In 1880, Basil von Anrep reported that injecting cocaine into his arm produced numbing of his skin, but this did not lead to clinical application [1]. Sigmund Freud (1856–1939) prompted the first clinical research into the drug. He had heard of the stimulating effects of cocaine, and began to research those aspects, hoping to find a drug to help a friend overcome his morphine addiction. His initial investigations produced a treatise on cocaine [2]. He subsequently enlisted the help of Carl Koller (1857–1944), a Vienna hospital intern whom he had befriended, Freud gave an envelope containing the powder to Koller, who immediately noticed that his tongue became numb when he licked some spilled powder. Koller, a physician in the ophthalmology clinic in Vienna, recognized the potential use of the numbing effect on the cornea, demonstrating this in animals. Then (true to his nineteenth century medicine tradition), he experimented on himself and a colleague, instilling cocaine into their eyes before touching each others’ corneas with the head of a pin. This successful self-experimentation led to an operation under topical cocaine anesthesia, in September of 1884 [3]. Koller reported this triumph a few weeks later to the German Ophthalmological Society Congress in Heidelberg. The paper was read by a colleague because Koller could not afford to attend the Congress. The news spread rapidly, and in that year, ophthalmologists in New York employed cocaine anesthesia for eye surgery. Prominent American surgeons (William Halsted [1852–1922] and Richard Hall [1856–1897]) at the Roosevelt Hospital in New York infiltrated cocaine to numb surgical fields.

In the next year, 60 reports from individual surgeons described successful local anesthesia of the skin. Halsted and Hall were first to describe the use of cocaine to block peripheral nerves, including a report of brachial plexus anesthesia by injection under direct vision. Again, in the tradition of self-experimentation, some of the original investigators, including Freud and Halsted, became addicted to cocaine. Halsted used morphine to end his dependence on cocaine’trading one devil for another. Although he never overcame his addiction, he managed to continue functioning at a high level. He moved to the Johns Hopkins Medical Center in Baltimore, and had a distinguished career as the father of modern surgical training in the US. Halsted’s early papers attest to his enthusiasm for the use of conduction anesthesia with the new local anesthetic [4]. After becoming addicted he ceased publishing work related to local anesthesia, and it is unclear whether he continued to use local or regional infiltration techniques in his practice.

The application of cocaine dramatically increased after the discovery of its beneficial properties as a spinal anesthetic. An initial report by James Corning (1855–1923) in 1885, of cocaine injected into the spinal column [5] appears, from his description, to have been the first epidural, rather than the first spinal, anesthetic. Corning’s injection into a single human subject followed a successful animal injection. No widespread use followed his report.

“Spinal” anesthesia followed from the improved descriptions of spinal anatomy by the German surgeon Heinrich Quincke (1842–1922) who used the spinal canal as an avenue for the treatment of tuberculous meningitis. His descriptions of the anatomy of the dural sac and the spinal cord led to the relatively “safe” insertion of hypodermic needles in the lower lumbar area. His surgical colleague, August Bier (1861–1949), performed the first intentional subarachnoid block [6]. Bier and his assistant, August Hildebrandt, performed subarachnoid injections of 5mg cocaine on each other in 1899. Hildebrandt’s initial attempt to inject the drug into Bier failed because the syringe outlet did not fit the hub of the needle. Bier suffered from a spinal headache for nine days. Injection into his assistant resulted in anesthesia of the lower extremities, as evidenced by lack of sensation in response to blows to the shin. Fortunately, the initial subarachnoid injection followed the introduction of aseptic technique, including the routine use of surgical gloves, and infection did not mar the early history of neuraxial block. In 1908, Bier described the first “intravenous regional anesthesia”, a technique that did not achieve popularity until the 1960s. Perhaps it was the perceived necessity to expose the veins surgically, or the short duration of procaine that limited enthusiasm, but the report by CM Holmes in 1963 described the percutaneous approach, using the “new” lidocaine, that became an accepted technique.

Bier and Hildebrandt’s success with subarachnoid injection addressed concerns regarding the toxicity and short duration of action of cocaine injections; a small dose of drug could profoundly block sensation to half the body. The news of their success spread rapidly to the US, and in 1899, Fredrick Tate and Guido Caglieri in San Francisco, performed surgical procedures under spinal anesthesia [7]. Spinal anesthesia soon became the most popular form of regional anesthesia because of its simplicity and low toxicity. In many countries it was popular because the surgeon could act, sequentially, as anesthetist and surgeon. Surgeons dealt with concerns regarding hypotension by controlling the level of spinal blockade through the use of hyperbaric and hypobaric solutions, and adjustment of patient position.

Some colorful and cavalier European surgeons, such as Thomas Jonnesco (1860–1926) of Bucharest, combined thoracic or cervical level injections of hypobaric stovaine with strychnine, to produce anesthesia for thoracic and even head and neck surgery [8].

“NEW AID IN SURGERY…Special Cable to The New York Times. LONDON, Nov 20 (1909). The safe use of stovaine as an anaesthetic was proved to-day by a remarkable operation performed by Prof. Thomas Jonnesco, Dean of the University of Bucharest, at the Seamen’s Hospital in Greenwich…To-day’s operation was the removal of a mass of tubercular glands in the neck…Prof. Jonnesco inserted a small hypodermic needle into the spinal canal, passing it between two of the vertebrae at the base of the neck. Attaching a small syringe to the needle three centigrammes of stovaine and five centigrammes of sulphate of strychnine were injected into the spinal canal. The patient was told to lie down on the operating table. His head and shoulders were lowered, so that the action of gravity would cause the numbing fluid to spread upward. Two minutes later the operation was carried out in an ordinary manner, the patient being perfectly conscious and talking to the surgeon during the whole proceeding. ‘Do you feel any pain?’ asked one surgeon. ‘No, Sir,’ replied the patient. ‘I am quite comfortable.’…Five minutes after the operation was finished the patient got off the operating table, walked into the next room, and was taken back to bed.”

The reader may wonder, “Why strychnine?” The above article explained that “…by coupling with (stovaine) an exhilarating drug like strychnine the bad effect on the heart is neutralized without interfering with the desired numbing influence of the anaesthetic.” Most surgeons were content with lumbar level injections, and the judicious use of the new vasoconstrictor, ephedrine, to manage hypotension.

The inherent drawbacks of cocaine tempered enthusiasm for neural blockade. Cocaine’s potential for addiction was well documented. More limiting was its short duration of action (approximately 45 minutes) and relatively small margin of safety. Thus, investigators searched for local anesthetics with minimal issues of toxicity and addiction, and a longer duration.

Niemann’s work with cocaine revealed its benzoic acid structural component. The first derivative of this moiety was amylocaine (stovaine), released in 1903. It was used for spinal anesthesia until identified as a nerve irritant. In Germany, Alfred Einhorn (1856–1917) synthesized the amino-ester, procaine, in 1904 [9]. Heinrich Braun (1862–1934) documented procaine’s favorable properties compared to those of stovaine. It was not a nerve irritant, and did not have the excitatory and addictive properties of cocaine, and therefore replaced stovaine for clinical use [10]. However, procaine also had a short duration of action, and introduced a new problem, allergic reactions to its metabolite, para-aminobenzoic acid. Other amino esters were synthesized to overcome these issues. Dibucaine (1925) and tetracaine (1928) were clinically useful, but displayed a narrower therapeutic ratio (tetracaine, for example, is 8 times more potent than procaine, but 12 times more toxic, partially related to its slower hydrolysis by plasma esterases). Systemic toxic reactions were more common with tetracaine when used in higher doses for topical anesthesia (bronchoscopy) or peripheral blockade, and thus its use was often limited to spinal anesthesia, where smaller doses of drugs were effective. Further development of regional techniques awaited the synthesis of aminoamide compounds in the 1940s.

Evangelical-like proponents (e.g., Jonnesco), virtually all surgeons, fathered the development of regional techniques. Braun in Germany published the first textbook describing these techniques in 1905 [11] along with enthusiastic reports of regional anesthesia. Another enthusiastic surgeon, Victor Pauchet (1869–1936) in France, likewise published a textbook of regional anesthesia based on the practice at his surgical theater in Paris. This period of energetic experimentation developed virtually all currently used regional anesthetic techniques, at least in a preliminary form. Subsequent expansion resulted from emergence of new local anesthetics, and new technical equipment for performance of blocks [12].

Gaston Labat (1876–1934) is credited with the wider introduction of regional anesthesia to the US. After graduating from medical school in 1916, he moved to Paris and practiced at the University of Paris under Pauchet. He was the third author of the third edition of Pauchet’s textbook on regional anesthesia. Labat was administering anesthesia when Charles Mayo happened to visit Pauchet’s surgical clinic, including Labat’s operating room in 1920. Impressed with Labat and his regional anesthetic techniques, Mayo invited him to join the faculty at the Mayo Clinic’to teach regional anesthesia and write a textbook in English. Labat moved to Rochester, Minnesota, in October 1920. He expanded interest in regional techniques, and, despite the brevity of his tenure at the Mayo clinic, wrote the textbook. Unfortunately, Labat and the Mayo administration appeared to have disagreed on the publication and royalties of his textbook (although Mayo wrote a positive introduction in the book). Perhaps because of this and perhaps because of marital discord, he left the Mayo Clinic before completing his one-year appointment, and moved to Bellevue Hospital in New York. Labat was a surgeon and there is no record of his assuming the title of “chief” of anesthesia at Bellevue. Emery Rovenstine (1895–1960), who succeeded Labat, established a residency and a department of anesthesia’which he headed. Published in 1922, [13] many of the illustrations and much of the text in Labat’s book resembled those in Pauchet’s French text. Labat’s text was the first comprehensive practical manual of regional techniques in English, and sold 7000 copies in three printings. Labat acknowledged his debt to Pauchet in the preface to the second edition in 1928, which sold an additional 3500 copies [14].

Labat developed a following in New York, including colleagues who met regularly to foster their skills. His enthusiasm led to the establishment of the American Society of Regional Anesthesia (ASRA) in New York in 1923. The organization met quarterly to discuss research in regional anesthesia. Several research papers were subsequently published in the new journal,Current Researches in Anesthesia and Analgesia, edited by Francis McMechan. The Society remained small (58 active members in 1937), but changed from a group dominated by surgeons to one including many of the prominent figures in the developing specialty of anesthesiology. The original ASRA then dwindled, voting to dissolve in 1939. Several factors were responsible for the decline in interest, including the development of new general anesthetic drugs (cyclopropane in 1930, thiopental in 1934,) at a time when there was ongoing concern about hypotension with spinal anesthesia and toxicity of the local anesthetics. Another factor was political, involving the positioning of the various societies of anesthesiologists to become the national representative of the specialty [15]. Rovenstine, Labat’s successor as president, chose to join the American Society of Anesthetists in endorsing the new American Board of Anesthesiology, and the prominent members of ASRA transferred their interest to those organizations.

Rovenstine, a founder of the ASA, succeeded Labat as chief of anesthesia at Bellevue Hospital in 1935. With the help of a Labat disciple, surgeon Hippolyte Wertheim, Rovenstine continued an emphasis on regional anesthesia at Bellevue [16]. Rovenstine largely abandoned the operating room, to apply regional techniques to patients having problems with pain, presaging a movement that gained momentum in the second half of the century.

George Crile (1864–1943), founder of the Cleveland Clinic and the American College of Surgeons, explored the effects of anesthesia on the phenomenon of “surgical shock” [17] in 1901. Using animals, he found that inhalational anesthetics did not block this physiologic response, while regional techniques prevented nociceptive impulses from reaching the brain, thereby abolishing the response. His concept of “anoci-association” foreshadowed concepts of “pre-emptive analgesia” presently described in conjunction with regional and multimodal analgesic techniques.

The surgeon, George Pitkin (1885–1943), an early American experimenter with spinal anesthetic techniques, shared Crile’s interest in reducing surgical stress. In 1927, he invented and popularized a mixture of procaine, strychnine (nominally to act as a vasoconstrictor), and alcohol (the formula was 0.195 gm procaine, 0.0022 gm strychnine, 0.324 gm alcohol, and normal saline to a volume of 2.2 ml) to produce a hypobaric solution which he named “Spinocain” [18,19]. Spinocain appears to have been widely used, with no suggestion of toxicity. Pitkin described the effect of position and gravity on the spread of spinal anesthesia, and developed a tilt indicator to assist in positioning the patient. He also developed a hyperbaric solution for obstetrical anesthesia. His life-long dedication to regional techniques culminated in his massive tome onConduction Anesthesia, [20] the second major American text on regional anesthesia.

Pitkin’s contemporary, William Babock (1872–1963), of Temple University in Philadelphia, also advocated the use of hypobaric spinal anesthesia. He preferred amylocaine (stovaine) mixed with alcohol, strychnine, distilled water and lactic acid, a combination he developed in 1909. Like the Mayo brothers, a visit to France in 1904 had impressed him with the benefits of regional anesthesia. Concern about the hypotension associated with spinal block caused him to advocate measuring the blood pressure and treating hypotension with adrenalin. He preferred spinal anesthesia because of the perceived lower mortality when compared with that of general anesthesia at the time [21].

In 1923, Lincoln Sise (1874–1942), a soft-spoken anesthesiologist, joined the Lahey Clinic in Boston to partner with the renowned surgeon, Frank Lahey. Sise started in general practice but gave anesthesia to supplement his income. He rapidly became a master in anesthesia for patients undergoing abdominal procedures. At the time, regional anesthesia centered on spinal anesthesia because of its short duration and the systemic toxicity associated with peripheral blocks. The introduction of procaine decreased toxicity, but hypotension and post-spinal headaches remained as concerns. Although surgeons appreciated the muscle relaxation provided by “high spinals”, a sufficiently high block often precipitated severe hemodynamic changes. Sise pioneered the use of hyperbaric solutions, administered to patients positioned laterally and in a slight Trendelenburg’s position, with the head and shoulders elevated. He tilted the table to adjust the block height to an optimum level. Sise deserves the credit for using fluid administration to minimize hypotension. He was also an early proponent of the use of ephedrine to combat hypotension.

Notable was his development of an introducer needle to penetrate the skin and interspinous ligaments, enabling use of a smaller gauge needle for the final dural puncture, thereby decreasing the frequency and severity of headaches. Allowing the spinal needle to bypass the skin may also have reduced the risk of infection, a key consideration in an age preceding antibiotics. And what was the right size needle? Fine gauge needles equaled fewer spinal headaches, but use of finer gauge or malleable needles could lead to broken needles, a phenomenon so common that Sise’s partner, Lahey, described how to extract broken needles in 1929 [22]. Other innovators designed new needles, including Green’s rounded bevel needle in 1923, subsequently shown to reduce the incidence of headaches. It was not commercially produced until almost sixty years later.

Labat had impressed the surgical staff at the Mayo Clinic. With his departure, they looked for a successor to establish a true department of anesthesia. William Mayo, Charles’ brother, accidentally met John Lundy (1874–1973) at a dinner meeting during a visit to Seattle in 1924. Lundy had not performed research or published since graduating from Rush Medical College in 1919, but the young man’s enthusiasm and curiosity about anesthetic topics impressed Mayo, and he recruited Lundy to assume the directorship of the anesthesia section at the Clinic. Mayo’s decision was based on little evidence, but in hindsight was justified. Lundy went on to introduce thiopental, establish a blood bank, and open the first recovery room. He also established an anatomy laboratory and a strong teaching program. Lundy had never performed a regional anesthetic before he assumed the role of Director of Regional Anesthesia. Nevertheless he joined ASRA, where he met Labat. Lundy continued the tradition of reliance on regional techniques at the Mayo Clinic, often combining regional with general anesthesia. He developed a concept of “balanced anesthesia” wherein a hypnotic agent produced anesthesia, neuromuscular blocking drugs facilitated relaxation, and a regional technique provided postoperative pain relief [23].

The pioneers of spinal anesthesia sought to increase the duration of spinal anesthesia by inserting a needle that could remain in place, and through which repeated doses of local anesthetic could be administered. In 1940, William Lemmon inserted the tip of a flexible (malleable) needle into the subarachnoid space, (SAS) and then had the patient lie on a mattress specially designed to accommodate the protruding needle. This allowed subsequent injections to be made through the needle into the SAS of the supine patient. Such intermittent injections presaged the development of “continuous” spinal anesthesia. Robert Hingson and Waldo Edwards adapted this technology in 1942 for injections into the caudal canal to produce prolonged lower extremity and pelvic analgesia, [24] and extended analgesia for labor and delivery. Hingson taught the technique to Gertie Marx in New York during her training. Edward Tuohy (1908–1959), of the Mayo Clinic, took the next step. Using the needle with a curved tip designed by Huber, Tuohy introduced a small-gauge ureteral catheter into the subarachnoid space to allow continuous spinal anesthesia [25].