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Thursday, February 21, 2019

History of general anesthesia

From Wikipedia, the free encyclopedia

Re-enactment of the first public demonstration of general anesthesia by William T. G. Morton on October 16, 1846 in the Ether Dome at Massachusetts General Hospital, Boston. Surgeons John Collins Warren and Henry Jacob Bigelow are included in this daguerrotype by Southworth & Hawes.
 
The Bulfinch Building, home of the Ether Dome
 
Attempts at producing a state of general anesthesia can be traced throughout recorded history in the writings of the ancient Sumerians, Babylonians, Assyrians, Egyptians, Greeks, Romans, Indians, and Chinese. During the Middle Ages, which correspond roughly to what is sometimes referred to as the Islamic Golden Age, scientists and other scholars made significant advances in science and medicine in the Muslim world and Eastern world

The Renaissance saw significant advances in anatomy and surgical technique. However, despite all this progress, surgery remained a treatment of last resort. Largely because of the associated pain, many patients with surgical disorders chose certain death rather than undergo surgery. Although there has been a great deal of debate as to who deserves the most credit for the discovery of general anesthesia, it is generally agreed that certain scientific discoveries in the late 18th and early 19th centuries were critical to the eventual introduction and development of modern anesthetic techniques.
Two major advances occurred in the late 19th century, which together allowed the transition to modern surgery. An appreciation of the germ theory of disease led rapidly to the development and application of antiseptic techniques in surgery. Antisepsis, which soon gave way to asepsis, reduced the overall morbidity and mortality of surgery to a far more acceptable rate than in previous eras. Concurrent with these developments were the significant advances in pharmacology and physiology which led to the development of general anesthesia and the control of pain.

In the 20th century, the safety and efficacy of general anesthesia was improved by the routine use of tracheal intubation and other advanced airway management techniques. Significant advances in monitoring and new anesthetic agents with improved pharmacokinetic and pharmacodynamic characteristics also contributed to this trend. Standardized training programs for anesthesiologists and nurse anesthetists emerged during this period. The increased application of economic and business administration principles to health care in the late 20th and early 21st centuries led to the introduction of management practices such as transfer pricing to improve the efficiency of anesthetists.

Etymology of "anesthesia"

The word "anesthesia", coined by Oliver Wendell Holmes (1809–1894) in 1846 from the Greek ἀν-, an-, "without"; and αἴσθησις, aisthēsis, "sensation"), refers to the inhibition of sensation.

Antiquity

The first attempts at general anesthesia were probably herbal remedies administered in prehistory. Alcohol is the oldest known sedative; it was used in ancient Mesopotamia thousands of years ago.

Opium

Opium poppy, Papaver somniferum
 
The Sumerians are said to have cultivated and harvested the opium poppy (Papaver somniferum) in lower Mesopotamia as early as 3400 BC, though this has been disputed. The most ancient testimony concerning the opium poppy found to date was inscribed in cuneiform script on a small white clay tablet at the end of the third millennium BC. This tablet was discovered in 1954 during excavations at Nippur, and is currently kept at the University of Pennsylvania Museum of Archaeology and Anthropology. Deciphered by Samuel Noah Kramer and Martin Leve, it is considered to be the most ancient pharmacopoeia in existence. Some Sumerian tablets of this era have an ideogram inscribed upon them, "hul gil", which translates to "plant of joy", believed by some authors to refer to opium. The term gil is still used for opium in certain parts of the world. The Sumerian goddess Nidaba is often depicted with poppies growing out of her shoulders. About 2225 BC, the Sumerian territory became a part of the Babylonian empire. Knowledge and use of the opium poppy and its euphoric effects thus passed to the Babylonians, who expanded their empire eastwards to Persia and westwards to Egypt, thereby extending its range to these civilizations. British archaeologist and cuneiformist Reginald Campbell Thompson writes that opium was known to the Assyrians in the 7th century BC. The term "Arat Pa Pa" occurs in the Assyrian Herbal, a collection of inscribed Assyrian tablets dated to c. 650 BC. According to Thompson, this term is the Assyrian name for the juice of the poppy and it may be the etymological origin of the Latin "papaver".

The ancient Egyptians had some surgical instruments, as well as crude analgesics and sedatives, including possibly an extract prepared from the mandrake fruit. The use of preparations similar to opium in surgery is recorded in the Ebers Papyrus, an Egyptian medical papyrus written in the Eighteenth dynasty. However, it is questionable whether opium itself was known in ancient Egypt. The Greek gods Hypnos (Sleep), Nyx (Night), and Thanatos (Death) were often depicted holding poppies.

Prior to the introduction of opium to ancient India and China, these civilizations pioneered the use of cannabis incense and aconitum. c. 400 BC, the Sushruta Samhita (a text from the Indian subcontinent on ayurvedic medicine and surgery) advocates the use of wine with incense of cannabis for anesthesia. By the 8th century AD, Arab traders had brought opium to India and China.

Classical antiquity

In Classical antiquity, anesthetics were described by:

China

Hua Tuo, Chinese surgeon, c. AD 200
 
Bian Que (Chinese: 扁鵲, Wade–Giles: Pien Ch'iao, c. 300 BC) was a legendary Chinese internist and surgeon who reportedly used general anesthesia for surgical procedures. It is recorded in the Book of Master Han Fei (c. 250 BC), the Records of the Grand Historian (c. 100 BC), and the Book of Master Lie (c. AD 300) that Bian Que gave two men, named "Lu" and "Chao", a toxic drink which rendered them unconscious for three days, during which time he performed a gastrostomy upon them.

Hua Tuo (Chinese:華佗, c. AD 145–220) was a Chinese surgeon of the 2nd century AD. According to the Records of Three Kingdoms (c. AD 270) and the Book of the Later Han (c. AD 430), Hua Tuo performed surgery under general anesthesia using a formula he had developed by mixing wine with a mixture of herbal extracts he called mafeisan (麻沸散). Hua Tuo reportedly used mafeisan to perform even major operations such as resection of gangrenous intestines. Before the surgery, he administered an oral anesthetic potion, probably dissolved in wine, in order to induce a state of unconsciousness and partial neuromuscular blockade.

The exact composition of mafeisan, similar to all of Hua Tuo's clinical knowledge, was lost when he burned his manuscripts, just before his death. The composition of the anesthetic powder was not mentioned in either the Records of Three Kingdoms or the Book of the Later Han. Because Confucian teachings regarded the body as sacred and surgery was considered a form of body mutilation, surgery was strongly discouraged in ancient China. Because of this, despite Hua Tuo's reported success with general anesthesia, the practice of surgery in ancient China ended with his death.

The name mafeisan combines ma (, meaning "cannabis, hemp, numbed or tingling"), fei (, meaning "boiling or bubbling"), and san (, meaning "to break up or scatter", or "medicine in powder form"). Therefore, the word mafeisan probably means something like "cannabis boil powder". Many sinologists and scholars of traditional Chinese medicine have guessed at the composition of Hua Tuo's mafeisan powder, but the exact components still remain unclear. His formula is believed to have contained some combination of:
Others have suggested the potion may have also contained hashish, bhang, shang-luh, or opium. Victor H. Mair wrote that mafei "appears to be a transcription of some Indo-European word related to "morphine"." Some authors believe that Hua Tuo may have discovered surgical analgesia by acupuncture, and that mafeisan either had nothing to do with or was simply an adjunct to his strategy for anesthesia. Many physicians have attempted to re-create the same formulation based on historical records but none have achieved the same clinical efficacy as Hua Tuo's. In any event, Hua Tuo's formula did not appear to be effective for major operations.

Other substances used from antiquity for anesthetic purposes include extracts of juniper and coca.

Middle Ages and Renaissance

Arabic and Persian physicians may have been among the first to utilize oral as well as inhaled anesthetics. Ferdowsi (940–1020) was a Persian poet who lived in the Abbasid Caliphate. In Shahnameh, his national epic poem, Ferdowsi described a caesarean section performed on Rudaba. A special wine prepared by a Zoroastrian priest was used as an anesthetic for this operation. Although Shahnameh is fictional, the passage nevertheless supports the idea that general anesthesia had at least been described in ancient Persia, even if not successfully implemented.

In 1000, Abu al-Qasim al-Zahrawi (936–1013), an Arab physician described as the father of surgery. who lived in Al-Andalus, published the 30-volume Kitab al-Tasrif, the first illustrated work on surgery. In this book, he wrote about the use of general anesthesia for surgery. c. 1020, Ibn Sīnā (980–1037) described the use of inhaled anesthesia in The Canon of Medicine. The Canon described the "soporific sponge", a sponge imbued with aromatics and narcotics, which was to be placed under a patient's nose during surgical operations. Ibn Zuhr (1091–1161) was another Arab physician from Al-Andalus. In his 12th century medical textbook Al-Taisir, Ibn Zuhr describes the use of general anesthesia. These three physicians were among many who performed operations under inhaled anesthesia with the use of narcotic-soaked sponges. Opium made its way from Asia Minor to all parts of Europe between the 10th and 13th centuries.

Throughout 1200–1500 A.D. in England, a potion called dwale was used as an anesthetic. This alcohol-based mixture contained bile, opium, lettuce, bryony, henbane, hemlock and vinegar. Surgeons roused them by rubbing vinegar and salt on their cheekbones. One can find records of dwale in numerous literary sources, including Shakespeare's Hamlet, and the John Keats poem "Ode to a Nightingale". In the 13th century, we have the first prescription of the "spongia soporifica"—a sponge soaked in the juices of unripe mulberry, flax, mandragora leaves, ivy, lettuce seeds, lapathum, and hemlock with hyoscyamus. After treatment and/or storage, the sponge could be heated and the vapors inhaled with anasthetic effect.

Alchemist Ramon Llull has been credited with discovering diethyl ether in 1275. Aureolus Theophrastus Bombastus von Hohenheim (1493–1541), better known as Paracelsus, discovered the analgesic properties of diethyl ether around 1525. It was first synthesized in 1540 by Valerius Cordus, who noted some of its medicinal properties. He called it oleum dulce vitrioli, a name that reflects the fact that it is synthesized by distilling a mixture of ethanol and sulfuric acid (known at that time as oil of vitriol). August Sigmund Frobenius gave the name Spiritus Vini Æthereus to the substance in 1730.

18th century

Satirical cartoon by James Gillray showing a Royal Institution lecture, with Humphry Davy holding the bellows and Count Rumford looking on at extreme right.
 
Joseph Priestley (1733–1804) was an English polymath who discovered nitrous oxide, nitric oxide, ammonia, hydrogen chloride and (along with Carl Wilhelm Scheele and Antoine Lavoisier) oxygen. Beginning in 1775, Priestley published his research in Experiments and Observations on Different Kinds of Air, a six-volume work. The recent discoveries about these and other gases stimulated a great deal of interest in the European scientific community. Thomas Beddoes (1760–1808) was an English philosopher, physician and teacher of medicine, and like his older colleague Priestley, was also a member of the Lunar Society of Birmingham. With an eye toward making further advances in this new science as well as offering treatment for diseases previously thought to be untreatable (such as asthma and tuberculosis), Beddoes founded the Pneumatic Institution for inhalation gas therapy in 1798 at Dowry Square in Clifton, Bristol. Beddoes employed chemist and physicist Humphry Davy (1778–1829) as superintendent of the institute, and engineer James Watt (1736–1819) to help manufacture the gases. Other members of the Lunar Society such as Erasmus Darwin and Josiah Wedgwood were also actively involved with the institute.

During the course of his research at the Pneumatic Institution, Davy discovered the anesthetic properties of nitrous oxide. Davy, who coined the term "laughing gas" for nitrous oxide, published his findings the following year in the now-classic treatise, Researches, chemical and philosophical–chiefly concerning nitrous oxide or dephlogisticated nitrous air, and its respiration. Davy was not a physician, and he never administered nitrous oxide during a surgical procedure. He was, however, the first to document the analgesic effects of nitrous oxide, as well as its potential benefits in relieving pain during surgery:
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.

19th century

Eastern hemisphere

Takamine Tokumei from Shuri, Ryūkyū Kingdom, is reported to have made a general anesthesia in 1689 in the Ryukyus, now known as Okinawa. He passed on his knowledge to the Satsuma doctors in 1690 and to Ryūkyūan doctors in 1714.

Hanaoka Seishū, a Japanese surgeon of the 18th and 19th centuries
 
Hanaoka Seishū (華岡 青洲, 1760–1835) of Osaka was a Japanese surgeon of the Edo period with a knowledge of Chinese herbal medicine, as well as Western surgical techniques he had learned through Rangaku (literally "Dutch learning", and by extension "Western learning"). Beginning in about 1785, Hanaoka embarked on a quest to re-create a compound that would have pharmacologic properties similar to Hua Tuo's mafeisan. After years of research and experimentation, he finally developed a formula which he named tsūsensan (also known as mafutsu-san). Like that of Hua Tuo, this compound was composed of extracts of several different plants, including:
  • 2 parts bai zhi (Chinese:白芷Angelica dahurica);
  • 2 parts cao wu (Chinese:草烏Aconitum sp., monkshood or wolfsbane);
  • 2 parts chuān ban xia (Pinellia ternata);
  • 2 parts chuān xiōng (Ligusticum wallichii, Cnidium rhizome, Cnidium officinale or Szechuan lovage);
  • 2 parts dong quai (Angelica sinensis or female ginseng);
  • 1 part tian nan xing (Arisaema rhizomatum or cobra lily)
  • 8 parts yang jin hua (Datura stramonium, Korean morning glory, thorn apple, jimson weed, devil's trumpet, stinkweed, or locoweed).
The reader will note that five of these seven ingredients were thought to be elements of Hua Tuo's anesthetic potion, 1600 years earlier. Some sources claim that Angelica archangelica (often referred to as garden angelica, holy ghost, or wild celery) was also an ingredient.

The active ingredients in tsūsensan are scopolamine, hyoscyamine, atropine, aconitine and angelicotoxin. When consumed in sufficient quantity, tsūsensan produces a state of general anesthesia and skeletal muscle paralysis. Shutei Nakagawa (1773–1850), a close friend of Hanaoka, wrote a small pamphlet titled "Mayaku-ko" ("narcotic powder") in 1796. Although the original manuscript was lost in a fire in 1867, this brochure described the current state of Hanaoka's research on general anesthesia.

On 13 October 1804, Hanaoka performed a partial mastectomy for breast cancer on a 60-year-old woman named Kan Aiya, using tsūsensan as a general anesthetic. This is generally regarded today as the first reliable documentation of an operation to be performed under general anesthesia. Hanaoka went on to perform many operations using tsūsensan, including resection of malignant tumors, extraction of bladder stones, and extremity amputations. Before his death in 1835, Hanaoka performed more than 150 operations for breast cancer.

Western hemisphere

Gardner Quincy Colton, 19th-century American dentist
 
Horace Wells, 19th-century American dentist
 
Crawford W. Long, 19th-century American physician
 
William T. G. Morton, 19th-century American dentist
 
Friedrich Sertürner (1783–1841) first isolated morphine from opium in 1804; he named it morphine after Morpheus, the Greek god of dreams.

Henry Hill Hickman (1800–1830) experimented with the use of carbon dioxide as an anesthetic in the 1820s. He would make the animal insensible, effectively via almost suffocating it with carbon dioxide, then determine the effects of the gas by amputating one of its limbs. In 1824, Hickman submitted the results of his research to the Royal Society in a short treatise titled Letter on suspended animation: with the view of ascertaining its probable utility in surgical operations on human subjects. The response was an 1826 article in The Lancet titled "Surgical Humbug" that ruthlessly criticized his work. Hickman died four years later at age 30. Though he was unappreciated at the time of his death, his work has since been positively reappraised and he is now recognized as one of the fathers of anesthesia.

By the late 1830s, Humphry Davy's experiments had become widely publicized within academic circles in the northeastern United States. Wandering lecturers would hold public gatherings, referred to as "ether frolics", where members of the audience were encouraged to inhale diethyl ether or nitrous oxide to demonstrate the mind-altering properties of these agents while providing much entertainment to onlookers. Four notable men participated in these events and witnessed the use of ether in this manner. They were William Edward Clarke (1819–1898), Crawford W. Long (1815–1878), Horace Wells (1815–1848), and William T. G. Morton (1819–1868).

While attending undergraduate school in Rochester, New York, in 1839, classmates Clarke and Morton apparently participated in ether frolics with some regularity. In January 1842, by now a medical student at Berkshire Medical College, Clarke administered ether to a Miss Hobbie, while Elijah Pope performed a dental extraction. In so doing, he became the first to administer an inhaled anesthetic to facilitate the performance of a surgical procedure. Clarke apparently thought little of his accomplishment, and chose neither to publish nor to pursue this technique any further. Indeed, this event is not even mentioned in Clarke's biography.

Crawford W. Long was a physician and pharmacist practicing in Jefferson, Georgia in the mid-19th century. During his time as a student at the University of Pennsylvania School of Medicine in the late 1830s, he had observed and probably participated in the ether frolics that had become popular at that time. At these gatherings, Long observed that some participants experienced bumps and bruises, but afterward had no recall of what had happened. He postulated that diethyl ether produced pharmacologic effects similar to those of nitrous oxide. On 30 March 1842, he administered diethyl ether by inhalation to a man named James Venable, in order to remove a tumor from the man's neck. Long later removed a second tumor from Venable, again under ether anesthesia. He went on to employ ether as a general anesthetic for limb amputations and parturition. Long, however, did not publish his experience until 1849, thereby denying himself much of the credit he deserved.

On 10 December 1844, Gardner Quincy Colton held a public demonstration of nitrous oxide in Hartford, Connecticut. One of the participants, Samuel A. Cooley, sustained a significant injury to his leg while under the influence of nitrous oxide without noticing the injury. Horace Wells, a Connecticut dentist present in the audience that day, immediately seized upon the significance of this apparent analgesic effect of nitrous oxide. The following day, Wells underwent a painless dental extraction while under the influence of nitrous oxide administered by Colton. Wells then began to administer nitrous oxide to his patients, successfully performing several dental extractions over the next couple of weeks.

William T. G. Morton, another New England dentist, was a former student and then-current business partner of Wells. He was also a former acquaintance and classmate of William Edward Clarke (the two had attended undergraduate school together in Rochester, New York). Morton arranged for Wells to demonstrate his technique for dental extraction under nitrous oxide general anesthesia at Massachusetts General Hospital, in conjunction with the prominent surgeon John Collins Warren. This demonstration, which took place on 20 January 1845, ended in failure when the patient cried out in pain in the middle of the operation.

On 30 September 1846, Morton administered diethyl ether to Eben Frost, a music teacher from Boston, for a dental extraction. Two weeks later, Morton became the first to publicly demonstrate the use of diethyl ether as a general anesthetic at Massachusetts General Hospital, in what is known today as the Ether Dome. On 16 October 1846, John Collins Warren removed a tumor from the neck of a local printer, Edward Gilbert Abbott. Upon completion of the procedure, Warren reportedly quipped, "Gentlemen, this is no humbug." News of this event rapidly traveled around the world. Robert Liston performed the first amputation in December of that year. Morton published his experience soon after. Harvard University professor Charles Thomas Jackson (1805–1880) later claimed that Morton stole his idea; Morton disagreed and a lifelong dispute began. For many years, Morton was credited as being the pioneer of general anesthesia in the Western hemisphere, despite the fact that his demonstration occurred four years after Long's initial experience. Long later petitioned William Crosby Dawson (1798–1856), a United States Senator from Georgia at that time, to support his claim on the floor of the United States Senate as the first to use ether anesthesia.

In 1847, Scottish obstetrician James Young Simpson (1811–1870) of Edinburgh was the first to use chloroform as a general anesthetic on a human (Robert Mortimer Glover had written on this possibility in 1842 but only used it on dogs). The use of chloroform anesthesia expanded rapidly thereafter in Europe. Chloroform began to replace ether as an anesthetic in the United States at the beginning of the 20th century. It was soon abandoned in favor of ether when its hepatic and cardiac toxicity, especially its tendency to cause potentially fatal cardiac dysrhythmias, became apparent.

In 1871, the German surgeon Friedrich Trendelenburg (1844–1924) published a paper describing the first successful elective human tracheotomy to be performed for the purpose of administration of general anesthesia.

In 1880, the Scottish surgeon William Macewen (1848–1924) reported on his use of orotracheal intubation as an alternative to tracheotomy to allow a patient with glottic edema to breathe, as well as in the setting of general anesthesia with chloroform. All previous observations of the glottis and larynx (including those of Manuel García, Wilhelm Hack and Macewen) had been performed under indirect vision (using mirrors) until 23 April 1895, when Alfred Kirstein (1863–1922) of Germany first described direct visualization of the vocal cords. Kirstein performed the first direct laryngoscopy in Berlin, using an esophagoscope he had modified for this purpose; he called this device an autoscope. The death of Emperor Frederick III (1831–1888) may have motivated Kirstein to develop the autoscope.

20th century

The 20th century saw the transformation of the practices of tracheotomy, endoscopy and non-surgical tracheal intubation from rarely employed procedures to essential components of the practices of anesthesia, critical care medicine, emergency medicine, gastroenterology, pulmonology and surgery.

In 1902, Hermann Emil Fischer (1852–1919) and Joseph von Mering (1849–1908) discovered that diethylbarbituric acid was an effective hypnotic agent. Also called barbital or Veronal (the trade name assigned to it by Bayer Pharmaceuticals), this new drug became the first commercially marketed barbiturate; it was used as a treatment for insomnia from 1903 until the mid-1950s.

Until 1913, oral and maxillofacial surgery was performed by mask inhalation anesthesia, topical application of local anesthetics to the mucosa, rectal anesthesia, or intravenous anesthesia. While otherwise effective, these techniques did not protect the airway from obstruction and also exposed patients to the risk of pulmonary aspiration of blood and mucus into the tracheobronchial tree. In 1913, Chevalier Jackson (1865–1958) was the first to report a high rate of success for the use of direct laryngoscopy as a means to intubate the trachea. Jackson introduced a new laryngoscope blade that had a light source at the distal tip, rather than the proximal light source used by Kirstein. This new blade incorporated a component that the operator could slide out to allow room for passage of an endotracheal tube or bronchoscope.

Also in 1913, Henry H. Janeway (1873–1921) published results he had achieved using a laryngoscope he had recently developed. An American anesthesiologist practicing at Bellevue Hospital in New York City, Janeway was of the opinion that direct intratracheal insufflation of volatile anesthetics would provide improved conditions for otolaryngologic surgery. With this in mind, he developed a laryngoscope designed for the sole purpose of tracheal intubation. Similar to Jackson's device, Janeway's instrument incorporated a distal light source. Unique, however, was the inclusion of batteries within the handle, a central notch in the blade for maintaining the tracheal tube in the midline of the oropharynx during intubation and a slight curve to the distal tip of the blade to help guide the tube through the glottis. The success of this design led to its subsequent use in other types of surgery. Janeway was thus instrumental in popularizing the widespread use of direct laryngoscopy and tracheal intubation in the practice of anesthesiology.

Sodium thiopental, the first intravenous anesthetic, was synthesized in 1934 by Ernest H. Volwiler (1893–1992) and Donalee L. Tabern (1900–1974), working for Abbott Laboratories. It was first used in humans on 8 March 1934 by Ralph M. Waters in an investigation of its properties, which were short-term anesthesia and surprisingly little analgesia. Three months later, John Silas Lundy started a clinical trial of thiopental at the Mayo Clinic at the request of Abbott Laboratories. Volwiler and Tabern were awarded U.S. Patent No. 2,153,729 in 1939 for the discovery of thiopental, and they were inducted into the National Inventors Hall of Fame in 1986. 

In 1939, the search for a synthetic substitute for atropine culminated serendipitously in the discovery of meperidine, the first opiate with a structure altogether different from that of morphine. This was followed in 1947 by the widespread introduction of methadone, another structurally unrelated compound with pharmacological properties similar to those of morphine.

After World War I, further advances were made in the field of intratracheal anesthesia. Among these were those made by Sir Ivan Whiteside Magill (1888–1986). Working at the Queen's Hospital for Facial and Jaw Injuries in Sidcup with plastic surgeon Sir Harold Gillies (1882–1960) and anesthetist E. Stanley Rowbotham (1890–1979), Magill developed the technique of awake blind nasotracheal intubation. Magill devised a new type of angulated forceps (the Magill forceps) that are still used today to facilitate nasotracheal intubation in a manner that is little changed from Magill's original technique. Other devices invented by Magill include the Magill laryngoscope blade, as well as several apparatuses for the administration of volatile anesthetic agents. The Magill curve of an endotracheal tube is also named for Magill. 

The first hospital anesthesia department was established at the Massachusetts General Hospital in 1936, under the leadership of Henry K. Beecher (1904–1976). Beecher, who received his training in surgery, had no previous experience in anesthesia.

Sir Robert Reynolds Macintosh (1897–1989) achieved significant advances in techniques for tracheal intubation when he introduced his new curved laryngoscope blade in 1943. The Macintosh blade remains to this day the most widely used laryngoscope blade for orotracheal intubation. In 1949, Macintosh published a case report describing the novel use of a gum elastic urinary catheter as an endotracheal tube introducer to facilitate difficult tracheal intubation. Inspired by Macintosh's report, P. Hex Venn (who was at that time the anesthetic advisor to the British firm Eschmann Bros. & Walsh, Ltd.) set about developing an endotracheal tube introducer based on this concept. Venn's design was accepted in March 1973, and what became known as the Eschmann endotracheal tube introducer went into production later that year. The material of Venn's design was different from that of a gum elastic bougie in that it had two layers: a core of tube woven from polyester threads and an outer resin layer. This provided more stiffness but maintained the flexibility and the slippery surface. Other differences were the length (the new introducer was 60 cm (24 in), which is much longer than the gum elastic bougie) and the presence of a 35° curved tip, permitting it to be steered around obstacles.

Many new intravenous and inhalational anesthetics were developed and brought into clinical use during the second half of the 20th century. Paul Janssen (1926–2003), the founder of Janssen Pharmaceutica, is credited with the development of over 80 pharmaceutical compounds. Janssen synthesized nearly all of the butyrophenone class of antipsychotic agents, beginning with haloperidol (1958) and droperidol (1961). These agents were rapidly integrated into the practice of anesthesia. In 1960, Janssen's team synthesized fentanyl, the first of the piperidinone-derived opioids. Fentanyl was followed by sufentanil (1974), alfentanil (1976), carfentanil (1976), and lofentanil (1980). Janssen and his team also developed etomidate (1964), a potent intravenous anesthetic induction agent.

The concept of using a fiberoptic endoscope for tracheal intubation was introduced by Peter Murphy, an English anesthetist, in 1967. By the mid-1980s, the flexible fiberoptic bronchoscope had become an indispensable instrument within the pulmonology and anesthesia communities.

21st century

A modern anaesthetic machine. This particular machine is a "Flow-I" model, manufactured by Maquet.
 
The "digital revolution" of the 21st century has brought newer technology to the art and science of tracheal intubation. Several manufacturers have developed video laryngoscopes which employ digital technology such as the complementary metal–oxide semiconductor active pixel sensor (CMOS APS) to generate a view of the glottis so that the trachea may be intubated. The Glidescope video laryngoscope is one example of such a device.

Xenon has recently been approved in some jurisdictions as an anaesthetic agent which does not act as a greenhouse gas.

Nitrous oxide

From Wikipedia, the free encyclopedia

Nitrous oxide
Nitrous oxide's canonical forms
Ball-and-stick model with bond lengths
Space-filling model of nitrous oxide
Names
IUPAC name
Dinitrogen monoxide
Other names
: Laughing gas, sweet air, protoxide of nitrogen, hyponitrous oxide
Identifiers
3D model (JSmol)
8137358
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.030.017
E number E942 (glazing agents, ...)
2153410
KEGG
PubChem CID
RTECS number QX1350000
UNII
UN number 1070 (compressed)
2201 (liquid)
Properties
N
2
O
Molar mass 44.013 g/mol
Appearance colorless gas
Density 1.977 g/L (gas)
Melting point −90.86 °C (−131.55 °F; 182.29 K)
Boiling point −88.48 °C (−127.26 °F; 184.67 K)
1.5 g/L (15 °C)
Solubility soluble in alcohol, ether, sulfuric acid
log P 0.35
Vapor pressure 5150 kPa (20 °C)
−18.9·10−6 cm3/mol
1.000516 (0 °C, 101,325 kPa)
Structure
linear, C∞v
0.166 D
Thermochemistry
219.96 J K−1 mol−1
+82.05 kJ mol−1
Pharmacology
N01AX13 (WHO)
  • US: C (Risk not ruled out)
Inhalation
Pharmacokinetics:
0.004%
5 minutes
Respiratory
Hazards
Safety data sheet Ilo.org, ICSC 0067
NFPA 704
Flammability code 0: Will not burn. E.g., waterHealth code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g., chloroformReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogenSpecial hazard OX: Oxidizer. E.g., potassium perchlorateNFPA 704 four-colored diamond
0
2
0
Flash point Nonflammable
Related compounds
Related nitrogen oxides
Nitric oxide
Dinitrogen trioxide
Nitrogen dioxide
Dinitrogen tetroxide
Dinitrogen pentoxide
Related compounds
Ammonium nitrate
Azide
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Nitrous oxide, commonly known as laughing gas or nitrous, is a chemical compound, an oxide of nitrogen with the formula N
2
O
. At room temperature, it is a colorless non-flammable gas, with a slight metallic scent and taste. At elevated temperatures, nitrous oxide is a powerful oxidizer similar to molecular oxygen. It is soluble in water.

Nitrous oxide has significant medical uses, especially in surgery and dentistry, for its anaesthetic and pain reducing effects. Its name "laughing gas", coined by Humphry Davy, is due to the euphoric effects upon inhaling it, a property that has led to its recreational use as a dissociative anaesthetic. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. It also is used as an oxidizer in rocket propellants, and in motor racing to increase the power output of engines.

Nitrous oxide occurs in small amounts in the atmosphere, but recently has been found to be a major scavenger of stratospheric ozone, with an impact comparable to that of CFCs. It is estimated that 30% of the N
2
O
in the atmosphere is the result of human activity, chiefly agriculture.

Uses

Rocket motors

Nitrous oxide may be used as an oxidizer in a rocket motor. This is advantageous over other oxidisers in that it is much less toxic, and due to its stability at room temperature is also easier to store and relatively safe to carry on a flight. As a secondary benefit, it may be decomposed readily to form breathing air. Its high density and low storage pressure (when maintained at low temperature) enable it to be highly competitive with stored high-pressure gas systems.

In a 1914 patent, American rocket pioneer Robert Goddard suggested nitrous oxide and gasoline as possible propellants for a liquid fueled rocket. Nitrous oxide has been the oxidizer of choice in several hybrid rocket designs (using solid fuel with a liquid or gaseous oxidizer). The combination of nitrous oxide with hydroxyl-terminated polybutadiene fuel has been used by SpaceShipOne and others. It also is notably used in amateur and high power rocketry with various plastics as the fuel.

Nitrous oxide also may be used in a monopropellant rocket. In the presence of a heated catalyst, N
2
O
will decompose exothermically into nitrogen and oxygen, at a temperature of approximately 1,070 °F (577 °C). Because of the large heat release, the catalytic action rapidly becomes secondary, as thermal autodecomposition becomes dominant. In a vacuum thruster, this may provide a monopropellant specific impulse (Isp) of as much as 180 s. While noticeably less than the Isp available from hydrazine thrusters (monopropellant or bipropellant with dinitrogen tetroxide), the decreased toxicity makes nitrous oxide an option worth investigating.

Nitrous oxide is said to deflagrate at approximately 600 °C (1,112 °F) at a pressure of 309 psi (21 atmospheres). At 600 psi for example, the required ignition energy is only 6 joules, whereas N
2
O
at 130 psi a 2500-joule ignition energy input is insufficient.

Internal combustion engine

In vehicle racing, nitrous oxide (often referred to as just "nitrous") allows the engine to burn more fuel by providing more oxygen than air alone, resulting in a more powerful combustion. The gas is not flammable at a low pressure/temperature, but it delivers more oxygen than atmospheric air by breaking down at elevated temperatures. Therefore, it often is mixed with another fuel that is easier to deflagrate. Nitrous oxide is a strong oxidant, roughly equivalent to hydrogen peroxide, and much stronger than oxygen gas. 

Nitrous oxide is stored as a compressed liquid; the evaporation and expansion of liquid nitrous oxide in the intake manifold causes a large drop in intake charge temperature, resulting in a denser charge, further allowing more air/fuel mixture to enter the cylinder. Sometimes nitrous oxide is injected into (or prior to) the intake manifold, whereas other systems directly inject, right before the cylinder (direct port injection) to increase power.

The technique was used during World War II by Luftwaffe aircraft with the GM-1 system to boost the power output of aircraft engines. Originally meant to provide the Luftwaffe standard aircraft with superior high-altitude performance, technological considerations limited its use to extremely high altitudes. Accordingly, it was only used by specialized planes such as high-altitude reconnaissance aircraft, high-speed bombers, and high-altitude interceptor aircraft. It sometimes could be found on Luftwaffe aircraft also fitted with another engine-boost system, MW 50, a form of water injection for aviation engines that used methanol for its boost capabilities. 

One of the major problems of using nitrous oxide in a reciprocating engine is that it can produce enough power to damage or destroy the engine. Very large power increases are possible, and if the mechanical structure of the engine is not properly reinforced, the engine may be severely damaged, or destroyed, during this kind of operation. It is very important with nitrous oxide augmentation of petrol engines to maintain proper operating temperatures and fuel levels to prevent "pre-ignition", or "detonation" (sometimes referred to as "knock"). Most problems that are associated with nitrous oxide do not come from mechanical failure due to the power increases. Since nitrous oxide allows a much denser charge into the cylinder, it dramatically increases cylinder pressures. The increased pressure and temperature can cause problems such as melting the piston or valves. It also may crack or warp the piston or head and cause pre-ignition due to uneven heating.

Automotive-grade liquid nitrous oxide differs slightly from medical-grade nitrous oxide. A small amount of sulfur dioxide (SO
2
) is added to prevent substance abuse. Multiple washes through a base (such as sodium hydroxide) can remove this, decreasing the corrosive properties observed when SO
2
is further oxidized during combustion into sulfuric acid, making emissions cleaner.

Aerosol propellant

Food grade N
2
O
whippets
 
The gas is approved for use as a food additive (also known as E942), specifically as an aerosol spray propellant. Its most common uses in this context are in aerosol whipped cream canisters and cooking sprays

The gas is extremely soluble in fatty compounds. In aerosol whipped cream, it is dissolved in the fatty cream until it leaves the can, when it becomes gaseous and thus creates foam. Used in this way, it produces whipped cream four times the volume of the liquid, whereas whipping air into cream only produces twice the volume. If air were used as a propellant, oxygen would accelerate rancidification of the butterfat, but nitrous oxide inhibits such degradation. Carbon dioxide cannot be used for whipped cream because it is acidic in water, which would curdle the cream and give it a seltzer-like "sparkling" sensation. 

The whipped cream produced with nitrous oxide is unstable, however, and will return to a more liquid state within half an hour to one hour.Thus, the method is not suitable for decorating food that will not be served immediately. 

During December 2016, some manufacturers reported a shortage of aerosol whipped creams in the United States due to an explosion at the Air Liquide nitrous oxide facility in Florida in late August. With a major facility offline, the disruption caused a shortage resulting in the company diverting the supply of nitrous oxide to medical clients rather than to food manufacturing. The shortage came during the Christmas and holiday season when canned whipped cream use is normally at its highest.

Similarly, cooking spray, which is made from various types of oils combined with lecithin (an emulsifier), may use nitrous oxide as a propellant. Other propellants used in cooking spray include food-grade alcohol and propane.

Medicine

Medical grade N
2
O
tanks used in dentistry
 
Nitrous oxide has been used in dentistry and surgery, as an anesthetic and analgesic, since 1844.

In the early days, the gas was administered through simple inhalers consisting of a breathing bag made of rubber cloth. Today, the gas is administered in hospitals by means of an automated relative analgesia machine, with an anesthetic vaporizer and a medical ventilator, that delivers a precisely dosed and breath-actuated flow of nitrous oxide mixed with oxygen in a 2:1 ratio.

Nitrous oxide is a weak general anesthetic, and so is generally not used alone in general anaesthesia, but used as a carrier gas (mixed with oxygen) for more powerful general anesthetic drugs such as sevoflurane or desflurane. It has a minimum alveolar concentration of 105% and a blood/gas partition coefficient of 0.46. The use of nitrous oxide in anesthesia, however, can increase the risk of postoperative nausea and vomiting.

Dentists use a simpler machine, that only delivers a N
2
O
/O
2
mixture for the patient to inhale while conscious. The patient is kept conscious throughout the procedure, and retains adequate mental faculties to respond to questions and instructions from the dentist.

Inhalation of nitrous oxide is used frequently to relieve pain associated with childbirth, trauma, oral surgery, and acute coronary syndrome (includes heart attacks). Its use during labor has been shown to be a safe and effective aid for birthing women. Its use for acute coronary syndrome is of unknown benefit.

In Britain and Canada, Entonox and Nitronox are used commonly by ambulance crews (including unregistered practitioners) as a rapid and highly effective analgesic gas.

50% nitrous oxide can be considered for use by trained non-professional first aid responders in prehospital settings, given the relative ease and safety of administering 50% nitrous oxide as an analgesic. The rapid reversibility of its effect would also prevent it from precluding diagnosis.

Recreational use

Aquatint depiction of a laughing gas party in the nineteenth century
 
Whippit remnants of recreational drug use, the Netherlands, 2017
 
Recreational inhalation of nitrous oxide, with the purpose of causing euphoria and/or slight hallucinations, began as a phenomenon for the British upper class in 1799, known as "laughing gas parties".

Starting in the nineteenth century, widespread availability of the gas for medical and culinary purposes allowed the recreational use to expand greatly, throughout the world. In the United Kingdom, as of 2014, nitrous oxide was estimated to be used by almost half a million young people at nightspots, festivals, and parties. The legality of that use varies greatly from country to country, and even from city to city in some countries.

Safety

The major safety hazards of nitrous oxide come from the fact that it is a compressed liquefied gas, an asphyxiation risk, and a dissociative anesthetic

While relatively non-toxic, nitrous oxide has a number of recognized ill effects on human health, whether through breathing it in or by contact of the liquid with skin or eyes. 

Nitrous oxide is a significant occupational hazard for surgeons, dentists, and nurses. Because nitrous oxide is minimally metabolized in humans (with a rate of 0.004%), it retains its potency when exhaled into the room by the patient, and can pose an intoxicating and prolonged exposure hazard to the clinic staff if the room is poorly ventilated. Where nitrous oxide is administered, a continuous-flow fresh-air ventilation system or N
2
O
scavenger system is used to prevent a waste-gas buildup.

The National Institute for Occupational Safety and Health recommends that workers' exposure to nitrous oxide should be controlled during the administration of anesthetic gas in medical, dental, and veterinary operators. It set a recommended exposure limit (REL) of 25 ppm (46 mg/m3) to escaped anesthetic.

Mental and manual impairment

Exposure to nitrous oxide causes short-term decreases in mental performance, audiovisual ability, and manual dexterity. These effects coupled with the induced spatial and temporal disorientation could result in physical harm to the user from environmental hazards.

Neurotoxicity and neuroprotection

Like other NMDA antagonists, N
2
O
was suggested to produce neurotoxicity in the form of Olney's lesions in rodents upon prolonged (several hour) exposure. New research has arisen suggesting that Olney's lesions do not occur in humans, however, and similar drugs such as ketamine are now believed not to be acutely neurotoxic. It has been argued that, because N
2
O
has a very short duration under normal circumstances, it is less likely to be neurotoxic than other NMDA antagonists. Indeed, in rodents, short-term exposure results in only mild injury that is rapidly reversible, and neuronal death occurs only after constant and sustained exposure. Nitrous oxide also may cause neurotoxicity after extended exposure because of hypoxia. This is especially true of non-medical formulations such as whipped-cream chargers (also known as "whippets" or "nangs"), which never contain oxygen, since oxygen makes cream rancid.

Additionally, nitrous oxide depletes vitamin B12 levels. This can cause serious neurotoxicity if the user has preexisting vitamin B12 deficiency.

Nitrous oxide at 75% by volume reduces ischemia-induced neuronal death induced by occlusion of the middle cerebral artery in rodents, and decreases NMDA-induced Ca2+ influx in neuronal cell cultures, a critical event involved in excitotoxicity.

Oxygen deprivation

If pure nitrous oxide is inhaled without oxygen mixed in, this can eventually lead to oxygen deprivation resulting in loss of blood pressure, fainting and even heart attacks. This can occur if the user inhales large quantities continuously, as with a strap-on mask connected to a gas canister. It can also happen if the user engages in excessive breath-holding or uses any other inhalation system that cuts off their supply of fresh air.

Vitamin B12 deficiency

Long-term exposure to nitrous oxide may cause vitamin B12 deficiency. It inactivates the cobalamin form of vitamin B12 by oxidation. Symptoms of vitamin B12 deficiency, including sensory neuropathy, myelopathy, and encephalopathy, may occur within days or weeks of exposure to nitrous oxide anaesthesia in people with subclinical vitamin B12 deficiency.

Symptoms are treated with high doses of vitamin B12, but recovery can be slow and incomplete.

People with normal vitamin B12 levels have stores to make the effects of nitrous oxide insignificant, unless exposure is repeated and prolonged (nitrous oxide abuse). Vitamin B12 levels should be checked in people with risk factors for vitamin B12 deficiency prior to using nitrous oxide anesthesia.

Prenatal development

Several experimental studies in rats indicate that chronic exposure of pregnant females to nitrous oxide may have adverse effects on the developing fetus.

Chemical/physical risks

At room temperature (20 °C (68 °F)) the saturated vapor pressure is 50.525 bar, rising up to 72.45 bar at 36.4 °C (97.5 °F)—the critical temperature. The pressure curve is thus unusually sensitive to temperature. Liquid nitrous oxide acts as a good solvent for many organic compounds; liquid mixtures may form shock sensitive explosives.

As with many strong oxidizers, contamination of parts with fuels have been implicated in rocketry accidents, where small quantities of nitrous/fuel mixtures explode due to "water hammer"-like effects (sometimes called "dieseling"—heating due to adiabatic compression of gases can reach decomposition temperatures). Some common building materials such as stainless steel and aluminium can act as fuels with strong oxidizers such as nitrous oxide, as can contaminants that may ignite due to adiabatic compression.

There also have been incidents where nitrous oxide decomposition in plumbing has led to the explosion of large tanks.

Mechanism of action

The pharmacological mechanism of action of N
2
O
in medicine is not fully known. However, it has been shown to directly modulate a broad range of ligand-gated ion channels, and this likely plays a major role in many of its effects. It moderately blocks NMDA and β2-subunit-containing nACh channels, weakly inhibits AMPA, kainate, GABAC, and 5-HT3 receptors, and slightly potentiates GABAA and glycine receptors. It also has been shown to activate two-pore-domain K+ channels. While N
2
O
affects quite a few ion channels, its anesthetic, hallucinogenic, and euphoriant effects are likely caused predominantly, or fully, via inhibition of NMDA receptor-mediated currents. In addition to its effects on ion channels, N
2
O
may act to imitate nitric oxide (NO) in the central nervous system, and this may be related to its analgesic and anxiolytic properties. Nitrous oxide is 30-40 times more soluble than nitrogen.
  
The effects of inhaling sub-anesthetic doses of Nitrous Oxide have been known to vary, based on several factors, including settings and individual differences, however, from his discussion, Jay (2008) suggests that it has been reliably known to induce the following states and sensations:
  • Intoxication
  • Euphoria/dysphoria
  • Spatial disorientation
  • Temporal disorientation
  • Reduced pain sensitivity
A minority of users also will present with uncontrolled vocalizations and muscular spasms. These effects generally disappear minutes after removal of the nitrous oxide source.

Euphoric effect

In rats, N
2
O
stimulates the mesolimbic reward pathway via inducing dopamine release and activating dopaminergic neurons in the ventral tegmental area and nucleus accumbens, presumably through antagonisation of NMDA receptors localized in the system. This action has been implicated in its euphoric effects, and notably, appears to augment its analgesic properties as well.

It is remarkable, however, that in mice, N
2
O
blocks amphetamine-induced carrier-mediated dopamine release in the nucleus accumbens and behavioral sensitization, abolishes the conditioned place preference (CPP) of cocaine and morphine, and does not produce reinforcing (or aversive) effects of its own. Effects of CPP of N
2
O
in rats are mixed, consisting of reinforcement, aversion, and no change. In contrast, it is a positive reinforcer in squirrel monkeys, and is well known as a drug of abuse in humans. These discrepancies in response to N
2
O
may reflect species variation or methodological differences. In human clinical studies, N
2
O
was found to produce mixed responses, similarly to rats, reflecting high subjective individual variability.

Anxiolytic effect

In behavioural tests of anxiety, a low dose of N
2
O
is an effective anxiolytic, and this anti-anxiety effect is associated with enhanced activity of GABAA receptors, as it is partially reversed by benzodiazepine receptor antagonists. Mirroring this, animals that have developed tolerance to the anxiolytic effects of benzodiazepines are partially tolerant to N
2
O
. Indeed, in humans given 30% N
2
O
, benzodiazepine receptor antagonists reduced the subjective reports of feeling "high", but did not alter psychomotor performance, in human clinical studies.

Analgesic effect

The analgesic effects of N
2
O
are linked to the interaction between the endogenous opioid system and the descending noradrenergic system. When animals are given morphine chronically, they develop tolerance to its pain-killing effects, and this also renders the animals tolerant to the analgesic effects of N
2
O
. Administration of antibodies that bind and block the activity of some endogenous opioids (not β-endorphin) also block the antinociceptive effects of N
2
O
. Drugs that inhibit the breakdown of endogenous opioids also potentiate the antinociceptive effects of N
2
O
. Several experiments have shown that opioid receptor antagonists applied directly to the brain block the antinociceptive effects of N
2
O
, but these drugs have no effect when injected into the spinal cord

Conversely, α2-adrenoceptor antagonists block the pain-reducing effects of N
2
O
when given directly to the spinal cord, but not when applied directly to the brain. Indeed, α2B-adrenoceptor knockout mice or animals depleted in norepinephrine are nearly completely resistant to the antinociceptive effects of N
2
O
. Apparently N
2
O
-induced release of endogenous opioids causes disinhibition of brain stem noradrenergic neurons, which release norepinephrine into the spinal cord and inhibit pain signalling. Exactly how N
2
O
causes the release of endogenous opioid peptides remains uncertain.

Properties and reactions

Nitrous oxide is a colorless, non-toxic gas with a faint, sweet odor. 

Nitrous oxide supports combustion by releasing the dipolar bonded oxygen radical, thus it can relight a glowing splint

N
2
O
is inert at room temperature and has few reactions. At elevated temperatures, its reactivity increases. For example, nitrous oxide reacts with NaNH
2
at 460 K (187 °C) to give NaN
3
 :
2 NaNH
2
+ N
2
O
NaN
3
+ NaOH + NH
3
The above reaction is the route adopted by the commercial chemical industry to produce azide salts, which are used as detonators.

History

The gas was first synthesised in 1772 by English natural philosopher and chemist Joseph Priestley who called it phlogisticated nitrous air or inflammable nitrous air. Priestley published his discovery in the book Experiments and Observations on Different Kinds of Air (1775), where he described how to produce the preparation of "nitrous air diminished", by heating iron filings dampened with nitric acid.

Early use

"LIVING MADE EASY"
A satirical print from 1830 depicting Humphry Davy administering a dose of laughing gas to a woman
 
The first important use of nitrous oxide was made possible by Thomas Beddoes and James Watt, who worked together to publish the book Considerations on the Medical Use and on the Production of Factitious Airs (1794). This book was important for two reasons. First, James Watt had invented a novel machine to produce "Factitious Airs" (i.e. nitrous oxide) and a novel "breathing apparatus" to inhale the gas. Second, the book also presented the new medical theories by Thomas Beddoes, that tuberculosis and other lung diseases could be treated by inhalation of "Factitious Airs".

Sir Humphry Davy’s Researches chemical and philosophical: chiefly concerning nitrous oxide (1800), pages 556 and 557 (right), outlining potential anaesthetic properties of nitrous oxide in relieving pain during surgery
 
The machine to produce "Factitious Airs" had three parts: a furnace to burn the needed material, a vessel with water where the produced gas passed through in a spiral pipe (for impurities to be "washed off"), and finally the gas cylinder with a gasometer where the gas produced, "air", could be tapped into portable air bags (made of airtight oily silk). The breathing apparatus consisted of one of the portable air bags connected with a tube to a mouthpiece. With this new equipment being engineered and produced by 1794, the way was paved for clinical trials, which began in 1798 when Thomas Beddoes established the "Pneumatic Institution for Relieving Diseases by Medical Airs" in Hotwells (Bristol). In the basement of the building, a large-scale machine was producing the gases under the supervision of a young Humphry Davy, who was encouraged to experiment with new gases for patients to inhale. The first important work of Davy was examination of the nitrous oxide, and the publication of his results in the book: Researches, Chemical and Philosophical (1800). In that publication, Davy notes the analgesic effect of nitrous oxide at page 465 and its potential to be used for surgical operations at page 556. Davy coined the name "laughing gas" for nitrous oxide.

Despite Davy's discovery that inhalation of nitrous oxide could relieve a conscious person from pain, another 44 years elapsed before doctors attempted to use it for anesthesia. The use of nitrous oxide as a recreational drug at "laughing gas parties", primarily arranged for the British upper class, became an immediate success beginning in 1799. While the effects of the gas generally make the user appear stuporous, dreamy, and sedated, some people also "get the giggles" in a state of euphoria, and frequently erupt in laughter.

One of the earliest commercial producers in the U.S. was George Poe, cousin of the poet Edgar Allan Poe, who also was the first to liquefy the gas.

Anaesthetic use

The first time nitrous oxide was used as an anaesthetic drug in the treatment of a patient was when dentist Horace Wells, with assistance by Gardner Quincy Colton and John Mankey Riggs, demonstrated insensitivity to pain from a dental extraction on 11 December 1844. In the following weeks, Wells treated the first 12–15 patients with nitrous oxide in Hartford, Connecticut, and according to his own record, only failed in two cases. In spite of these convincing results having been reported by Wells to the medical society in Boston in December 1844, this new method was not immediately adopted by other dentists. The reason for this was most likely that Wells, in January 1845 at his first public demonstration to the medical faculty in Boston, had been partly unsuccessful, leaving his colleagues doubtful regarding its efficacy and safety. The method did not come into general use until 1863, when Gardner Quincy Colton successfully started to use it in all his "Colton Dental Association" clinics, that he had just established in New Haven and New York City. Over the following three years, Colton and his associates successfully administered nitrous oxide to more than 25,000 patients. Today, nitrous oxide is used in dentistry as an anxiolytic, as an adjunct to local anesthetic.

Nitrous oxide was not found to be a strong enough anaesthetic for use in major surgery in hospital settings, however. Instead, diethyl ether, being a stronger and more potent anaesthetic, was demonstrated and accepted for use in October 1846, along with chloroform in 1847. When Joseph Thomas Clover invented the "gas-ether inhaler" in 1876, however, it became a common practice at hospitals to initiate all anesthetic treatments with a mild flow of nitrous oxide, and then gradually increase the anesthesia with the stronger ether or chloroform. Clover's gas-ether inhaler was designed to supply the patient with nitrous oxide and ether at the same time, with the exact mixture being controlled by the operator of the device. It remained in use by many hospitals until the 1930s. Although hospitals today are using a more advanced anesthetic machine, these machines still use the same principle launched with Clover's gas-ether inhaler, to initiate the anesthesia with nitrous oxide, before the administration of a more powerful anesthetic.

As a patent medicine

Colton's popularization of nitrous oxide led to its adoption by a number of less than reputable quacksalvers, who touted it as a cure for consumption, scrofula, catarrh, and other diseases of the blood, throat, and lungs. Nitrous oxide treatment was administered and licensed as a patent medicine by the likes of C. L. Blood and Jerome Harris in Boston and Charles E. Barney of Chicago.

Production

Reviewing various methods of producing nitrous oxide is published.

Industrial methods

Nitrous oxide production
 
Nitrous oxide is prepared on an industrial scale by careful heating of ammonium nitrate at about 250 C, which decomposes into nitrous oxide and water vapor.
NH
4
NO
3
→ 2 H
2
O
+ N
2
O
The addition of various phosphate salts favors formation of a purer gas at slightly lower temperatures. This reaction may be difficult to control, resulting in detonation.

Laboratory methods

The decomposition of ammonium nitrate is also a common laboratory method for preparing the gas. Equivalently, it can be obtained by heating a mixture of sodium nitrate and ammonium sulfate:
2 NaNO
3
+ (NH
4
)2SO
4
Na
2
SO
4
+ 2 N
2
O
+ 4 H
2
O
.
Another method involves the reaction of urea, nitric acid, and sulfuric acid:
2 (NH2)2CO + 2 HNO
3
+ H
2
SO
4
→ 
2 N
2
O
+ 2 CO
2
+ (NH4)2SO4 + 2H
2
O
.
Direct oxidation of ammonia with a manganese dioxide-bismuth oxide catalyst has been reported: cf. Ostwald process.
2 NH
3
+ 2 O
2
N
2
O
+ 3 H
2
O
Hydroxylammonium chloride reacts with sodium nitrite to give nitrous oxide. If the nitrite is added to the hydroxylamine solution, the only remaining by-product is salt water. If the hydroxylamine solution is added to the nitrite solution (nitrite is in excess), however, then toxic higher oxides of nitrogen also are formed:
NH
3
OH
Cl + NaNO
2
N
2
O
+ NaCl + 2 H
2
O
Treating HNO
3
with SnCl
2
and HCl also has been demonstrated:
2 HNO
3
+ 8 HCl + 4 SnCl
2
→ 5 H
2
O
+ 4 SnCl
4
+ N
2
O
Hyponitrous acid decomposes to N2O and water with a half-life of 16 days at 25 °C at pH 1–3.
H2N2O2→ H2O + N2O

Atmospheric occurrence

Nitrous oxide is a minor component of Earth's atmosphere, currently with a concentration of about 0.330 ppm.

Emissions by source

As of 2010, it was estimated that about 29.5 million tonnes of N
2
O
(containing 18.8 million tonnes of nitrogen) were entering the atmosphere each year; of which 64% were natural, and 36% due to human activity.

Most of the N
2
O
emitted into the atmosphere, from natural and anthropogenic sources, is produced by microorganisms such as bacteria and fungi in soils and oceans. Soils under natural vegetation are an important source of nitrous oxide, accounting for 60% of all naturally produced emissions. Other natural sources include the oceans (35%) and atmospheric chemical reactions (5%).

The main components of anthropogenic emissions are fertilized agricultural soils and livestock manure (42%), runoff and leaching of fertilizers (25%), biomass burning (10%), fossil fuel combustion and industrial processes (10%), biological degradation of other nitrogen-containing atmospheric emissions (9%), and human sewage (5%). Agriculture enhances nitrous oxide production through soil cultivation, the use of nitrogen fertilizers, and animal waste handling. These activities stimulate naturally-occurring bacteria to produce more nitrous oxide. Nitrous oxide emissions from soil can be challenging to measure as they vary markedly over time and space, and the majority of a year's emissions may occur when conditions are favorable during "hot moments" and/or at favorable locations known as "hotspots".

Among industrial emissions, the production of nitric acid and adipic acid are the largest sources of nitrous oxide emissions. The adipic acid emissions specifically arise from the degradation of the nitrolic acid intermediate derived from nitration of cyclohexanone.

Biological processes

Natural processes that generate nitrous oxide may be classified as nitrification and denitrification. Specifically, they include:
  • aerobic autotrophic nitrification, the stepwise oxidation of ammonia (NH
    3
    ) to nitrite (NO
    2
    ) and to nitrate (NO
    3
    )
  • anaerobic heterotrophic denitrification, the stepwise reduction of NO
    3
    to NO
    2
    , nitric oxide (NO), N
    2
    O
    and ultimately N
    2
    , where facultative anaerobe bacteria use NO
    3
    as an electron acceptor in the respiration of organic material in the condition of insufficient oxygen (O
    2
    )
  • nitrifier denitrification, which is carried out by autotrophic NH
    3
    −oxidizing bacteria and the pathway whereby ammonia (NH
    3
    ) is oxidised to nitrite (NO
    2
    ), followed by the reduction of NO
    2
    to nitric oxide (NO), N
    2
    O
    and molecular nitrogen (N
    2
    )
  • heterotrophic nitrification
  • aerobic denitrification by the same heterotrophic nitrifiers
  • fungal denitrification
  • non-biological chemodenitrification
These processes are affected by soil chemical and physical properties such as the availability of mineral nitrogen and organic matter, acidity, and soil type; as well as climate-related factors such as soil temperature and water content. 

The emission of the gas to the atmosphere is limited greatly by its consumption inside the cells, by a process catalyzed by the enzyme nitrous oxide reductase.

Environmental impact

Greenhouse effect

Greenhouse gas trends
 
Nitrous oxide has significant global warming potential as a greenhouse gas. On a per-molecule basis, considered over a 100-year-period, nitrous oxide has 298 times the atmospheric heat-trapping ability of carbon dioxide (CO
2
), however, because of its low concentration (less than 1/1000 of that of CO
2
), its contribution to the greenhouse effect is less than one-third that of carbon dioxide, and also less than water vapor and methane. On the other hand, since 38% or more of the N
2
O
entering the atmosphere is the result of human activity, and its concentration has increased 15% since 1750, control of nitrous oxide is considered part of efforts to curb greenhouse gas emissions. 

A 2008 study by Nobel Laureate Paul Crutzen suggests that the amount of nitrous oxide release attributable to agricultural nitrate fertilizers has been seriously underestimated, most of which presumably, would come under soil and oceanic release in the Environmental Protection Agency data.

Globally, about 40 percent of total N2O emissions come from human activities.2 Nitrous oxide is emitted from agriculture, transportation, and industry activities, described below. 

Agriculture. Nitrous oxide can result from various agricultural soil management activities, such as synthetic and organic fertilizer application and other cropping practices, the management of manure, or burning of agricultural residues. Agricultural soil management is the largest source of N2O emissions in the United States, accounting for about 77 percent of total U.S. N2O emissions in 2016. 

Fuel Combustion. Nitrous oxide is emitted when fuels are burned. The amount of N2O emitted from burning fuels depends on the type of fuel and combustion technology, maintenance, and operating practices. 

Industry. Nitrous oxide is generated as a byproduct during the production of nitric acid, which is used to make synthetic commercial fertilizer, and in the production of adipic acid, which is used to make fibers, like nylon, and other synthetic products. 

Ozone layer depletion

Nitrous oxide also has been implicated in thinning of the ozone layer. A new study suggests that N
2
O
emission currently is the single most important ozone-depleting substance (ODS) emission and is expected to remain the largest throughout the twenty-first century.

Legality

In the United States, possession of nitrous oxide is legal under federal law and is not subject to DEA purview. It is, however, regulated by the Food and Drug Administration under the Food Drug and Cosmetics Act; prosecution is possible under its "mis-branding" clauses, prohibiting the sale or distribution of nitrous oxide for the purpose of human consumption

Many states have laws regulating the possession, sale, and distribution of nitrous oxide. Such laws usually ban distribution to minors or limit the amount of nitrous oxide that may be sold without special license. For example, in the state of California, possession for recreational use is prohibited and qualifies as a misdemeanor.

In August 2015, the Council of the London Borough of Lambeth (UK) banned the use of the drug for recreational purposes, making offenders liable to an on-the-spot fine of up to £1,000.

In New Zealand, the Ministry of Health has warned that nitrous oxide is a prescription medicine, and its sale or possession without a prescription, is an offense under the Medicines Act. This statement would seemingly prohibit all non-medicinal uses of nitrous oxide, although it is implied that only recreational use will be targeted legally. 

In India, transfer of nitrous oxide from bulk cylinders to smaller, more transportable E-type, 1590 liter-capacity tanks, is legal when the intended use of the gas is for medical anesthesia.

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