INTRAVENOUS ANESTHETICS

The development of intravenous anesthetics has been an important component of anesthetic management for over 70 years (see Chapter 10 and Chapter 11 ). Before the introduction of rapid-acting intravenous agents, induction of general anesthesia necessarily required inhalation of gases or vapors, an unpleasant experience for some patients.

Aristotle thought the arteries contained air, but Galen proved that the arteries and veins contained blood by opening, then ligating, the vessels of live animals. Galen's error was to place the origin of the blood in the liver, from where it flowed outward to the organs. With this arrangement, an intravenous injection would not be expected to produce a systemic effect.

William Harvey (1578–1657) announced his discovery of the circulation of the blood on April 17, 1616, one week before Shakespeare's death, but he did not publish until 1628, when a miserably printed book of 72 pages from Frankfurt, Germany, outlined one of the greatest discoveries in the annals of medicine: Blood flows from the heart to arteries, to veins, and back to the heart.^[301] A crucial step in Harvey's analysis of the circulation was that the venous blood flowed to the heart and not to the periphery, opening the possibility of intravenous therapy. Chauncey Leake, a 20th-century pharmacologist who also contributed significantly to the development of anesthetic agents, translated the works of Harvey from Latin to English. The following excerpt from the Leake translation of De Motu Cordis concerns the function of the valves in the venous system, previously described by Harvey's teacher, Hieronymus Fabricius Ab Aquapendente (1537–1619) of Padua:

The discoverer of these valves and his followers did not rightly appreciate their function. It is not to prevent blood from falling by its weight into areas lower down, for there are some in the jugular vein which are directed downwards, and which prevent blood from being carried upwards. They are thus not always looking upwards, but more correctly, always toward the main venous trunks and the heart. ... to this may be added that there are none in the arteries, and that one may note that dogs, oxen, and all such animals have valves at the branches of the crural veins at the top of the sacrum, and in branches from the haunches, in which no such weight effect of an erect stature is to be feared. ... From many experiments it is evident that the function of the valves in the veins is the same as that of the three sigmoid valves placed at the opening of the aorta and pulmonary artery, to prevent, when they are tightly closed, the reflex of blood passing over them.

Between 1656 and 1657, Christopher Wren and Timothy Clarck experimented with the intravenous

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Various phenomena occurred over and over again which held me in doubt, whether such operations could ever be safely employed ... it would require that previous alteration of the injection should be rendered fit for use.

This final remark might have referred to infectious or other side effects from injecting unsterile or hypertonic solutions.

Pierre-Cyprien Ore^[303] (1828–1891) performed the first successful attempt at intravenous anesthesia in 1872 by using chloral hydrate to anesthetize a human subject. Although he believed it superior to chloroform, his contemporaries did not adopt the method. Intravenous paraldehyde was briefly used as an anesthetic during and after World War I. At the same time, the combination of intravenous morphine and scopolamine gained wide popularity, particularly in obstetric anesthesia.^[304] The method became known as twilight sleep, but this drug combination was slowly abandoned because of unpredictable side effects when given to some patients. Tribromoethanol (Avertin) was originally promoted as a full anesthetic agent to be administered rectally.^[305] Although the rectal administration of agents had been promoted by Pirogoff, Gwathmey, and others, the use of rectal tribromoethanol fell into disfavor when rectal ulcerations after use of the agent were reported. Thereafter, tribromoethanol was used briefly an intravenous agent, but because it had a prolonged duration of action and produced profound respiratory depression and probable hepatotoxicity, other suitable intravenous agents were sought.

Adolf von Baeyer discovered the first barbiturate, barbituric acid, in 1864, but the drug had no sedative properties. It is said that Baeyer celebrated the discovery of the compound on Saint Barbara's Day, and he coined the word barbiturate as a combination of Barbara with urea, because barbituric acid results from the combination of malonic acid and urea.^[306] The first sedative barbiturate was synthesized in 1903 by Emil Fischer^[307] (1852–1919) of Berlin, but short-acting intravenous agents such as hexobarbital were not introduced until nearly 30 years later. Helmut Weese^[308] (1897–1954), considered by many to be the originator of successful intravenous anesthetic methods, reported several thousand cases of hexobarbital use in 1932. Sodium thiopental followed hexobarbital in 1934, and the first detailed analysis of its use was described by John Lundy of the Mayo Clinic.^{[309] [310]} The use of thiopental was a further refinement of his earlier concept of balanced anesthesia, whereby anesthesia is administered with the use of multiple agents.^[310] According to Lundy, general anesthesia was safer with the use of multiple agents, because the dose of any one particular agent was less and fewer side effects were observed.

It was soon learned that thiopental could be dangerous to administer in certain circumstances. When the drug was used for induction of anesthesia for injured personnel after the bombing of Pearl Harbor in 1941, the frequent occurrence of sudden death emphasized the profound depressant effect this drug has on the cardiovascular system.^[311] A later analysis of the use of thiopental at Pearl Harbor, however, did not implicate the drug as the cause of the high mortality rate observed at that time.^[312] The only other commonly used short-acting barbiturate is methohexital, an oxybarbiturate that has similar depressant effects on the circulation. Because of its unique proconvulsive effect, methohexital is used as an anesthetic for electroshock therapy.

There have been several attempts to replace the barbiturates with shorter-acting drugs with less cardiovascular depression. Some of these drugs, such as althesin,^[313] propanidid, and eltanolone, were withdrawn from clinical use because of unwanted side effects. Etomidate, an intravenous anesthetic used to induce anesthesia that was introduced in 1973, produces only minimal hemodynamic depression and has found use in patients with hypovolemia and in those with significant cardiovascular disease.^[314] Etomidate can cause undesirable myoclonic movements during induction in some patients.

The benzodiazepines midazolam, diazepam, and lorazepam are useful intravenous agents that relieve anxiety without the same degree of sedation produced with the barbiturates. Experimental studies on this class of drugs began in 1933 at the University of Kracow in Poland, with the first clinically useful drug, chlordiazepoxide (Librium), introduced in 1960. Diazepam (1963) and midazolam (1978) followed.^[315] A specific antagonist can be used to treat overdosage.^[316]

Ketamine was introduced as an anesthetic in 1966.^[317] It was initially used intravenously or intramuscularly as a complete agent by itself, but reports of postoperative hallucinations led to re-evaluation of its use, and it is now typically used only in combination with other sedative agents. Ketamine is a unique agent in the armamentarium of the anesthesiologist because it does not depress the cardiovascular system, even when used in full anesthetic doses.

Propofol, introduced clinically^{[313] [318]} in 1977, is an alkylphenol compound that has some advantages over thiopental. It appears to have antiemetic properties and suppresses laryngeal reflexes to a greater extent than thiopental, allowing easy placement of supraglottic airways. It has achieved widespread use since its introduction, partially because of its rapid recovery profile. Propofol is often administered as a continuous infusion for general anesthesia, with or without the addition of inhalation anesthetics. When combined with analgesic agents such as opioids, propofol can provide all the components of a satisfactory general anesthetic. This method, often called total intravenous anesthesia (TIVA), can eliminate the need for any gaseous or volatile agents. Propofol is a profound cardiovascular depressant, and it can produce significant pain on injection.

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Although intravenous opioids were once considered unsafe in the private rooms of hospitals, a modality of administration called patient-controlled analgesia (PCA) is now routinely used in most hospitals. The rationale is that because pain is a subjective experience, only the patients can assess the need for analgesics and balance that with their experience of side effects. Overdose is obviated by lock-out intervals and by the inability to perform the task of drug administration as somnolence ensues. The methods for intravenous PCA therapy in the postoperative setting were developed by anesthesiologists more than 30 years ago,^{[319] [320] [321]} but they are now used by several specialty groups within the hospital.