocaine, an amino amide local anesthetic.⁷³ Lidocaine gained immediate popularity because of its potency, rapid onset, decreased incidence of allergic reactions, and overall effectiveness for all types of regional anesthetic blocks. Since the introduction of lidocaine, all local anesthetics developed and marketed have been of the amino amide variety.

Because of the increase in lengthy and sophisticated surgical procedures, the development of a long-acting local anesthetic took precedence. From that demand, bupivacaine was introduced in 1965. Synthesized by B. Ekenstam in 1957,⁷⁶ bupivacaine was initially discarded after it was found to be highly toxic. By 1980, several years after being introduced to the United States, there were several reports of almost simultaneous seizures and cardiovascular collapse following unintended intravascular injection.⁷⁷ Shortly after this, as a result of the cardiovascular toxicity associated with bupivacaine and the profound motor block associated with etidocaine, the pharmaceutical industry began searching for a new long-acting alternative. Introduced in 1996, ropivacaine is structurally similar to mepivacaine and bupivacaine, although it is prepared as a single levorotatory isomer rather than a racemic mixture. The levorotatory isomer has less potential for toxicity than the dextrorotatory isomer.⁷⁸ The potential safety of ropivacaine is controversial because ropivacaine is approximately 25% less potent than bupivacaine. Therefore, at equal-potent doses the margin of safety between ropivacaine and bupivacaine becomes less apparent, although systemic toxicity with ropivacaine may respond more quickly to conventional resuscitation.⁷⁹

Each local anesthetic developed has had its own positive and negative attributes, which is why some are still used today and others have fallen out of favor. Currently, the pharmaceutical industry is in the process of developing extended-release local anesthetics using liposomes and microspheres.^80,81

Opioids

Opioids (historically referred to as narcotics, although semantically incorrect—see Chapter 19) remain the analgesic workhorse in anesthesia practice. They are used routinely in the perioperative period, in the management of acute pain, and in a variety of terminal and chronic pain states. The availability of short-, medium-, and long-acting opioids, as well as the many routes of administration, gives physicians considerable flexibility in the use of these agents. The analgesic and sedating properties of opium have been known for more than two millennia. Certainly the Greeks and Chinese civilizations harnessed these properties in medical and cultural practices. Opium is derived from the seeds of the poppy (Papaver somniferum), and is an amalgam of more than 25 pharmacologic alkaloids. The first alkaloid isolated, morphine, was extracted by Prussian chemist Freidrich A. W. Sertürner in 1803. He named this alkaloid after the Greek god of dreams, Morpheus. Morphine became commonly used as a supplement to inhaled anesthesia and for postoperative pain control during the latter half of the 19th century. Codeine, another alkaloid of opium, was isolated in 1832 by Robiquet but its relatively weaker analgesic potency and nausea at higher doses limits its role in managing moderate-to-severe perioperative surgical pain.

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Meperidine was the first synthetic opioid and was developed in 1939 by two German researchers at IG Farben, Otto Eisleb and O. Schaumann. Although many pharmacologists are remembered for the introduction of a single drug, one prolific researcher, Paul Janssen, has since 1953 brought forward more than 70 agents from among 70,000 chemicals created in his laboratory. His products have had profound effects on disciplines as disparate as parasitology and psychiatry. The pace of productive innovation in Janssen's research laboratory is astonishing. Chemical R4263 (fentanyl), synthesized in 1960, was followed only a year later by R4749 (droperidol), and then etomidate in 1964. Innovar, the fixed combination of fentanyl and droperidol, is less popular now but Janssen's phenylpiperidine derivatives, fentanyl, sufentanil and alfentanil, are staples in the anesthesia pharmacopoeia. Remifentanil, an ultra short-acting opioid introduced by Glaxo-Wellcome in 1996, is a departure from other opioids in that it has very rapid onset and equally rapid offset due to metabolism by nonspecific tissue esterases. Ketorolac, a nonsteroidal antiinflammatory drug (NSAID) approved for use in 1990, was the first parenteral NSAID indicated for postoperative pain. With a 6- to 8-mg morphine equivalent analgesic potency, Ketorolac provides significant postoperative pain control and has particular use when an opioid-sparing approach is essential. Ketorolac use is limited by side effects and may be inappropriate in patients with underlying renal dysfunction, bleeding problems, or compromised bone healing.

Muscle Relaxants

Muscle relaxants entered anesthesia practice nearly a century after inhalational anesthetics (Table 1-1). Curare, the first known neuromuscular blocking agent, was originally used in hunting and tribal warfare by native peoples of South America. The curares are alkaloids prepared from plants native to equatorial rain forests. The refinement of the harmless sap of several species of vines into toxins that were lethal only when injected was an extraordinary triumph introduced by paleopharmacologists in loincloths. Their discovery was the more remarkable because it was independently repeated on three separate continents—South America, Africa, and Asia. These jungle tribes also developed nearly identical methods of delivering the toxin by darts, which, after being dipped in curare, maintained their potency indefinitely until they were propelled through blowpipes to strike the flesh of monkeys and other animals of the treetops. Moreover, the American Indians knew of the juice of an herb that would counteract the effects of the poison if administered in time.⁸²

The earliest clinical use of curare in humans was to ameliorate the tortuous muscle spasms of infectious tetanus. In 1858, New York physician Louis Albert Sayres reported two cases in which he attempted to treat severe tetanus with curare at the Bellevue Hospital. Both of his patients died. Similar efforts were undertaken to use muscle relaxants to treat epilepsy, rabies, and choreiform disorders. Treatment of Parkinson-like rigidity and the prevention of trauma from seizure therapy also preceded the use of curare in anesthesia.⁸³

Interestingly, curare antagonists were developed well before muscle relaxants were ever used in surgery. In 1900, Jacob Pal, a Viennese physician, recognized that curare could be antagonized by physostigmine. This substance had been isolated from the calabar bean some 36 years earlier by Scottish pharmacologist Sir T. R. Fraser. Neostigmine methylsulphate was synthesized in 1931 and was significantly more potent in antagonizing the effects of curare.⁸⁴

In 1938, Richard and Ruth Gill returned to New York from South America, bringing with them 11.9 kg of crude curare collected near their Ecuadorian ranch. Their motivation was a mixture of personal and altruistic goals. Some months before, while on an earlier visit to the United States, Richard Gill learned that he had multiple sclerosis. His physician, Dr. Walter Freeman, mentioned the possibility that curare might have a therapeutic role in the management of spastic disorders. When the Gills returned to the United States with their supply of crude curare, they encouraged scientists at E. R. Squibb & Co. to take an interest in its unique properties. Squibb soon offered semirefined curare to two groups of American anesthesiologists, who assessed its action but quickly abandoned their studies when it caused total respiratory paralysis in two patients and the death of laboratory animals.

The earliest effective clinical application of curare in medicine occurred in physiatry. After A. R. McIntyre refined a portion of the raw curare in 1939, Abram E. Bennett of Omaha, Nebraska, injected it into children with spastic disorders. While no persistent benefit could be observed in these patients, he next administered it to patients about to receive Metrazol, a precursor to electroconvulsive therapy. Because it eliminated seizure-induced fractures, they termed it a “shock absorber.” By 1941, other psychiatrists followed this practice and, when they found that the action of curare was protracted, occasionally used neostigmine as an antidote.

Curare was used initially in surgery by Arthur Lawen in 1912, but the published report was written in German and was ignored for decades. Lawen, a physiologist and physician from Leipzig, used curare in his laboratory before boldly producing abdominal relaxation at a light level of anesthesia in a surgical patient. Lawen's efforts were not appreciated for decades, and while his pioneering work anticipated later clinical application, safe use would have to await the introduction of regular intubation of the trachea and controlled ventilation of the lungs.⁸⁵

Thirty years after Lawen, Harold Griffith, the chief anesthetist of the Montreal Homeopathic Hospital, learned of A. E. Bennett's successful use of curare and resolved to apply it in anesthesia. As Griffith was already a master of tracheal intubation, he was much better prepared than were most of his contemporaries to attend to potential complications. On January 23, 1942, Griffith and his resident, Enid Johnson, anesthetized and intubated the trachea of a young man before injecting curare early in the course of his appendectomy. Satisfactory abdominal relaxation was obtained and the surgery proceeded without incident. Griffith and Johnson's report of the successful use of curare in the 25 patients of their series launched a revolution in anesthetic care.⁸⁶

Anesthesiologists who practiced before muscle relaxants recall the anxiety they felt when a premature attempt to intubate the trachea under cyclopropane caused persisting laryngospasm. Before 1942, abdominal relaxation was possible only if the patient tolerated high concentrations of an inhaled anesthetic, which might bring profound respiratory depression and protracted recovery. Curare and the drugs that followed transformed anesthesia profoundly. Because intubation of the trachea could now be taught in a deliberate manner, a neophyte could fail on a first attempt without compromising the safety of the patient. For the first time, abdominal relaxation could be attained when curare was supplemented by light planes of inhaled anesthetics or by a combination of intravenous agents providing “balanced anesthesia.” New frontiers opened. Sedated and paralyzed patients could now successfully undergo the major physiologic trespasses of cardiopulmonary bypass, deliberate hypothermia, or long-term respiratory support after surgery.

Credit for successful and safe introduction of curare and d-tubocurarine into anesthesia must in part be given to a Squibb researcher named H. A. Holaday. Crude, unstandardized preparations of curare produced uncertain clinical effects and undesirable side effects related to various impurities. Isolation

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of d-tubocurarine in 1935 renewed clinical interest but a method for standardizing “Intocostrin” and its purer derivative, d-tubocurarine, had yet to be devised. In the early 1940s, in part as a result of Griffith and Johnson's successful trials, Squibb embarked on wide-scale production. Holaday developed a reliable, easily reproducible method for standardizing curare doses that became known as the rabbit head-drop assay (Fig. 1-5). The assay consisted of aqueous curare solution injected intravenously in 0.1-mL doses every 15 seconds until the end point, when the rabbit became unable to raise its head, was reached.⁸⁷

Table 1-1 Events in the Development of Muscle Relaxants

YEAR EVENT 1516 Peter Martyr d'Anghera, De orbe novo, published account of South American Indian arrow poisons 1596 Sir Walter Raleigh provides detailed account of arrow poison effects and antidote 1745 Charles-Marie de la Condamine returns from Ecuador and conducts curare experiments with chickens and attempted to use sugar as an antidote 1780 Abbe Felix Fontana inserts curare directly into exposed sciatic nerve of rabbit without effect, concludes that mechanism is the destruction of the irritability of voluntary muscles. Publishes On the American Poison Ticunas (name of South American tribe) 1811 Benjamin Collins Brodie demonstrates that animals mechanically ventilated may survive significant doses of curare 1812 William Sewell suggests use of curare in “hydrophobia” (rabies) and tetanus 1844 Claude Bernard determines that death occurs by respiratory failure, motor nerves are unable to transmit stimuli from higher centers, differential effect on muscles with peripheral and thoracic muscles being affected before respiratory muscles. Bernard concludes that the site of action is the junction between muscles and nerves, neuromuscular junction 1858 Louis Albert Sayres, New York physician, uses curare to treat tetanus in two patients 1864 Physostigmine isolated from Calabar beans by Sir T. R. Fraser, a Scottish pharmacologist 1886–1897 R. Boehm, a German chemist, demonstrated three separate classes of alkaloids in each of three types of indigenous containers: tube-curares, pot-curares, and calabash-curares 1900 Jacob Pal recognizes that physostigmine can antagonize the effects of curare 1906 Succinylcholine prepared by Reid Hunt and R. Taveau, experimented on rabbits pretreated with curare to learn of cardiac effects and so paralysis went unrecognized 1912 Arthur Lawen uses curare in surgery but report published in German so it goes largely unrecognized 1938 Richard and Ruth Gill bring large quantity of curare to New York for further study by pharmaceutical company 1939 Abram E. Bennett uses curare in children with spastic disorders and to prevent trauma from Metrazol therapy (precursor to ECT) 1942 Harold Griffith and Enid Johnson use curare for abdominal relaxation in surgery 1942 H. A. Halody develops rabbit head-drop assay for standardization and large-scale production of curare and d-tubocurarine 1948 Decamethonium, a depolarizing relaxant, is synthesized 1949 Succinylcholine prepared by Daniel Bovet, and the following year by J. C. Castillo and Edwin de Beer 1956 Distinction between depolarizing and nondepolarizing neuromuscular blockade is made by William D. M. Paton 1964 Pancuronium released for use in humans, synthesized by Savage and Hewett 1979 Vecuronium introduced, specifically designed to be more hepatically metabolized than pancuronium 1993 Mivacurium released for clinical use 1994 Rocuronium introduced to clinical practice

Successful clinical use of curare led to the introduction of other muscle relaxants. By 1948, gallamine and decamethonium had been synthesized. Metubine, a curare “rediscovered” in the 1970s, was used clinically in the same year. Succinylcholine was prepared by the Nobel laureate Daniel Bovet in 1949 and was in wide international use before historians noted that the drug had been synthesized and tested long beforehand. In 1906, Reid Hunt and R. Taveaux prepared succinylcholine among a series of choline esters, which they had injected into rabbits to observe their cardiac effects. If their rabbits had not been previously paralyzed with curare, the

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depolarizing action of succinylcholine might have been recognized decades earlier.

Figure 1-5. The Rabbit head-drop assay. H. A. Halloday of Squibb pharmaceutical company developed a method of standardizing doses of curare and d-tubocurarine a normal rabbit (A) had 0.1 ml of aqueous cecurane solution injected every 15 seconds until it could no longer raise its head (B).

The ability to monitor intraoperative neuromuscular blockade with nerve stimulators began in 1958. Working at St. Thomas' Hospital in London, T. H. Christie and H. Churchill-Davidson developed a method for monitoring peripheral neuromuscular blockade during anesthesia. It was not until 1970, however, that H. H. Ali and colleagues devised the technique of delivering four supramaximal impulses delivered at 2 Hz (0.5 seconds apart), or a “Train of Four,” as a method of quantifying the degree of residual neuromuscular blockade.⁸⁸

Research in relaxants was rekindled in 1960 when researchers became aware of the action of maloetine, a relaxant from the Congo basin. It was remarkable in that it had a steroidal nucleus. Investigations of maloetine led to pancuronium in 1968. In the 1970s and 1980s, research shifted toward identification of specific receptor biochemistry and development of receptor-specific drugs. From these isoquinolines, four related products emerged: vecuronium, pipecuronium, rocuronium, and rapacuronium. Rapacuronium, released in the early 1990s, was withdrawn from clinical use after several cases of intractable bronchospasm led to brain damage or death. Four clinical products based on the steroid parent drug d-tubocurarine (atracurium, mivacurium, doxacurium, and cis-atracurium) also made it to clinical use. Recognition that atracurium and cis-atracurium undergo spontaneous degradation by Hoffmann elimination has defined a role for these muscle relaxants in patients with liver and renal insufficiency.

Antiemetics

Effective treatment for postoperative nausea and vomiting (PONV) evolved relatively recently and has been driven by incentives to limit hospitalization expenses and improve patient satisfaction. But PONV is an old problem for which late 19th century practitioners recognized many causes including anxiety, severe pain, sudden changes in blood pressure, ileus, ingestion of blood, and the residual effects of opioids and inhalational anesthetics. Risk of pulmonary aspiration of gastric contents and subsequent death from asphyxia or aspiration pneumonia was a feared consequence of anesthetics, especially those preceding use of cuffed endotracheal tubes. Vomiting and aspiration during anesthesia led to the practice of maintaining an empty stomach preoperatively, a policy that continues today despite evidence that clear fluids up to 3 hours before surgery do not increase gastric volumes, change gastric pH, or increase the risk of aspiration.

A variety of treatments for nausea and vomiting were proposed by early anesthetists. James Gwathemy's 1914 publication, Anesthesia, commented that British surgeons customarily gave tincture of iodine in a teaspoonful of water every half hour for three or four doses. Inhalation of vinegar fumes, and rectal injection of 30 to 40 drops of tincture of opium with 60 grains of sodium bromide, were also thought to quiet the vomiting center.⁸⁹ Other practitioners attempted olfactory control by placing a piece of gauze moistened with essence of orange or an aromatic oil on the upper lip of the patient.⁹⁰ A 1937 anesthesia textbook encouraged treatment of PONV with lateral positioning, “iced soda water, strong black coffee, and chloretone.”⁹¹ Counterirritation, such as mustard leaf on the epigastrium, was also believed useful in limiting emesis.⁹² As late as 1951, anesthesia texts recommended oxygen administration, whiffs of ammonia spirits, and control of blood pressure and positioning.⁹³ The complex central mechanisms of nausea and vomiting were largely unaffected by most of these treatments. Newer drugs capable of intervening at specific pathways were needed to have an impact on PONV. As more short-acting anesthetics were developed, the problem received sharper focus in awake postoperative patients in the recovery room. The nausea attending use of newer chemotherapy agents provided additional impetus to the development of antiemetic medications.

In 1955, a nonrandomized study using the antihistamine cyclizine showed a reduction in PONV from 27% to 21% in a group of 3,000 patients. The following year, a more rigorous study by Knapp and Beecher reported a significant benefit from prophylaxis with the neuroleptic chlorpromazine. In 1957, promethazine (Phenergan) and chlorpromazine were both found to reduce PONV when used prophylactically. Thirteen years later, a double-blind study evaluating metoclopramide was published and that drug became a first-line drug in the management of PONV. Droperidol, released in the early 1960s, became widely used until 2001 when concerns regarding prolongation of QT intervals prompted a warning from the Food and Drug Administration about its continued use.

The antiemetic effects of corticosteroids were first recognized by oncologists treating intracranial edema from tumors.⁹⁴ Subsequent studies have borne out the antiemetic properties of this class of drugs in treating PONV. Recognition of the serotonin 5-HT3 pathway in PONV has led to a unique

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class of drugs devoted only to addressing this particular problem. Ondansetron, the first representative of this drug class, was approved by the Food and Drug Administration in 1991. Additional serotonin 5-HT3 antagonists have been approved and are available today.

Anesthesia Subspecialties

Regional Anesthesia

Cocaine, an extract of the coca leaf, was the first effective local anesthetic. After Albert Niemann refined the active alkaloid and named it cocaine, it was used in experiments by a few investigators. It was noted that cocaine provided topical anesthesia and even produced local insensibility when injected, but Carl Koller, a Viennese surgical intern, first recognized the utility of cocaine in clinical practice.

In 1884, Carl Koller was completing his medical training at a time when many operations on the eye were performed without general anesthesia. Almost four decades after the discovery of ether, general anesthesia by mask still had limitations for ophthalmic surgery: lack of patient cooperation, interference of the anesthesia apparatus with surgical access, and the high incidence of PONV. At that time, since fine sutures were not available and surgical incisions of the eye were not closed, postoperative vomiting threatened the extrusion of the globe's contents, putting the patient at risk for irrevocable blindness.⁹⁵

While a medical student, Koller had worked in a Viennese laboratory in a search of a topical ophthalmic anesthetic to overcome the limitations of general anesthesia. Unfortunately, the suspensions of morphine, chloral hydrate, and other drugs that he had used had been ineffectual. In 1884, Koller's friend, Sigmund Freud, became interested in the cerebral-stimulating effects of cocaine and gave him a small sample in an envelope, which he placed in his pocket. When the envelope leaked, a few grains of cocaine stuck to Koller's finger and he absentmindedly licked his tongue. When his tongue became numb, Koller instantly realized that he had found the object of his search. In his laboratory, he made a suspension of cocaine crystals that he and a laboratory associate tested in the eyes of a frog, a rabbit, and a dog. Satisfied with the anesthetic effects seen in the animal models, Koller dropped the solution onto his own cornea. To his amazement, his eyes were insensitive to the touch of a pin.⁹⁶ As an intern, Carl Koller could not afford to attend a Congress of German Ophthalmologists in Heidelberg on September 15, 1884. However, a friend presented his article at the meeting and a revolution in ophthalmic surgery and other surgical disciplines began. Within the next year, more than 100 articles supporting the use of cocaine appeared in European and American medical journals. In 1888, Koller immigrated to New York, where he practiced ophthalmology for the remainder of his career.

American surgeons quickly developed new applications for cocaine. Its efficacy in anesthetizing the nose, mouth, larynx, trachea, rectum, and urethra was described in October 1884. The next month, the first reports of its subcutaneous injection were published. In December 1884, two young surgeons, William Halsted and Richard Hall, described blocks of the sensory nerves of the face and arm. Halsted even performed a brachial plexus block but did so under direct vision while the patient received an inhaled anesthetic.⁹⁷ Unfortunately, self-experimentation with cocaine was hazardous, as both surgeons became addicted.⁹⁸ Addiction was an ill-understood but frequent problem in the late 19th century, especially when cocaine and morphine were present in many patent medicines and folk remedies.

Other regional anesthetic techniques were attempted before the end of the 19th century. The term spinal anesthesia was coined in 1885 by Leonard Corning, a neurologist who had observed Hall and Halsted. Corning wanted to assess the action of cocaine as a specific therapy for neurologic problems. After first assessing its action in a dog, producing a blockade of rapid onset that was confined to the animal's rear legs, he performed a neuraxial block using cocaine on a man “addicted to masturbation.” Corning administered one dose without effect, then after a second dose, the patient's legs “felt sleepy.” The man had impaired sensibility in his lower extremity after about 20 minutes and left Corning's office “none the worse for the experience.”⁹⁹ Although Corning did not describe escape of cerebrospinal fluid (CSF) in either case, it is likely that the dog had a spinal anesthetic and that the man had an epidural anesthetic. No therapeutic benefit was described, but Corning closed his account and his attention to the subject by suggesting that cocainization might in time be “a substitute for etherization in genito-urinary or other branches of surgery.”¹⁰⁰

Two other authors, August Bier and Theodor Tuffier, described authentic spinal anesthesia, with mention of CSF, injection of cocaine, and an appropriately short onset of action. In a comparative review of the original articles by Bier, Tuffier, and Corning, it was concluded that Corning's injection was extradural, and Bier merited the credit for introducing spinal anesthesia.¹⁰¹

Fourteen years passed before spinal anesthesia was performed for surgery. In the interval, Heinrich Quincke of Kiel, Germany, had described his technique of lumbar puncture. He offered the valuable observation that it was most safely performed at the level of the third or fourth lumbar interspace because entry at that level was below the termination of the spinal cord. Quincke's technique was used in Kiel for the first deliberate cocainization of the spinal cord in 1899 by his surgical colleague, August Bier. Six patients received small doses of cocaine intrathecally, but because some cried out during surgery while others vomited and experienced headaches, Bier considered it necessary to conduct further experiments before continuing this technique for surgery.

Professor Bier permitted his assistant, Dr. Hildebrandt, to perform a lumbar puncture, but after the needle penetrated the dura, Hildebrandt could not fit the syringe to the needle and a large volume of the professor's spinal fluid escaped. They were at the point of abandoning the study when Hildebrandt volunteered to be the subject of a second attempt. Their persistence was rewarded with an astonishing success. Twenty-three minutes after the spinal injection, Bier noted: “A strong blow with an iron hammer against the tibia was not felt as pain. After 25 minutes: Strong pressure and pulling on a testicle were not painful.”⁹⁴ They celebrated their success with wine and cigars. That night, both developed violent headaches, which they attributed at first to their celebration. Bier's headache was relieved after 9 days of bed rest. Hildebrandt, as a house officer, did not have the luxury of continued rest. Bier postulated that their headaches were a result of the loss of large volumes of CSF and urged that this be avoided if possible. The high incidence of complications following lumbar puncture with wide-bore needles and the toxic reactions attributed to cocaine explain his later loss of interest in spinal anesthesia.¹⁰²

Surgeons in several other countries soon practiced spinal anesthesia and progress occurred by many small contributions to the technique. Theodor Tuffier published the first series of 125 spinal anesthetics from France and he later counseled that the solution should not be injected before CSF was seen. The first American report was by Rudolph Matas of New Orleans, whose first patient developed postanesthetic meningismus, a frequent complication that was overcome in part by the use of hermetically sealed sterile solutions recommended by E. W. Lee of Philadelphia and sterile gloves as advocated by Halsted. During 1899, Dudley Tait and Guidlo Caglieri of San Francisco

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performed experimental studies in animals and therapeutic spinals for orthopaedic patients. They encouraged the use of fine needles to lessen the escape of CSF and urged that the skin and deeper tissues be infiltrated beforehand with local anesthesia.¹⁰³ This had been suggested earlier by William Halsted and the foremost advocate of infiltration anesthesia, Carl Ludwig Schleich of Berlin. An early American specialist in anesthesia, Ormond Goldan, published an anesthesia record appropriate for recording the course of “intraspinal cocainization” in 1900. In the same year, Heinrich Braun learned of a newly described extract of the adrenal gland, epinephrine, which he used to prolong the action of local anesthetics with great success. Braun developed several new nerve blocks, coined the term conduction anesthesia, and is remembered by European writers as the “father of conduction anesthesia.” Braun was the first person to use procaine, which, along with stovaine, was one of the first synthetic local anesthetics produced to reduce the toxicity of cocaine.

Before 1907, anesthesiologists were sometimes disappointed to observe that their spinal anesthetics were incomplete. Most believed that the drug spread solely by local diffusion before the property of baricity was investigated by Arthur Barker, a London surgeon.¹⁰⁴ Barker constructed a glass tube shaped to follow the curves of the human spine and used it to demonstrate the limited spread of colored solutions that he had injected through a T-piece in the lumbar region. Barker applied this observation to use solutions of stovaine made hyperbaric by the addition of 5% glucose, which worked in a more predictable fashion. After the injection was complete, Barker placed his patient's head on pillows to contain the anesthetic below the nipple line. Lincoln Sise acknowledged Barker's work in 1935 when he introduced the use of hyperbaric solutions of tetracaine (Pontocaine). John Adriani advanced the concept further in 1946 when he used a hyperbaric solution to produce “saddle block,” or perineal anesthesia. Adriani's patients remained seated after injection as the drug descended to the sacral nerves.

Tait, Jonnesco, and other early masters of spinal anesthesia used a cervical approach for thyroidectomy and thoracic procedures, but this radical approach was supplanted in 1928 by the lumbar injection of hypobaric solutions of “light” nupercaine by G. P. Pitkin. Although the use of hypobaric solutions is now limited primarily to patients positioned in the jackknife position, their former use for thoracic procedures demanded skill and precise timing. The enthusiasts of hypobaric anesthesia devised formulas to attempt to predict the time in seconds needed for a warmed solution of hypobaric nupercaine to spread in patients of varying size from its site of injection in the lumbar area to the level of the fourth thoracic dermatome.

The recurring problem of inadequate duration of single-injection spinal anesthesia led a Philadelphia surgeon, William Lemmon, to devise an apparatus for continuous spinal anesthesia in 1940.¹⁰⁵ Lemmon began with the patient in the lateral position. The spinal tap was performed with a malleable silver needle, which was left in position. As the patient was turned supine, the needle was positioned through a hole in the mattress and table. Additional injections of local anesthetic could be performed as required. Malleable silver needles also found a less cumbersome and more common application in 1942 when Waldo Edwards and Robert Hingson encouraged the use of Lemmon's needles for continuous caudal anesthesia in obstetrics. In 1944 Edward Tuohy of the Mayo Clinic introduced two important modifications of the continuous spinal techniques. He developed the now familiar Tuohy needle¹⁰⁶ as a means of improving the ease of passage of lacquered silk ureteral catheters through which he injected incremental doses of local anesthetic.¹⁰⁷

In 1949, Martinez Curbelo of Havana, Cuba, used Tuohy's needle and a ureteral catheter to perform the first continuous epidural anesthetic. Silk and gum elastic catheters were difficult to sterilize and sometimes caused dural infections before being superseded by disposable plastics. Yet, deliberate single-injection peridural anesthesia had been practiced occasionally for decades before continuous techniques brought it greater popularity. At the beginning of the 20th century, two French clinicians experimented independently with caudal anesthesia. The neurologist Jean Athanase Sicard applied the technique for a nonsurgical purpose, the relief of back pain. Fernand Cathelin used caudal anesthesia as a less dangerous alternative to spinal anesthesia for hernia repairs. He also demonstrated that the epidural space terminated in the neck by injecting a solution of India ink into the caudal canal of a dog. The lumbar approach was first used solely for multiple paravertebral nerve blocks before the Pagés-Dogliotti single-injection technique became accepted. As they worked separately, the technique carries the names of both men. Captain Fidel Pagés prepared an elegant demonstration of segmental single-injection peridural anesthesia in 1921, but died soon after his article appeared in a Spanish military journal.¹⁰⁸ Ten years later, Achille M. Dogliotti of Turin, Italy, wrote a classic study that made the epidural technique well known.⁷³ Whereas Pagés used a tactile approach to identify the epidural space, Dogliotti identified it by the loss-of-resistance technique.

Surgery on the extremities lent itself to other regional anesthesia techniques. In 1902, Harvey Cushing coined the phrase regional anesthesia for his technique of blocking either the brachial or sciatic plexus under direct vision during general anesthesia to reduce anesthesia requirements and provide postoperative pain relief.⁷⁵ Fifteen years before his publication, George Crile advanced a similar approach to reduce the stress and shock of surgery. Crile, a dedicated advocate of regional and infiltration techniques during general anesthesia, coined the term anoci-association.¹⁰⁹

An intravenous regional technique with procaine was reported in 1908 by August Bier, the surgeon who had pioneered spinal anesthesia. Bier injected procaine into a vein of the upper limb between two tourniquets. Even though the technique is termed the Bier block, it was not used for many decades until it was reintroduced 55 years later by Mackinnon Holmes, who modified the technique by exsanguination before applying a single proximal cuff. Holmes used lidocaine, the very successful amide local anesthetic synthesized in 1943 by Lofgren and Lundquist of Sweden.

Several investigators achieved upper extremity anesthesia by percutaneous injections of the brachial plexus. In 1911, based on his intimate knowledge of the anatomy of the axillary area, Hirschel promoted a “blind” axillary injection. In the same year, Kulenkampff described a supraclavicular approach in which the operator sought out paresthesias of the plexus while keeping the needle at a point superficial to the first rib and the pleura. The risk of pneumothorax with Kulenkampff's approach led Mulley to attempt blocks more proximally by a lateral paravertebral approach, the precursor of what is now popularly known as the Winnie block.

Heinrich Braun wrote the earliest textbook of local anesthesia, which appeared in its first English translation in 1914. After 1922, Gaston Labat's Regional Anesthesia dominated the American market. Labat migrated from France to the Mayo Clinic in Minnesota, where he served briefly before taking a permanent position at the Bellevue Hospital in New York. He formed the first American Society for Regional Anesthesia.¹¹⁰ After Labat's death, Emery A. Rovenstine was recruited to Bellevue to continue Labat's work, among other responsibilities. Rovenstein created the first American clinic for the treatment of chronic pain, where he and his associates refined techniques of lytic and therapeutic injections and used the American Society of Regional Anesthesia to further the knowledge of pain management across the United States.¹¹¹

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The development of the multidisciplinary pain clinic was one of many contributions to anesthesiology made by John J. Bonica, a renowned teacher of regional techniques. During his periods of military, civilian, and university service at the University of Washington, Bonica formulated a series of improvements in the management of patients with chronic pain. His classic text The Management of Pain, now in its third edition, is regarded as a standard of the literature of anesthesia.

Cardiovascular Anesthesia

The earliest attempts to operate on the heart were limited to repairing cardiac wounds. These attempts generally failed until German surgeon Ludwig Rehn repaired a right ventricular stab wound in September 1896.¹¹² Despite this success, the field was not ready to advance. The taboo of cardiac surgery was summarized by Theodore Billroth when he supposedly said “any surgeon who would attempt an operation on the heart should lose the respect of his colleagues.”¹¹³ The resistance to such operations was partly because of fledgling anesthetic medications, lack of adequate monitors, and even a clear understanding of cardiovascular physiology that pervades modern anesthesia practice.

Fortunately, the turn of the 20th century saw many advances in anesthesia practice, blood typing and transfusion, anticoagulation, antibiosis, as well as surgical instrumentation and technique. Some continued to attempt procedures like closed mitral valvotomy in the midst of these technological advancements, but outcomes were still very poor with mortality rates exceeding 80%. Many believe that the successful ligation of a 7-year-old girl's patent ductus arteriosus by Robert Gross in 1938 served as the landmark case for modern cardiac surgery. Soon after Gross' achievement, a host of new procedures were developed for repairing congenital cardiac lesions, including the first Blalock-Taussig shunt performed on a 15 month-old “blue baby” in 1944.¹¹⁴ Although the shunt had been successfully demonstrated in animal models, Austin Lamont, Chief of Anesthesia at Johns Hopkins, was not supportive of the procedure. He emphatically stated “I will not put that child to death” and left the open drop ether-oxygen anesthetic to resident anesthesiologist Merel Harmel.¹¹⁵ Lamont attended on the second Blalock-Taussig shunt 2 months later. Together, Harmel and Lamont would publish the first article on anesthesia for cardiac surgery in 1946 based on 100 cases with Alfred Blalock and repair of congenital pulmonic stenosis.¹¹⁶

Closed cardiac surgery ensued and anesthesia pioneers like William McQuiston and Kenneth Keown worked side-by-side with surgeons during procedures like the first aortic-pulmonary anastomosis and the first transmyocardial mitral commissurotomy. Never before had anesthesia providers worked as intimately with surgeons for the patient's welfare. Anesthesiologist and World War II physician Max Samuel Sadove remarked “the small-arms fire of the anesthesiologist joins the spy system of the lab to back up the surgeon's big artillery in a coordinated attack to conquer disease.”¹¹⁷

Through the 1930s and 1940s, John Gibbon had been experimenting with several extracorporeal circuit designs and by 1947 was able to successfully place dogs on heart-lung bypass. The first successful use of Gibbon's cardiopulmonary bypass machine in humans in May 1953 was a monumental advance in the surgical treatment of complex cardiac pathology that stimulated international interest in open heart surgery and the specialty of cardiac anesthesia.

Over the next decade, rapid growth and expanded applications of cardiac surgery, including artificial valves and coronary artery bypass grafting, required many more anesthesiologists acquainted with these specialized techniques. In 1967, J. Earl Waynards published one of the first articles on anesthetic management of patients undergoing surgery for coronary artery disease.

As cardiac surgery evolved, so did the perioperative monitoring and care of patients undergoing cardiac surgery. Postoperative mechanical ventilation and surgical intensive care units appeared by the late 1960s. Devices like the left atrial pressure monitor and the intra-aortic balloon pump offered new methods of understanding cardiopulmonary physiology and treating postoperative ventricular failure. Cardiac anesthesiologists were quick to bring the pulmonary artery catheter (PAC) into the operating room, permitting more precise hemodynamic monitoring and intervention. Joel Kaplan, already known for using the V₅ lead to monitor for myocardial ischemia and nitroglycerin infusions to treat ischemia, popularized the use of the PAC to detect myocardial ischemia. At Texas Heart Institute, Slogoff and Keats demonstrated the negative impact of myocardial ischemia on clinical outcome. By the end of the 1980s, the same duo would reveal that the choice of anesthetic agent had little impact on outcome, challenging the earlier paradigm of isoflurane steal proposed by Reiz.

Developments like cold potassium cardioplegia, monitoring and reversal of heparin, and reduction of blood loss with aprotinin would change the practice of cardiac anesthesia. Transesophageal echocardiography, introduced into cardiac surgery by Roizen, Cahalan, and Kremer in the 1980s, helped to further define the subspecialty of cardiac anesthesia.

Neuroanesthesia

Brain surgery is considered by some to be the oldest of the practiced medical arts. Evidence of trepanation, a form of neurosurgery in which a hole is drilled or scraped into the skull to access the dura, was discovered in skulls dating back to 6500 BC at a French burial site. Prehistoric brain surgery was also practiced by civilizations in South America, Africa, and Asia.¹¹⁸

With the introduction of inhalational anesthesia in the mid-1800s, Scottish surgeon and neurosurgery pioneer Sir William Macewen used this novel practice while performing the first successful craniotomy for tumor removal in 1879. Macewen, well known for introducing the technique of orotracheal intubation, promoted the idea of teaching medical students at Glasgow Royal Infirmary the art of chloroform anesthesia.

Like Macewen, Sir Victor Horsely was a neurosurgeon with an interest in anesthesia. His experiments of how ether, chloroform, and morphine affected intracranial contents led him to conclude that “the agent of choice was chloroform and that morphine had some value because of its cerebral constriction effects.”¹¹⁹ He first published his anesthetic technique for brain surgery in the British Medical Journal in 1886.¹²⁰ Later, he omitted morphine from his regimen after discovering its tendency to produce respiratory depression.

Meanwhile, Harvard medical student and aspiring neurosurgeon Harvey Cushing developed the first charts to record heart rate, temperature, and respiration during anesthesia. Soon after, he would add blood pressure readings to the record. Cushing was one of the first surgeons to recognize the importance of dedicated, specially trained anesthesia personnel versed in neurosurgery. Charles Frazier, a neurosurgical contemporary of Cushing, also recognized this need, stating that “no [cranial] operation be undertaken unless the services of a skilled anesthetizer are available.”¹²¹

Since ether and chloroform anesthesia had significant drawbacks, beginning in 1918 Cushing and his contemporaries explored the advantages of regional or local anesthesia for intracranial surgery. Part of the motivation driving this change was the increased duration in surgical time. Cushing

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and colleagues used a “slow” surgical technique for most surgical procedures, where the average duration for cranial operations was 5 hours.¹²² In contrast, early neurosurgeons like Horseley and Sir Percy Sargeant could perform similar procedures in less than 90 minutes. Therefore, prolonged patient exposure to chloroform or ether anesthesia were likely to result in increased bleeding, postoperative headache, confusion, and/or vomiting. Cushing and contemporaries thought the use of local or regional anesthesia lessened the risk of these complications.

After a decade, it was realized that the remote positioning of the anesthetist was troublesome when managing the airway of an awake or lightly sedated patient undergoing cranial surgery with regional anesthesia. Also, endotracheal tubes, although introduced at the beginning of the century, had become popular instruments for securing a patient's airway and providing inhalation anesthesia. Combined, these circumstances led to the rapid resurgence of popularity in general anesthesia for cranial surgery, a trend that would continue to present day.

While the introduction of agents like thiopental, curare, and halothane advanced the practice of anesthesiology in general, the development of methods to measure brain electrical activity, cerebral blood flow and metabolic rate by Kety and Schmidt, and intracranial pressure by Lundburg “put neuroanesthesia practice on a scientific foundation and opened doors to neuroanesthesia research.”¹²³ Clinician-scientists like John D. (Jack) Michenfelder, later known as the father of neuroanesthesia, conducted basic science and clinical research on cerebral blood flow and brain function and protection in response to various anesthetic agents and techniques. Many lessons learned during this period of groundbreaking research are still commonly used in modern neuroanesthesia practice.

Obstetric Anesthesia

Social attitudes about pain associated with childbirth began to change in the 1860s and women started demanding anesthesia for childbirth. Societal pressures were so great that physicians, although unconvinced of the benefits of analgesia, felt obligated to offer this service to their obstetric patients.¹²⁴ In 1907 an Austrian physician, Richard von Steinbúchel used a combination of morphine and scopolamine to produce Dämmerschlaff or “Twilight Sleep.”¹²⁵ Although these two drugs were well known, physicians remained skeptical that Twilight Sleep was essential to labor and delivery, which unfortunately contrasted with the opinion of most women. This method gained popularity after German obstetricians Carl Gauss and Bernhardt Krónig widely publicized the technique. Numerous advertisements touted the benefits of Twilight Sleep (analgesia, partial pain relief, and amnesia) as compared to ether and chloroform, which resulted in total unconsciousness.¹²⁶ Gauss recognized the narrow therapeutic margin of these medications and gave precise instructions on its use: the first injection (morphine 10 mg and scopolamine) was to be given shortly after active labor began—this was intended to blunt the pain of labor—and subsequent injections consisted of only scopolamine, which was dosed to obliterate the memory of labor. Because of the effects of scopolamine, many patients became disoriented and would scream and thrash about during labor and delivery. Gauss believed that he could minimize this reaction by decreasing the sensory input; therefore, he would put patients in a dark room, cover their eyes with gauze, and insert oil-soaked cotton into their ears. The patients were often confined to a padded bed and restrained with leather straps during the delivery.¹²⁷ Over time, the doses of morphine administered seemed to increase, although there were few, if any, reports of adverse neonatal effects. Virginia Apgar's system for evaluating newborns, developed in 1953, demonstrated that there actually was a difference in the neonates of mothers who had been anesthetized.¹²⁸

The bulk of the interest in this technique appears to have been popular rather than medical and, for a brief period, was intensely followed in the United States.¹²⁹ Public enthusiasm for Twilight Sleep quickly subsided after a prominent advocate of the method died during childbirth. Her physicians claimed her death was not related to complications from the method of Twilight Sleep that was used.¹³⁰

The first articles describing the obstetric application of spinal, epidural, caudal, paravertebral, parasacral, and pudendal nerve blocks appeared between 1900 and 1930. However, their benefits were underappreciated for many years because the obstetricians seldom used these techniques.¹³⁰ Continuous caudal anesthesia was introduced in 1944 by Hingson and Edwards¹³¹ and spinal anesthesia became popular shortly thereafter. Initially, spinal anesthesia could be administered by inexperienced personnel without monitoring. The combination of inexperienced providers and lack of patient monitoring led to higher rates of morbidity and mortality than those observed for general anesthesia.¹³² Therefore, the use of spinal anesthesia was highly discouraged in the 1950s, leading to the “dark ages of obstetric anesthesia” when pain relief in obstetrics was essentially abandoned and women were forced to endure “natural childbirth” to avoid serous anesthesia-related complications.¹³³

With an increased understanding of neuraxial anesthesia, involvement by well-trained anesthesiologists, and an appreciation for the physiologic changes during pregnancy, maternal and fetal safety greatly improved. In the past decade, anesthesia-related deaths during cesarean sections under general anesthesia have become more likely than neuraxial anesthesia-related deaths, making regional anesthesia the method of choice.^134,135 With the availability of safe and effective options for pain relief during labor and delivery, today's focus is improving the quality of the birth experience for expectant parents.

Transfusion Medicine

Paleolithic cave drawings found in France depict a bear losing blood from multiple spear wounds, indicating that primitive man understood the simple relationship between blood and life.¹³⁶ More than 10,000 years later, modern anesthesiologists attempt to preserve this intimate relationship by replacing fluids and blood products when faced with intravascular volume depletion or diminished oxygen-carrying capacity from blood loss.

Blood transfusion was first attempted in 1667 by physician to Louis XIV, Jean Baptiste Denis. Denis had learned of Richard Lower's transfusion of lamb's blood into a dog the previous year. Lamb's blood was most frequently used because the donating animal's essential qualities were thought to be transferred to the recipient. Despite this dangerous trans-species transfusion, Denis' first patient got better. His next two patients were not as fortunate, however, and Denis avoided further attempts. Given the poor outcomes of these early blood transfusions, and heated religious controversy regarding the implications of transferring animal-specific qualities across species, blood transfusion in humans was banned for more than a hundred years in both France and England beginning in 1670.¹¹⁴

In 1900, Karl Landsteiner and Samuel Shattock independently helped lay the scientific basis of all subsequent transfusions by recognizing that blood compatibility was based on different blood groups. Landsteiner, an Austrian physician, originally organized human blood into three groups based on

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substances present on the red blood cells. The fourth type, AB group, was identified in 1902 by two students, A. Decastrello and A. Sturli. Based on these findings, Reuben Ottenberg performed the first type-specific blood transfusion in 1907. Transfusion of physiologic solutions occurred in 1831, independently performed by O'Shaughnessy and Lewins in Great Britain. In his letter to The Lancet, Lewins described transfusing large volumes of saline solutions into patients with cholera. He reported that he would inject into adults from 5 to 10 pounds of saline solution and repeat as needed.¹³⁷ Despite its publication in a prominent journal, Lewins' technique was apparently overlooked for decades, and balanced physiologic solution availability would have to await the coming of analytical chemistry.

Professionalism and Anesthesia Practice

Organized Anesthesiology

Physician anesthetists sought to obtain respect among their surgical colleagues by organizing professional societies and improving the quality of training. The first American organization was founded by nine members on October 6, 1905, and called the Long Island Society of Anesthetists with annual dues of $1.00. In 1911, the annual assessment rose to $3.00 when the Long Island Society became the New York Society of Anesthetists. Although the new organization still carried a local title, it drew members from several states and had a membership of 70 physicians in 1915.¹³⁸

One of the most noteworthy figures in the struggle to professionalize anesthesiology was Francis Hoffer McMechan. McMechan had been a practicing anesthesiologist in Cincinnati until 1911, when he suffered a severe first attack of rheumatoid arthritis, which eventually left him confined to a wheelchair and forced his retirement from the operating room in 1915. McMechan had been in practice only 15 years, but he had written 18 clinical articles in this short time. A prolific researcher and writer, McMechan did not permit his crippling disease to sideline his career. Instead of pursuing goals in clinical medicine, he applied his talents to establishing anesthesiology societies.¹³⁹

McMechan supported himself and his devoted wife through editing the Quarterly Anesthesia Supplement from 1914 until August 1926. He became editor of the first journal devoted to anesthesia, Current Researches in Anesthesia and Analgesia, the precursor of Anesthesia and Analgesia, the oldest journal of the specialty. As well as fostering the organization of the International Anesthesia Research Society (IARS) in 1925, McMechan and his wife, Laurette, became overseas ambassadors of American anesthesia. Since Laurette was French, it was understandable that McMechan combined his own ideas about anesthesiology with concepts from abroad.¹²³

In 1926, McMechan held the Congress of Anesthetists in a joint conference with the Section on Anaesthetics of the British Medical Association. Subsequently, he traveled throughout Europe, giving lectures and networking physicians in the field. On his final return to America, he was gravely ill and was confined to bed for 2 years. His hard work and constant travel paid dividends, however: in 1929, the IARS, which McMechan founded in 1922, had members not only from North America but also from several European countries, Japan, India, Argentina, and Brazil.¹²²

In the 1930s, McMechan expanded his mission from organizing anesthesiologists to promoting the academic aspects of the specialty. In 1931, work began on what would become the International College of Anesthetists. This body began to award fellowships in 1935. For the first time, physicians were recognized as specialists in anesthesiology. The certification qualifications were universal, and fellows were recognized as specialists in several countries. Although the criteria for certification were not strict, the College was a success in raising the standards of anesthesia practice in many nations.¹⁴⁰ In 1939, McMechan finally succumbed to illness, and the anesthesia world lost its tireless leader.

Other Americans promoted the growth of organized anesthesiology. Ralph Waters and John Lundy, among others, participated in evolving organized anesthesia. Waters' greatest contribution to the specialty was raising its academic standards. After completing his internship in 1913, he entered medical practice in Sioux City, Iowa, where he gradually limited his practice to anesthesia. His personal experience and extensive reading were supplemented by the only postgraduate training available, a 1-month course conducted in Ohio by E. I. McKesson. At that time, the custom of becoming a self-proclaimed specialist in medicine and surgery was not uncommon. Waters, who was frustrated by low standards and who would eventually have a great influence on establishing both anesthesia residency training and the formal examination process, recalled that, before 1920, “The requirements for specialization in many Midwestern hospitals consisted of the possession of sufficient audacity to attempt a procedure and persuasive power adequate to gain the consent of the patient or his family.”¹⁴¹

Academic Anesthesia

In an effort to improve anesthetic care, Waters regularly corresponded with Dennis Jackson and other scientists. In 1925, he relocated to Kansas City with a goal of gaining an academic post at the University of Kansas, but the professor of surgery failed to support his proposal. The larger city did allow him to initiate his freestanding outpatient surgical facility, “The Downtown Surgical Clinic,” which featured one of the first postanesthetic recovery rooms.¹³⁰ In 1927, Erwin Schmidt, professor of surgery at the University of Wisconsin's medical school, encouraged Dean Charles Bardeen to recruit Waters.

In accepting the first American academic position in anesthesia, Waters described four objectives that have been since adopted by many other academic departments. His goals were as follows: “(1) to provide the best possible service to patients of the institution; (2) to teach what is known of the principles of Anesthesiology to all candidates for their medical degree; (3) to help long-term graduate students not only to gain a fundamental knowledge of the subject and to master the art of administration, but also to learn as much as possible of the effective methods of teaching; (4) to accompany these efforts with the encouragement of as much cooperative investigation as is consistent with achieving the first objectives.”¹²⁹

Waters' personal and professional qualities impressed talented young men and women who sought residency posts in his department. He encouraged residents to initiate research interests in which they collaborated with two pharmacologists whom Waters had known before arriving in Wisconsin, Arthur Loevenhart and Chauncey Leake, as well as others with whom he became associated in Madison. Clinical concerns were also investigated. As an example, anesthesia records were coded onto punch cards to form a database that was used to analyze departmental activities. Morbidity and mortality meetings, now a requirement of all training programs, also originated in Madison. Members of the department and distinguished visitors from other centers attended these meetings. As a consequence of their critical reviews of the conduct of anesthesia, responsibility for an operative

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tragedy gradually passed from the patient to the physician. In more casual times, a practitioner could complain, “The patient died because he did not take a good anesthetic.” Alternatively, the death might be attributed to a mysterious force such as “status lymphaticus,” of which Arthur Guedel, a master of sardonic humor, observed, “Certainly status lymphaticus is at times a great help to the anesthetist. When he has a fatality under anesthesia with no other cleansing explanation he is glad to recognize the condition as an entity.”¹²⁹

In 1929, John Lundy at the Mayo Clinic organized the Anaesthetists' Travel Club, whose members were leading American or Canadian teachers of anesthesia. Each year one member was the host for a group of 20 to 40 anesthesiologists who gathered for a program of informal discussions. There were demonstrations of promising innovations for the operating room and laboratory, which were all subjected to what is remembered as a “high-spirited, energetic, critical review.”¹²⁷ The Travel Club would be critical in the upcoming battle to form the American Board of Anesthesiology.

Even during the lean years of the Depression, international guests also visited Waters' department. For Geoffrey Kaye of Australia, Torsten Gordh of Sweden, Robert Macintosh and Michael Nosworthy of England, and scores of others, Waters' department was their “mecca of anesthesia.” Ralph Waters trained 60 residents during the 22 years he was the “Chief.” From 1937 onward, the alumni, who declared themselves the “Aqualumni” in his honor, returned annually for a professional and social reunion. Thirty-four Aqualumni took academic positions and, of these, 14 became chairpersons of departments of anesthesia. They maintained Waters' professional principles and encouraged teaching careers for many of their own graduates.¹⁴² His enduring legacy was once recognized by the dean who had recruited him in 1927, Charles Bardeen, who observed, “Ralph Waters was the first person the University hired to put people to sleep, but, instead, he awakened a world-wide interest in anesthesia.”¹⁴³

Establishing a Society

Waters and Lundy, along with Paul Wood of New York City, had an important role in establishing organized anesthesia and the definition of the specialty. In the heart of the Great Depression, these three physicians realized that anesthesiology needed to have a process to determine who was an anesthetic specialist with American Medical Association (AMA) backing. Using the New York Society of Anesthetists, of which Paul Wood was secretary-treasurer, a new class of members, “Fellows,” was created. The Fellows criteria followed established AMA guidelines for specialty certification. However, the AMA wanted a national organization to sponsor a specialty board. The New York Society of Anesthetists changed its name to the American Society of Anesthetists (ASA) in 1936. Combined with the American Society of Regional Anesthesia, whose president was Emery Rovenstein, the American Board of Anesthesiology (ABA) was organized as a subordinate board to the American Board of Surgery in 1938. With McMechan's death in 1939, the AMA favored independence for the ABA, and in 1940, independence was granted.^126,131

A few years later, the officers of the American Society of Anesthetists were challenged by Dr. M. J. Seifert, who wrote, “An Anesthetist is a technician and an Anesthesiologist is the specific authority on anesthesia and anesthetics. I cannot understand why you do not term yourselves the American Society of Anesthesiologists.”¹³³ Ralph Waters was declared the first president of the newly named ASA in 1945. In that year, when World War II ended, 739 (37%) of 1,977 ASA members were in the armed forces. In the same year, the ASA's first Distinguished Service Award was presented to Paul M. Wood for his tireless service to the specialty, one element of which can be examined today in the extensive archives preserved in the Society's Wood Library Museum at ASA headquarters, Park Ridge, Illinois.¹⁴³

Conclusions

This overview of the development of anesthesiology is but a brief outline of our current roles in which anesthesiologists serve in hospitals, clinics, and laboratories. The operating room and obstetric delivery suite remain the central interest of most specialists. Aside from being the location where the techniques described in this chapter find regular application, service in these areas brings us into regular contact with new advances in pharmacology and bioengineering.

After surgery, patients are transported to the postanesthesia care unit or recovery room, an area that is now considered the anesthesiologist's “ward.” Fifty years ago, patients were carried directly from the operating room to a surgical ward to be attended only by a junior nurse. That person lacked both the skills and equipment to intervene when complications occurred. After the experiences of World War II taught the value of centralized care, physicians and nurses created recovery rooms, which were soon mandated for all major hospitals. By 1960 the evolution of critical care progressed through the use of mechanical ventilators. Patients who required many days of intensive medical and nursing management were cared for in a curtained corner of the recovery room. In time, curtains drawn about one or two beds gave way to fixed partitions and the relocation of those areas to form intensive care units. The principles of resuscitative and supportive care established by anesthesiologists transformed critical care medicine.

The future of anesthesiology is a bright one. The safer drugs that once revolutionized the care of patients undergoing surgery are constantly being improved. The role of the anesthesiologist continues to broaden as physicians with backgrounds in the specialty have developed clinics for chronic pain control and outpatient surgery. Anesthesia practice will continue to increase in scope, both inside and outside the operating suite, such that anesthesiologists will become an integral part of the entire perioperative experience.

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1. Joyce H: The Journals and Letters of Fanny Burney. Oxford, Clarendon 1975. As quoted in: Papper EM: Romance, Poetry, and Surgical Sleep. Westport, CT, Greenwood Press, 1995, p. 12

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2. Epitaph to W.T.G. Morton on a memorial from the Mt. Auburn Cemetery, Cambridge, Massachusetts

3. These Egyptian Pictographs are dated approximately 2500 B.C. See Ellis ES: Ancient Anodynes: Primitive Anaesthesia and Allied Conditions. London, WM Heinemann Medical Books, 1946, p 80

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10. Davy H: Researches Chemical and Philosophical Chiefly Concerning Nitrous Oxide or Dephlogisticated Nitrous Air, and Its Respiration. London, J Johnson, 1800, p 533.

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16. Long CW: An account of the first use of sulphuric ether by inhalation as an anaesthetic in surgical operations. South Med Surg J 1849;5:705

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91. Chloretone (chlorobutanol) is prepared by mixing chloroform and acetone, and has a camphor-like odor that some find pleasant. Chloretone is now commonly used for euthanizing reptiles and amphibians

92. Hewer CL: Recent Advances in Anaesthesia and Analgesia. Philadelphia: P Blakiston's Son & Co. Inc., 1937, p 237

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Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine