The history of modern general anaesthesia
Wednesday, April 1st, 2015
Safe and effective anaesthesia is among the greatest advances in medical history. Modern surgery and the considerable benefits it brings would be impossible without the significant academic, pharmacological, and practical advances in anaesthesia over the past 200 years. At the forefront of these are the major developments in general anaesthesia and airway management. This article aims to provide a basic framework to understand the development of modern general anaesthesia.
A brief history of general anaesthesia
Anaesthesia is a relatively new field in modern medicine. Prior to its development, most surgical procedures were either minor or emergency operations.  It is clear that modern surgery and the considerable benefits it brings would be impossible without the significant academic, pharmacological, and practical advances in anaesthesia during the 19th and 20th centuries. First and foremost among these is the development of safe and effective general anaesthesia.
Carbon dioxide was first explored as an anaesthetic in the 1820s by the English physician Henry H. Hickman. By inducing partial asphyxiation, Hickman demonstrated that animals could be rendered unconscious for a prolonged period, enabling surgical procedures to be performed.  This was a major breakthrough, however the risks associated with hypoxic anaesthesia were too great to see the widespread adoption of carbon dioxide as an anaesthetic.
Diethyl ether, a solvent commonly referred to simply as ‘ether’, was first used clinically by American physician William E. Clarke for a tooth extraction in January 1842. [3, 4] Several months later Crawford W. Long, an American surgeon and pharmacist, famously used ether as a surgical anaesthetic to remove a growth on a young man’s neck. He published his findings after seven years, revealing that the patient felt nothing throughout the procedure.  The discovery of ether’s clinical utility represented a significant advance in effective general anaesthesia, spurring a flurry of interest in potential anaesthetic agents.
Still used today for its anaesthetic properties, nitrous oxide was experimented with during the 19th century. Positive experiences by chemist Humphrey Davy lead to public gatherings, in which members of the public would inhale nitrous oxide for its exhilarating and pleasurable effects.  A medical student, Gardner Quincy Colton, made over $400 profit from one such affair that attracted three to four thousand attendees.  These events were similar to those held for ether, known as ‘ether frolics.’  Following the observation in these gatherings of nitrous oxide’s analgesic and anaesthetic effects, it was formally tested in December 1844. Horace Wells, a dentist who had attended one of Colton’s exhibitions, persuaded a colleague to extract one of Wells’ teeth while Colton administered nitrous oxide gas.  The procedure was performed successfully, reportedly the first tooth ever removed painlessly. 
A former student of Wells, William T. G. Morton, was instrumental in the popularisation of ether as an anaesthetic. Morton performed a successful public demonstration of the anaesthetic capabilities of ether in October 1846 at Massachusetts General Hospital.  This event is often considered to mark the birth of modern anaesthesia, following which ether was widely adopted around the world. Later that year, Oliver W. Holmes, a writer and professor of anatomy, named the process which Morton demonstrated anaesthesia, derived from the Greek for ‘without sensation.’ 
Scottish obstetrician James Y. Simpson was the first to adopt the organic compound chloroform to relieve the pain of childbirth in 1847. Chloroform anaesthesia grew in popularity around the world and was in wide use when Queen Victoria gave birth to Prince Leopold under its influence in 1853. The chloroform was administered by the famous physician and epidemiologist John Snow.  In the early 20th century, chloroform came to supersede ether as a general anaesthetic in light of its less offensive odour, and rapid induction and emergence.
Though the first intravenous injections took place in 1656,  the first intravenous anaesthetic, sodium thiopental (thiopentone), was not synthesised until 1934.  Thiopentone is a short-acting, rapid-onset barbiturate sometimes used for anaesthetic induction. Its earliest documented use in humans was later in 1934 by Ralph Waters, an American anaesthetist.  Intravenous anaesthesia allowed more precise dosing and a less confrontational experience for the patient, and thiopentone rapidly entered common usage. Although it remained popular for many years, thiopentone was gradually replaced by propofol as the preferred induction agent. Introduced in the late 1980s, propofol allowed rapid induction and emergence, reliable hypnosis, and has antiemetic properties. 
Significant advances were also made in the 20th century in developing better halogenated inhaled agents. The advent of improved volatile agents, in parallel with a rising interest and focus on patient safety, saw a shift from ether and chloroform anaesthesia to the use of newer intravenous and inhalational agents with more favourable characteristics. Routinely used today, these agents provide fast induction and emergence, and are ideally suited for maintenance of anaesthesia. After halothane and enflurane came isoflurane, then sevoflurane, and finally desflurane in the early 1990s.  These new volatile agents had a number of desirable properties including low solubility, minimal cardiorespiratory depression, and unlike ether, are non-flammable. In contrast to ether and chloroform however, they lack analgesic effects, necessitating the use of other agents such as opioids, local anaesthetics, or nitrous oxide to ensure adequate pain relief. Nitrous oxide saw a steady decline in use over the following years, in part due to the availability of these newer agents, but also because of concerns about potential toxicity and its link with postoperative nausea and vomiting. 
The introduction of muscle relaxants to clinical practice in the early 1950s allowed for major advances in anaesthetic techniques and thereby surgery. Curare, a natural alkaloid historically used on poison darts and arrows by aboriginal people across Africa, Asia, and the Americas,  was the first non-depolarising muscle relaxant used. Through the late 1970s to 1990s, quaternary ammonium muscle relaxants were developed, including vecuronium, atracurium, and rocuronium. These compounds brought several advantages, including more favourable cardiovascular effects and minimal release of histamine.  Due to their clearance by Hoffman elimination rather than renal excretion, atracrurium and subsequently cisatracurium also possess the additional benefit of predictably rapid recovery with little cumulative effect following repeated administration. Suxamethonium, still in use today, was also developed in the 1950s. It is a depolarising neuromuscular blocking agent with fast onset and offset of action. It is considered by many as the agent of choice for rapid-onset neuromuscular blockade and has a short duration of action, although its side-effects of potassium release and increased intra-thoracic, intra-abdominal, and intra-cranial pressures will sometimes contraindicate its use.
Advances in monitoring have significantly impacted upon the practice of anaesthesia including the introduction of pulse oximetry and capnography in the 1980s.  The routinely used combination of these has contributed to a reduction in the proportion of anaesthesia-related complications that are preventable by monitoring from 39% in the 1970s to only 9% in the 1990s.  Other advances have included the measurement of inspired and end-tidal gases, including oxygen, nitrous oxide, and the volatile agents. The advent of ‘depth of anaesthesia’ monitors such as bispectral index (BIS) monitors has advanced our understanding of anaesthetic practice. Modern anaesthesia has achieved such an impressive degree of safety that the anaesthesia-related mortality in Australia is less than 3 deaths per million annually. 
A brief history of endotracheal intubation
In the late 19th century great advances were made in airway management for patients undergoing general anaesthesia. Without advanced airway support, the great safety and efficacy of modern anaesthesia would be impossible. The laryngeal tube had reportedly existed since at least 1791, and was used for a range of purposes including to facilitate breathing in oedema of the glottis, for direct delivery of medications to lung tissue, and for artificial respiration. 
Charles Trueheart of Texas published an account in 1869 describing a biphasic artificial respiration device, which included a laryngeal airway. However, the first successful delivery of endotracheal general anaesthesia was performed through tracheotomy by German surgeon Friedrich Trendelenburg in 1871.  Over the following decades, this technique was adapted in multiple settings to be delivered by oro-tracheal intubation and thus avoid the need for a surgical airway. [16, 17]
A further breakthrough in intubation came in 1895, when German physician Alfred Kirstein performed the first laryngoscopy with direct visualisation of the vocal cords.  Previously, direct visualisation was thought impossible, and the glottis and larynx had been visible only by indirect vision using mirrors. Kirstein called his device the autoscope, now known as a laryngoscope, and in the process of its development he established many of the principles of laryngoscopy which continue to be used in clinical practice. 
In 1913, Chevalier Jackson introduced a new laryngoscope blade with a light source at the distal tip, rather than the proximal light source used by Kirstein.  That same year, Henry Janeway expanded upon this, also including batteries in the handle, a central notch for maintaining the tracheal tube in the midline of the oropharynx, and a slight curve to the tip of the blade.  These changes were instrumental in popularising the use of direct laryngoscopy and tracheal intubation in anaesthesia, and the use of endotracheal intubation spread greatly following the First World War. 
Sir Ivan Magill went further with his invention, the Magill laryngoscope blade. The most significant features of this blade included a flat and wide distal end of the speculum, improving control of the epiglottis, and a slot on the side allowing the passage of catheters and tubes without obscuring vision. [21, 22] He also developed the technique of awake blind nasotracheal intubation in 1928, along with a new type of angulated forceps (the Magill forceps) for nasotracheal intubation, and a new endotracheal tube.  The Magill laryngoscope blade remains in use today, however in 1943 Sir Robert Macintosh introduced the Macintosh blade, a curved model which is currently the most widely used laryngoscope blade.  Other specific blades may be used for certain patient subsets, such as straight laryngoscope blades in infants or the McCoy laryngoscope blade for difficult intubations.
The laryngeal mask airway (LMA) was first used in 1981 before being officially released in 1988.  The LMA revolutionised airway management – it provides a clear airway, forms an effective seal at the glottic inlet, and largely avoids the risk of trauma associated with intubation.  Endotracheal intubation remains an indispensable skill for the anaesthetist, with both LMAs and endotracheal tubes widely used.
A range of equipment for intubation is now available, including video laryngoscopes and fibre-optic bronchoscopes to aid in visualising the difficult airway, tubes with and without cuffs, reinforced tubes, and double-lumen tubes. Measurement of end-tidal carbon dioxide by capnometry has also provided a useful adjunct to direct visualisation for confirming correct placement of the endotracheal tube. [25, 26] Despite these advances, the modern endotracheal intubation still relies heavily on the principles laid down by Kirstein and his successors.
Considerable progress has been made in the field of anaesthesia over the past two centuries. The development of safe, effective general anaesthesia is one of the most important advances in medical history, allowing the widespread expansion of surgery and the considerable benefits it brings. Significant advances beyond the scope of this article include the developments of local anaesthesia, regional anaesthesia, conscious sedation, and analgesia.
Conflict of interest
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