General anesthetics depress the central nervous system to a sufficient degree to permit the performance of surgery and other noxious or unpleasant procedures. Not surprisingly, general anesthetics have low therapeutic indices and thus require great care in administration. While all general anesthetics produce a relatively similar anesthetic state, they are quite dissimilar in their secondary actions (side effects) on other organ systems. The selection of specific drugs and routes of administration to produce general anesthesia is based on their pharmacokinetic properties and on the secondary effects of the various drugs, in the context of the proposed diagnostic or surgical procedure and with the consideration of the individual patient’s age, associated medical condition, and medication use. Anesthesiologists also employ sedatives, neuromuscular blocking agents, and local anesthetics as the situation requires.

Before describing the general features of anesthesia, the basic principles that underlie anesthetic actions, and the specific properties of inhalational and intravenous anesthetics and the practical aspects of their use, it is sobering to recall the time, not so very long ago, when surgical anesthesia did not exist, and to be reminded of the development of this field since 1846.

Historical Perspectives

Although Crawford Long, a physician in rural Georgia, first used ether anesthesia in 1842, not until the first public demonstration in 1846 by William T.G. Morton, a Boston dentist and medical student, did general anesthesia achieve worldwide discovery, spawning a revolution in medical care. The operating room, now known as “the ether dome” where Gilbert Abbott underwent surgery in an unconscious state at the Massachusetts General Hospital, remains a memorial to this day. Although no longer used in modern practice, ether was the ideal “first” anesthetic. Chemically, it is readily made in pure form and is relatively nontoxic to vital organs. A liquid at room temperature, it readily vaporizes, and as such is easy to administer. Unlike nitrous oxide, ether is potent, so it can produce anesthesia without diluting the oxygen in room air to hypoxic levels. Finally, ether does not greatly compromise respiration or circulation, crucial properties at a time when our understanding of human physiology and technical prowess did not allow for assisted respiration and circulation.

Chloroform was the next anesthetic to receive wide use. Introduced by the Scottish obstetrician James Simpson in 1847, it became quite popular, perhaps because its odor is more pleasant than that of ether. Other than this and its nonflammability, there was little to recommend it; the drug is a hepatotoxin and a severe cardiovascular depressant. Despite the relatively high incidence of intraoperative and postoperative death associated with the use of chloroform, it was championed, especially in Great Britain, for nearly 100 years.

It was at a stage show that Horace Wells, a dentist, noted that while under the influence of nitrous oxide, one of the participants injured himself yet felt no pain. The next day Wells, while breathing nitrous oxide, had one of his own teeth extracted painlessly by a colleague. Shortly thereafter, in 1845, Wells attempted to demonstrate his discovery at the Massachusetts General Hospital in Boston. Unfortunately the patient cried out during the operation, the demonstration was deemed a failure, and nitrous oxide fell into disuse until 1863 when Gardner Q. Colton, a showman, entrepreneur, and partially trained physician reintroduced the drug into American dental and surgical practice. In 1868, the coadministration of nitrous oxide and oxygen was described by Edmond Andrews, a Chicago surgeon, and soon thereafter the two gases became available in steel cylinders, greatly increasing their practical use.

The anesthetic properties of cyclopropane were accidentally discovered in 1929 when chemists were analyzing impurities in an isomer, propylene. After extensive clinical trials at the University of Wisconsin, the drug was introduced into practice; cyclopropane was perhaps the most widely used general anesthetic for the next 30 years. However, cyclopropane was flammable, indeed explosive, and with the increasing use of electronic equipment and electrocautery, the need for a safe, nonflammable anesthetic was clear. Efforts by the British Research Council and by chemists at Imperial Chemical Industries were rewarded by the development of halothane, a nonflammable anesthetic agent that was introduced into clinical practice in 1956 and quickly became the dominant anesthetic. Most of the newer agents, which are halogenated alkanes and ethers, are modeled after halothane.

Although the desirability of an intravenous anesthetic agent must have been apparent to physicians early in the 20th century, the drugs at hand were few and unsatisfactory. The situation changed dramatically in 1935, when Lundy demonstrated the clinical usefulness of thiopental, a rapidly-acting thiobarbiturate. It originally was considered useful as a sole anesthetic agent, but the doses required resulted in serious depression of the circulatory, respiratory, and nervous systems. However, thiopental and other intravenous anesthetics now have become the most common agents for induction of general anesthesia.

GENERAL PRINCIPLES OF SURGICAL ANESTHESIA

Unlike the practice of every other branch of medicine, anesthesia is usually neither therapeutic nor diagnostic. The exceptions to this, such as treatment of status asthmaticus with halothane and intractable angina with epidural local anesthetics, should not obscure this critical point that permeates the training and practice of the specialty. Hence, administration of general anesthesia, as well as the development of new anesthetic agents and physiologic monitoring technology, has been driven by three general objectives:

Minimizing the potentially deleterious direct and indirect effects of anesthetic agents and techniques.

Sustaining physiologic homeostasis during surgical procedures that may involve major blood loss, tissue ischemia, reperfusion of ischemic tissue, fluid shifts, exposure to a cold environment, and impaired coagulation.

Improving postoperative outcomes by choosing techniques that block or treat components of the surgical stress response, which may lead to short- or long-term sequelae (Mangano et al., 1996; Balser et al., 1998).

Hemodynamic Effects of General Anesthesia

The most prominent physiological effect of anesthesia induction, associated with the majority of both intravenous and inhalational agents, is a decrease in systemic arterial blood pressure. The causes include direct vasodilation, myocardial depression or both, a blunting of baroreceptor control, and a generalized decrease in central sympathetic tone (Sellgren et al., 1990). Agents vary in the magnitude of their specific effects (see below), but in all cases the hypotensive response is enhanced by underlying volume depletion or preexisting myocardial dysfunction. Even anesthetics that show minimal hypotensive tendencies under normal conditions (e.g., etomidate and ketamine) must be used with caution in trauma victims, in whom intravascular volume depletion is being compensated by intense sympathetic discharge. Smaller-than-normal anesthetic dosages are employed in patients presumed to be sensitive to hemodynamic effects of anesthetics.

Respiratory Effects of General Anesthesia

Airway maintenance is essential following induction of anesthesia, as nearly all general anesthetics reduce or eliminate both ventilatory drive and the reflexes that maintain airway patency. Therefore, ventilation generally must be assisted or controlled for at least some period during surgery. The gag reflex is lost, and the stimulus to cough is blunted. Lower esophageal sphincter tone also is reduced, so both passive and active regurgitation may occur. Endotracheal intubation was introduced by Kuhn in the early 1900s and has been a major reason for a decline in the number of aspiration deaths during general anesthesia. Muscle relaxation is valuable during the induction of general anesthesia where it facilitates management of the airway, including endotracheal intubation. Neuromuscular blocking agents commonly are used to effect such relaxation reducing the risk of coughing or gagging during laryngoscopic-assisted instrumentation of the airway, and thus reducing the risk of aspiration prior to secure placement of an endotracheal tube. Alternatives to an endotracheal tube include a facemask and a laryngeal mask, an inflatable mask placed in the oropharynx forming a seal around the glottis. The choice of airway management is based on the type of procedure and characteristics of the patient.

Hypothermia

Patients commonly develop hypothermia (body temperature ?36?C) during surgery. The reasons for the hypothermia include low ambient temperature, exposed body cavities, cold intravenous fluids, altered thermoregulatory control, and reduced metabolic rate. General anesthetics lower the core temperature set point at which thermoregulatory vasoconstriction is activated to defend against heat loss. Furthermore, vasodilation produced by both general and regional anesthesia offsets cold-induced peripheral vasoconstriction, thereby redistributing heat from central to peripheral body compartments, leading to a decline in core temperature (Sessler, 2000). Metabolic rate and total body oxygen consumption decrease with general anesthesia by about 30%, reducing heat generation.

Even small drops in body temperatures may lead to an increase in perioperative morbidity, including cardiac complications (Frank et al., 1997), wound infections (Kurz et al., 1996), and impaired coagulation. Prevention of hypothermia has emerged as a major goal of anesthetic care. Modalities to maintain normothermia include using warm intravenous fluids, heat exchangers in the anesthesia circuit, forced-warm-air covers, and new technology involving water-filled garments with microprocessor feedback control to a core temperature set point.

Nausea and Vomiting

Nausea and vomiting in the postoperative period continue to be significant problems following general anesthesia and are caused by an action of anesthetics on the chemoreceptor trigger zone and the brainstem vomiting center, which are modulated by serotonin (5-HT), histamine, acetylcholine, and dopamine. The 5-HT3-receptor antagonist ondansetron is very effective in suppressing nausea and vomiting. Common treatments also include droperidol, metoclopramide, dexamethasone, and avoidance of N2O. The use of propofol as an induction agent and the nonsteroidal antiinflammatory drug ketorolac as a substitute for opioids may decrease the incidence and severity of postoperative nausea and vomiting.

Other Emergence and Postoperative Phenomena

The physiological changes accompanying emergence from general anesthesia can be profound. Hypertension and tachycardia are common as the sympathetic nervous system regains its tone and is enhanced by pain. Myocardial ischemia can appear or markedly worsen during emergence in patients with coronary artery disease. Emergence excitement occurs in 5% to 30% of patients and is characterized by tachycardia, restlessness, crying, moaning and thrashing, and various neurological signs. Postanesthesia shivering occurs frequently because of core hypothermia. A small dose of meperidine (12.5 mg) lowers the shivering trigger temperature and effectively stops the activity. The incidence of all of these emergence phenomena is greatly reduced when opioids are employed as part of the intraoperative regimen.

Airway obstruction may occur during the postoperative period because residual anesthetic effects continue to partially obtund consciousness and reflexes (especially in patients who normally snore or who have sleep apnea). Strong inspiratory efforts against a closed glottis can lead to negative-pressure pulmonary edema. Pulmonary function is reduced postoperatively following all types of anesthesia and surgery, and hypoxemia may occur. Hypertension can be prodigious, often requiring aggressive treatment.

Pain control can be complicated in the immediate postoperative period. The respiratory suppression associated with opioids can be problematic among postoperative patients who still have a substantial residual anesthetic effect. Patients can alternate between screaming in apparent agony and being deeply somnolent with airway obstruction, all in a matter of moments. The nonsteroidal antiinflammatory agent ketorolac (30 to 60 mg intravenously) frequently is effective, and the development of injectable cyclooxygenase-2 inhibitors holds promise for analgesia without respiratory depression. In addition, regional anesthetic techniques are an important part of a perioperative multimodal approach that employs local anesthetic wound infiltration; epidural, spinal, and plexus blocks; and nonsteroidal antiinflammatory drugs, opioids, ?2 adrenergic-receptor agonists, and NMDA-receptor antagonists. Patient-controlled administration of intravenous and epidural analgesics makes use of small, computerized pumps activated on demand but programmed with safety limits to prevent overdose. The agents used are opioids (frequently morphine) by the intravenous route, and opioid, local anesthetic, or both, by the epidural route. These techniques have revolutionized postoperative pain management, can be continued for hours or days, and promote ambulation and improved bowel function until oral pain medications are initiated.

Sources: GOODMAN & GILMAN’S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Chapter 13.

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