Chapter 46: Anesthesia for the Surgical Patient

1. The incremental interchange of ideas across the specialties of anesthesia and surgery demonstrates the collaborative nature of science in general and medicine in particular. Many surgeons contributed to the growth in anesthesia; more comprehensive anesthesia, in turn, allowed more complex surgery to develop.

2. The role of the anesthesiologist has expanded to become the perioperative physician. The anesthesiologist evaluates the patient preoperatively, provides the anesthetic, and is involved in postoperative pain relief.

3. New and improved airway and intubation devices, such as the laryngeal mask airway and the video laryngoscope, along with the American Society of Anesthesiologists’ airway management algorithm, have led to improved management and control of routine and difficult airways.

4. The specialties of critical care medicine and pain medicine have grown out of the expanded field of anesthesiology. The postanesthesia care unit gave rise to the intensive care unit; the treatment of acute and chronic pain syndromes by anesthesiologists contributed to the growth of pain medicine as a specialty.

5. The study of proteomics will lead to anesthetics tailored to individuals, maximizing effects and reducing side effects of various anesthetic drugs.

The discipline of anesthesia embodies control of three great concerns of humankind: consciousness, pain, and movement. The field of anesthesiology combines the administration of anesthesia with the perioperative management of the patient’s concerns, pain management, and critical illness. The fields of surgery and anesthesiology are truly collaborative and continue to evolve together, enabling the care of sicker patients and rapid recovery from outpatient and minimally invasive procedures.

The discovery of anesthesia is one of the seminal American contributions to the world. Along with infection control and blood transfusion, anesthesia has enabled surgery to occupy its fundamental place in medicine. Before the advent of modern anesthesia in the 1840s, many substances and methods were tried in the search for pain relief and better operating conditions. Opium, alcohol, exposure to cold, compression of peripheral nerves, constriction of the carotid arteries to produce unconsciousness, and hypnosis (mesmerism) all proved less than satisfactory and dictated rapid and crude surgical procedures. Patients had to be restrained by several attendants, and only the most stoic could tolerate the screams heard in the operating theater. Charles Darwin, who witnessed two such operations, “rushed away before they were completed. Nor did I ever attend again, for hardly any inducement would have been strong enough to make me do so; this being long before the blessed days of chloroform. The two cases fairly haunted me for many a long year.”¹

Modern Beginnings

Although Humphrey Davy (1778–1829) suggested using nitrous oxide for the relief of pain in surgical procedures in 1800, this was not pursued until 1844 by dentist Horace Wells (1815–1848). Wells astutely observed that a man who was injured after inhaling nitrous oxide during an exhibition of the “laughing gas”displayed no awareness of pain. After experimenting on himself, Wells attempted to demonstrate the analgesic effects of nitrous oxide for a dental procedure at Harvard Medical School in 1845. The public demonstration was a failure because nitrous oxide has analgesic properties, but does not suffice as the sole anesthetic agent in every patient. Wells never recovered from his humiliating experience and eventually committed suicide. However, he does hold a place in history as the first person to recognize and use the only anesthetic from the 1800s that is still in use today—nitrous oxide.

In 1842, Crawford Long (1815–1878), a physician in rural Georgia, used diethyl ether to induce surgical anesthesia for the removal of two small neck tumors. Diethyl ether had been known for over 800 years but was not used for analgesic purposes. It became an inexpensive and popular recreational drug in the mid-nineteenth century and was used by American medical students at “ether frolics.” Although Long did experiments to verify the analgesic effects of ether, he did not publish his work until 1848, in the Southern Medical Journal, too late to be the unquestioned discoverer of anesthesia.²

Ether Day

William Morton (1819–1868) was a dentist and partner of ­Horace Wells. After taking a course in anesthesia from Wells, Morton left the partnership in Hartford, Connecticut, and established himself in Boston. He continued his interest in anesthesia, but with diethyl ether replacing nitrous oxide. Ether proved a good choice, as it supports respiration and the cardiovascular system at analgesic levels and is potent enough to administer in room air without hypoxia. He practiced the administration of ether on a dog and then used it when extracting teeth from patients in his office. On October 16, 1846, Morton gave the first public demonstration of ether as an anesthetic for Johns Collins Warren, distinguished surgeon and a founder of Massachusetts General Hospital. In attendance in the surgical amphitheater were several surgeons, medical students, and a newspaper reporter. After anesthesia was induced using a makeshift inhaler, Warren successfully removed a vascular mass from the patient’s neck with no ill effects. Warren was an originator of the Boston Medical and Surgical Journal (now The New England Journal of Medicine), and by November 1846, the demonstration was published in an article by Henry J. Bigelow.³ The stature of Warren and Bigelow lent considerable credence to the advent of surgical anesthesia; as news spread rapidly, surgeons around the world were quick to adopt this “American invention.” Massachusetts General Hospital has restored and preserved the original amphitheater where the demonstration took place, now called the Ether Dome. It is designated as a Registered National Historic Landmark commemorating the first public demonstration, rather than discovery, of the use of ether as an anesthetic.

The First Anesthesiologists

John Snow (1813–1858) made science out of the art of anesthesia. He was a respected London physician who applied a scholarly, scientific method to investigate the clinical properties and pharmacology of ether, chloroform, and other anesthetic agents. Snow was an astute observer and published a detailed account of the five degrees of etherization in 1847. He vastly improved the apparatus for administering ether and mastered the clinical techniques of anesthetizing patients. As the leading anesthetist of his day, he gave anesthetics to the royal family, including chloroform during labor to Queen Victoria for the birth of Prince Leopold. The Queen’s endorsement of “that blessed chloroform” removed the moral and social stigma against relieving pain during childbirth and brought anesthesia into public awareness. Chloroform, popularized in England by James Simpson (1811–1870), had a narrow therapeutic index and placed great clinical demands on the anesthetist. Ether, with its ability to maintain the cardiovascular and respiratory systems, remained in common use in the United States and often was administered by house staff, medical students, or nurses. Snow encouraged the administration of anesthesia by a physician and felt that a physician dedicated specifically to that purpose was appropriate and necessary. Snow and other exceptional British physicians specializing in anesthesia (Joseph Clover [1825–1882] and Sir Frederick Hewitt [1857–1916]) created a standard of excellence in the latter half of the nineteenth century. This atmosphere of professionalism led to the formation of anesthesia societies and the publication of papers in the prestigious British Medical Journal and The Lancet in England years before such organizations existed in America.⁴

Cocaine: The First Local Anesthetic

The ancient Incas chewed coca leaves as a stimulant and may have been aware of its local anesthetic properties, allegedly facilitating trephination of the skull by chewing a clump of coca leaves and dripping the resultant saliva into the wound. The active alkaloid of the coca leaf was synthesized in 1860 and called cocaine by German chemist Albert Niemann, who noted that it “benumbs the nerves of the tongue, depriving it of feeling.”⁵ Sigmund Freud (1856–1939) of Vienna received a supply of cocaine from Merck, studied its properties, and wrote the famous monograph “Uber Coca” in 1884. Freud was primarily interested in the stimulant and euphoric effects of cocaine and attempted to use it to treat morphine addiction. Freud and Karl Koller (1857–1944), an ophthalmologic intern, began to perform physiologic experiments with cocaine, measuring its effects on muscle strength. Although they both noted that the drug caused numbness of the tongue when swallowed, it was Koller who first instilled it into his own cornea; report of its use as a local anesthetic galvanized the medical world. Soon after, young American surgeons William Halsted (1852–1922) and Richard Hall described intradermal injection of cocaine and were the first to use it for regional blocks of the facial nerves, brachial plexus, and internal pudendal and posterior tibial nerves.⁶ Halstead later became the first professor of surgery and chief surgeon at Johns Hopkins University, where he remained for more than 30 years. One of the founding fathers of modern surgery, he pioneered radical mastectomy with lymphadenectomy and the use of rubber gloves. While experimenting on themselves, Halstead and other early researchers became addicted to cocaine.⁷ Its toxic effects were the stimulus to find other local anesthetics—procaine was synthesized in 1905 and lidocaine in 1943.

The New York neurologist Leonard Corning (1855–1923) observed the regional blocks of Halstead and Hall, analytically studied local anesthesia effects on dogs, applied his knowledge to humans, and published the first textbook on local anesthesia in 1886. After experimenting on the spinal nerves of a dog, he intradurally injected a solution of cocaine into a patient, called it spinal anesthesia, and commented that it might be useful in surgery. His suggestion went unheeded for more than 10 years, until August Bier (1861–1949), a prominent German surgeon, gave the first deliberate spinal anesthetic.⁸ This incremental interchange of ideas and advances across the Atlantic and across the specialties of anesthesia and surgery demonstrates the collaborative nature of science in general and medicine in particular. The development of surgery and anesthesia exemplifies the dichotomy of two fledgling specialties that are mutually dependent, yet increasingly autonomous.

The Twentieth Century

Developments in anesthesia on both sides of the Atlantic progressed rapidly in the twentieth century. The convergence of technologies that produced the hollow needle and syringe, coupled with the synthesis of barbiturates, gave rise to intravenous (IV) anesthesia in the early 1900s. Barbital, followed by hexobarbital and thiopental in 1934, produced rapid and more pleasant induction of anesthesia than the inhaled gases. The concept of “balanced anesthesia” began in 1925, when John Lundy (1894–1973) proposed the use of thiopentone for induction, followed by inhaled agents for maintenance of anesthesia. Lundy directed the department of anesthesiology at the Mayo Clinic for 28 years. He established the first recovery room and blood bank, authored the first textbook on modern anesthesia, and helped found the American Board of Anesthesiology.

Nitrous oxide, diethyl ether, and chloroform, all discovered fortuitously by observation, remained the dominant inhalation agents until the accidental discovery of cyclopropane’s anesthetic properties in 1923. Although rapid acting and pleasant smelling, cyclopropane was limited by its flammability and cardiac irritability. Because it was known that fluorination would reduce or eliminate flammability of chemical compounds, British chemist Charles Suckling set out to synthesize an anesthetic that was stable, potent, volatile, and not flammable. He successfully produced halothane in 1953. Introduced into clinical practice in 1956 after extensive testing in Manchester, England, and paired with an accurate calibrated vaporizer, halothane quickly became the most widely used fluorinated anesthetic. Enflurane and isoflurane, synthesized in the United States by Ross Tyrell, were introduced into clinical practice in 1972 and 1981, respectively. The newest agents, desflurane and sevoflurane, were introduced into clinical practice in the early 1990s. They possess a low solubility and are characterized by rapid onset and recovery, making them particularly well suited to outpatient surgery.

The motto of the American Society of Anesthesiologists (ASA) is “Vigilance,” and to that end, there has been continued progress in objective mechanical measurement of patient well-being. The early anesthesiologists used clinical signs such as patient color, depth of respiration, and pulse rate to monitor depth of anesthesia and patient homeostasis. Harvey Cushing, who eventually became Moseley Professor of Surgery at the Peter Bent Brigham Hospital, began the first anesthesia records or “ether charts” in 1895 while a medical student. They recorded pulse, respiratory rates, pupillary diameter, and the amounts of ether and other drugs administered. He later introduced the use of the portable sphygmomanometer of Riva-Rocci to measure blood pressure and the precordial stethoscope to monitor breath and heart sounds. Monitoring has since progressed to its current state with incremental developments in electrocardiography, pulse oximetry, and mass spectrometry, all mandatory for the safe administration of any anesthetic.

The control of the patient’s airway and respiration as the purview of the anesthesiologist evolved with techniques of endotracheal intubation as pioneered by Sir Ivan Magill (1888–1986) and the invention of the cuffed endotracheal tube by Arthur Guedel (1883–1965). This later merged with the invention of mechanical ventilation and its introduction to the operating room as the embodiment of today’s anesthesia machine. It was this expertise at control of respiration that paved the way for the most revolutionary modern development in anesthesia—the use of muscle relaxants. Curare, a nondepolarizing muscle relaxant, was popularized by Harold Griffith of Montreal. His report of the successful use of curare was a galvanizing event that revolutionized the practice of anesthesia, as the relaxation of abdominal muscles could be controlled to facilitate surgery.⁹ The depolarizing relaxant succinylcholine was introduced in 1949, and research has continued to provide the newer nondepolarizing drugs mivacurium, pancuronium, rocuronium, atracurium, and cisatracurium.

Anesthesiology Today—The Perioperative Physician

The specialty of anesthesia is no longer limited to the operating room. It is natural that anesthesiology, born out of the quest to relieve pain, gave rise to the field of acute and chronic pain medicine. The anesthesiologist consulting on the acute pain service may recommend oral, intramuscular, or IV analgesia with a variety of agents, or patient-controlled analgesia. Postsurgical patients also may be treated with nerve blocks: regional (e.g., brachial plexus, popliteal, and femoral) or neuraxial (epidural or intrathecal). The discipline of chronic pain addresses patients who suffer for months or years with cancer or other debilitating diseases. Treatment modalities escalate from orally administered drugs, to diagnostic and therapeutic nerve blocks, to more invasive measures like dorsal column nerve stimulators and radiofrequency or cryosurgical nerve ablation.

Daily management of the airway, fluids and transfusions, ventilation, drug delivery, monitoring, and caring for the sickest patients in the postanesthesia care unit prepared anesthesiologists to become major contributors to the development of critical care medicine. Of the 28 founding members of the Society of Critical Medicine, 10 were anesthesiologists.¹⁰

The American Board of Anesthesiology became an independent board in 1941 and, since then, has granted board certification to more than 25,000 diplomates. Certificates in Anesthesia Pain Management and Anesthesia Critical Care Medicine are granted to those completing additional postgraduate training. The ASA has more than 35,000 members, and its official journal, Anesthesiology, has a monthly circulation of 40,000 worldwide.

Pharmacokinetics

Pharmacokinetics or the time dependency of a drug describes the relationship between the dose of a drug and its plasma or tissue concentration. It is what the body does to the drug. It relates to absorption, distribution, metabolism, and elimination. The route of administration, metabolism, protein binding, and tissue distribution all affect the pharmacokinetics of a particular drug.

Administration, Distribution, Metabolism, and Elimination

Administration of a drug affects its pharmacokinetics, as there will be different rates of drug entry into the circulation. For example, the oral and IV routes are subject to first-pass effect of the portal circulation; this can be bypassed with the nasal or sublingual route. Other routes of drug administration include transdermal, intramuscular, subcutaneous, or inhalation.

Distribution is the delivery of a drug from the systemic circulation to the tissues. Once a drug has entered the systemic circulation, the rate at which it will enter the tissues depends on several factors:

• Molecular size of the drug, capillary permeability, polarity, and lipid solubility. Small molecules will pass more freely and quickly across cell membranes than large ones, but capillary permeability is variable and results in different diffusion rates. Renal glomerular capillaries are permeable to almost all non–protein-bound drugs; capillaries in the brain are fused (i.e., they have tight junctions) and are relatively impermeable to all but the tiniest molecules (the blood-brain barrier). Un-ionized molecules pass more ­easily across cell membranes than charged molecules; ­diffusability also increases with increasing lipid solubility.

• Plasma protein and tissue binding. Many drugs bind to circulating proteins like albumin, glycoproteins, and globulins. Disease, age, and the presence of other drugs will affect the amount of protein binding; drug distribution is affected because only the unbound free portion of the drug can pass across the cell membrane. Drugs also bind reversibly to body tissues; if they bind with high affinity, they are said to be sequestered in that tissue (e.g., heavy metals are sequestered in bone).¹¹

• The fluid volume in which a drug distributes is termed the volume of distribution (Vd). This mathematically derived value gives a rough estimation of the overall physical distribution of a drug in the body. A general rule for volume distribution is that the greater the Vd, the greater the diffusability of the drug. Because drugs have variable ionization rates and bind differently to plasma proteins and tissues, the Vd is not a good predictor of the actual concentration of the drug after administration. Determining the apparent Vd (dose/concentration) is an attempt to more accurately ascertain the drug dose administered and its final concentration.

Metabolism is the permanent breakdown of original compounds into smaller metabolites. Drug elimination varies widely; some drugs are excreted unchanged by the body, some decompose via plasma enzymes, and some are degraded by organ-based enzymes in the liver. Many drugs rely on multiple pathways for elimination (i.e., metabolized by liver enzymes and then excreted by the kidney).

When a drug is given orally, it reaches the liver via the portal circulation and is partially metabolized before reaching the systemic circulation. This is why an oral dose of a drug often must be much higher than an equally effective IV dose. Some drugs (e.g., nitroglycerine) are hydrolyzed presystemically in the gut wall and must be administered sublingually to achieve an effective concentration.

It is important to remember that the response to drugs varies widely. The disposition of drugs is affected by age; weight; sex; pregnancy; disease states; and the concomitant use of alcohol, tobacco, and other licit and illicit drugs. Genetic polymorphism, or variations in genes that cause differing drug effects, is another explanation of varying drug response. This will be discussed later in the Future Direction of Anesthesia section on proteomics. This as yet unpredictable response to drugs underscores the importance of the most important monitor in the operating room—the anesthesiologist, who continuously assesses the patient’s vital signs and adjusts the doses of anesthetic agents to match the surgical stimulus.

Pharmacodynamics

Pharmacodynamics, or how the plasma concentration of a drug translates into its effect on the body, depends on biologic variability, receptor physiology, and clinical evaluations of the actual drug. It is what the drug does to the body. An agonist is a drug that causes a response. A full agonist produces the full tissue response, and a partial agonist provokes less than the maximum response induced by a full agonist. An antagonist is a drug that does not provoke a response itself, but blocks agonist-mediated responses. An additive effect means that a second drug acts with the first drug and will produce an effect that is equal to the algebraic summation of both drugs. A synergistic effect means that two drugs interact to produce an effect that is greater than expected from the two drugs’ algebraic summation.¹²

Hyporeactivity means a larger than expected dose is required to produce a response, and this effect is termed tolerance, desensitization, or tachyphylaxis. Tolerance usually results from chronic drug exposure, either through enzyme induction (e.g., alcohol) or depletion of neurotransmitters (e.g., cocaine).

Potency, Efficacy, Lethal Dose, and Therapeutic Index

The potency of a drug is the dose required to produce a given effect, such as pain relief or a change in heart rate. The average sensitivity to a particular drug can be expressed through the calculation of the effective dose; ED₅₀ would have the desired effect in 50% of the general population. The efficacy of any therapeutic agent is its power to produce a desired effect. Two drugs may have the same efficacy but different potencies. The difference in potency of the two drugs is described by the ratio ED₅₀b/ED₅₀a, where a is the less potent drug. If the ED₅₀b equals 4 and the ED₅₀a equals 0.4, then drug a is 10 times as potent as drug b. For example, 10 mg of morphine produces analgesia equal to that of 1 mg of hydromorphone. They are equally effective, but hydromorphone is 10 times as potent as morphine.

Dose-response curves show the relationship between the dose of a drug administered (or the resulting plasma concentration) and the pharmacologic effect of the drug. The pharmacologic effect might be secretion of a hormone, a change in heart rate, or contraction of a muscle. Between 20% and 80% of the maximum effect, the logarithm of the dose and its response has a linear relationship. The term dose only applies to the amount administered and not the actual concentration. If the concentration of an antagonist is increased (in the presence of a fixed concentration of agonist), the dose-response curve will be shifted to the right, and a higher agonist concentration will be required to achieve the desired effect. A basic dose-response curve is shown in Fig. 46-1.

The lethal dose (LD₅₀) of a drug produces death in 50% of animals to which it is given. The ratio of the lethal dose and effective dose, LD₅₀/ED₅₀, is the therapeutic index. A drug with a high therapeutic index is safer than a drug with a low or narrow therapeutic index.

Anesthesia can be local, regional, or general (Table 46-1). Local anesthesia is accomplished using a local anesthetic drug that can be injected intradermally and is used for the removal of small lesions or to repair traumatic injuries. Local anesthesia is the most frequent anesthetic administered by surgeons and may be accompanied by IV sedation to improve patient comfort.

General Anesthesia

General anesthesia describes a triad of three major and separate effects: unconsciousness (and amnesia), analgesia, and muscle relaxation (see Table 46-1). IV drugs usually produce a single, discrete effect, while most inhaled anesthetics produce elements of all three. General anesthesia is achieved with a combination of IV and inhaled drugs, each used to its maximum benefit. The science and art of anesthesia are dynamic processes. As the amount of stimulus to the patient changes during surgery, the patient’s vital signs are used as a guide and the quantity of drugs is adjusted, maintaining an equilibrium between stimulus and dose. General anesthesia is what patients commonly think of when they are to be “put under” and can be a cause of considerable preoperative anxiety.¹³

Intravenous Agents

Unconsciousness and Amnesia

The IV agents that produce unconsciousness and amnesia are frequently used for the induction of general anesthesia. They include barbiturates, benzodiazepines, propofol, etomidate, and ketamine. Except for ketamine, the following agents have no analgesic properties and do not cause paralysis or muscle relaxation.

Barbiturates

The most common barbiturates are thiopental, thiamylal, and methohexital. The mechanism of action is at the γ-aminobutyric acid (GABA) receptor, where they inhibit excitatory synaptic transmission. They produce a rapid, smooth induction within 60 seconds, and wear off in about 5 minutes. In higher doses and in patients with intravascular depletion, they cause hypotension and myocardial depression. The barbiturates are anticonvulsants and protect the brain during neurosurgery by reducing cerebral metabolism.

Propofol

Propofol is an alkylated phenol that inhibits synaptic transmission through its effects at the GABA receptor. With a short duration, rapid recovery, and low incidence of nausea and vomiting, it has emerged as the agent of choice for ambulatory and minor general surgery. Additionally, propofol has bronchodilatory properties that make its use attractive in asthmatic patients and smokers. Propofol may cause hypotension and should be used cautiously in patients with suspected hypovolemia and/or coronary artery disease (CAD), the latter of which may not tolerate a sudden drop in blood pressure. It can be used as a continuous infusion for sedation in the intensive care unit setting. Propofol is an irritant and frequently causes pain on injection.

Benzodiazepines

The most important uses of the benzodiazepines are for reduction of anxiety and to produce amnesia. Frequently used IV benzodiazepines are diazepam, lorazepam, and midazolam. They all inhibit synaptic transmission at the GABA receptor but have differing durations of action. The benzodiazepines can produce peripheral vasodilatation and hypotension but have minimal effects on respiration when used alone. They must be used with caution when given with opioids; a synergistic reaction causing respiratory depression is common. The benzodiazepines are excellent anticonvulsants and only rarely cause allergic reactions.

Etomidate

Etomidate is an imidazole derivative used for IV induction. Its rapid and almost complete hydrolysis to inactive metabolites results in rapid awakening. Like the above IV agents, etomidate acts on the GABA receptor. It has little effect on cardiac output and heart rate, and induction doses usually produce less reduction in blood pressure than that seen with thiopental or propofol. Etomidate is associated with pain on injection and more nausea and vomiting than thiopental or ­propofol.

Ketamine

Ketamine differs from the above IV agents in that it produces analgesia as well as amnesia. Its principal action is on the N-methyl-d-aspartate receptor; it has no action on the GABA receptor. It is a dissociative anesthetic, producing a cataleptic gaze with nystagmus. Patients may associate this with delirium and hallucinations while regaining consciousness. The addition of benzodiazepines has been shown to prevent these side effects. Ketamine can increase heart rate and blood pressure, which may cause myocardial ischemia in patients with CAD. Ketamine is useful in acutely hypovolemic patients to maintain blood pressure via sympathetic stimulation but is a direct myocardial depressant in patients who are catecholamine depleted. Ketamine is a bronchodilator, making it useful for asthmatic patients, and rarely is associated with allergic reactions.

Analgesia

The IV analgesics most frequently used in anesthesia today have little effect on consciousness, amnesia, or muscle relaxation. The most important class is the opioids, so called because they were first isolated from opium, with morphine, codeine, meperidine, hydromorphone, and the fentanyl family being the most common. The most important nonopioid analgesics are ketamine (discussed earlier in the Ketamine section) and ketorolac, an IV nonsteroidal anti-inflammatory drug (NSAID).

Opioid Analgesics

The commonly used opioids—morphine, codeine, oxymorphone, meperidine, and the fentanyl-based compounds—act centrally on μ-receptors in the brain and spinal cord. The main side effects of opioids are euphoria, sedation, constipation, and respiratory depression, which also are mediated by the same μ-receptors in a dose-dependent fashion. Although opioids have differing potencies required for effective analgesia, equianalgesic doses of opioids result in equal degrees of respiratory depression. Thus, there is no completely safe opioid analgesic. The synthetic opioid fentanyl and its analogues sufentanil, alfentanil, and remifentanil are commonly used in the operating room. They differ pharmacokinetically in their lipid solubility, tissue binding, and elimination profiles and thus have differing potencies and durations of action. Remifentanil is remarkable in that it undergoes rapid hydrolysis that is unaffected by sex, age, weight, or renal or hepatic function, even after prolonged infusion. Recovery is within minutes, but there is little residual postoperative analgesia.

Naloxone and the longer-acting naltrexone are pure opioid antagonists. They can be used to reverse the side effects of opioid overdose (e.g., respiratory depression), but the analgesic effects of the opioid also will be reversed.

Nonopioid Analgesics

Ketamine, an N-methyl-d-aspartate receptor antagonist, is a potent analgesic, but is one of the few IV agents that also causes significant sedation and amnesia. Unlike the μ-receptor agonists, ketamine supports respiration. It can be used in combination with opioids, but the dysphoric effects must be masked with the simultaneous use of sedatives, usually a benzodiazepine like midazolam.

Ketorolac is a parenteral NSAID that produces analgesia by reducing prostaglandin formation via inhibition of the enzyme cyclooxygenase (COX). Intraoperative use of ketorolac reduces postoperative need for opioids. Two forms of COX have been identified: COX-1 is responsible for the synthesis of several prostaglandins as well as prostacyclin, which protects gastric mucosa, and thromboxane, which supports platelet function. COX-2 is induced by inflammatory reactions to produce more prostaglandins. Ketorolac (as well as many oral NSAIDs, aspirin, and indomethacin) inhibits both COX-1 and COX-2, which causes the major side effects of gastric bleeding, platelet dysfunction, and hepatic and renal damage. Parecoxib is a parenteral, predominantly COX-2 NSAID that presumably produces analgesia and reduces inflammation without causing gastrointestinal bleeding or platelet dysfunction.

Dexmedetomidine is an IV α₂-adrenergic agonist, administered as a continuous infusion, and has sedative and analgesic properties. It is useful for sedation in an intensive care unit setting and as an adjunct to general anesthesia. Side effects are hypotension and bradycardia.

IV acetaminophen is an analgesic drug and antipyretic of moderate potency; its site of action is in the central nervous system (CNS), not peripherally. It does not have anti-inflammatory properties and is not considered an NSAID.¹⁴ When used as part of postoperative analgesic therapy, it will reduce the amount of opioids required, reducing side effects (e.g., constipation, sedation, respiratory depression).

Neuromuscular Blocking Agents

Neuromuscular blocking agents have no amnestic, hypnotic, or analgesic properties; patients must be properly anesthetized before and in addition to the administration of these agents. A paralyzed but unsedated patient will be aware, conscious, and in pain, yet be unable to communicate their predicament. Inappropriate administration of a neuromuscular blocking agent to an awake patient is one of the most traumatic experiences imaginable. Neuromuscular blockade is not a substitute for adequate anesthesia, but is rather an adjunct to the anesthetic. Depth of neuromuscular blockade is best monitored with a nerve stimulator to ensure patient immobility intraoperatively and to confirm a lack of residual paralysis postoperatively.¹⁵

Unlike the local anesthetics, which affect the ability of nerves to conduct impulses, the neuromuscular blockers have no effect on either nerves or muscles, but act primarily on the neuromuscular junction.

There is one commonly used depolarizing neuromuscular blocker—succinylcholine. This agent binds to acetylcholine receptors on the postjunctional membrane in the neuromuscular junction and causes depolarization of muscle fibers.

Although the rapid onset (<60 seconds) and rapid offset (5–8 minutes) make succinylcholine ideal for management of the airway in certain situations, total body muscle fasciculations can cause postoperative aches and pains, an elevation in serum potassium levels, and an increase in intraocular and intragastric pressure. Its use in patients with burns or traumatic tissue injuries may result in a high enough rise in serum potassium levels to produce arrhythmias and cardiac arrest. Unlike other neuromuscular blocking agents, the effects of succinylcholine cannot be reversed. Succinylcholine is rapidly hydrolyzed by plasma cholinesterase, also referred to as pseudocholinesterase. There are many reasons for a patient to have low pseudocholinesterase levels, such as liver disease, concomitant use of other drugs, pregnancy, and cancer. These factors are usually not clinically problematic, delaying return of motor function only by several minutes. Some patients have a genetic disorder manifesting as atypical plasma cholinesterase; the atypical enzyme has less-than-normal activity, and/or the patient has extremely low levels of the enzyme. The incidence of the homozygous form is approximately 1 in 3000; the effects of a single dose of succinylcholine may last several hours instead of several minutes. Treatment is to keep the patient sedated and unaware he or she is paralyzed, continue mechanical ventilation, test the return of motor function with a peripheral nerve stimulator, and extubate the patient only after he or she has fully regained motor strength. Two separate blood tests must be drawn: pseudocholinesterase level to determine the amount of enzyme present, and dibucaine number, which indicates the quality of the enzyme. Patients with laboratory-confirmed abnormal pseudocholinesterase levels and/or dibucaine numbers should be counseled to avoid succinylcholine as well as mivacurium, which is also hydrolyzed by pseudocholinesterase. First-degree family members should also be tested. Succinylcholine is the only IV triggering agent of malignant hyperthermia (discussed later in the Malignant Hyperthermia section).

There are several competitive nondepolarizing agents available for clinical use. The longest acting is pancuronium, which is excreted almost completely unchanged by the kidney. Intermediate-duration neuromuscular blockers include vecuronium and rocuronium, which are metabolized by both the kidneys and liver, and atracurium and cisatracurium, which undergo breakdown in plasma known as Hofmann elimination. The agent with shortest duration is mivacurium, the only nondepolarizer that is metabolized by plasma cholinesterase, and like succinylcholine, is subject to the same prolonged blockade in patients with plasma cholinesterase deficiency. All nondepolarizers reversibly bind to the postsynaptic terminal in the neuromuscular junction and prevent acetylcholine from depolarizing the muscle. Muscle blockade occurs without fasciculation and without the subsequent side effects seen with succinylcholine. The most commonly used agents of this type and their advantages and disadvantages are listed in Table 46-2.

The reversal of neuromuscular blockade is not a true reversal of the drug (as with protamine reversal of heparin) but a reversal of the effect of the neuromuscular blockade. ­Neuromuscular blocking reversal agents, usually neostigmine, edrophonium, or pyridostigmine, increase acetylcholine levels by inhibiting acetylcholinesterase, the enzyme that breaks down acetylcholine. The subsequently increased circulating levels of acetylcholine prevail in the competition for the postsynaptic receptor, and motor function returns. Use of the peripheral nerve stimulator is required to follow depth and reversal of motor blockade, but it is essential to correlate data from the nerve stimulator with clinical signs that indicate return of motor function, including tidal volume, vital capacity, hand grip, and 5-second sustained head lift.

Inhalational Agents

Unlike the IV agents, the inhalational agents provide all three characteristics of general anesthesia: unconsciousness, analgesia, and muscle relaxation. However, it would be impractical to use an inhalation-only technique in larger surgical procedures, because the doses required would cause unacceptable side effects, so IV adjuncts such as opioid analgesics and neuromuscular blockers are added to optimize the anesthetic. All inhaled anesthetics display a dose-dependent reduction in mean arterial blood pressure except for nitrous oxide, which maintains or slightly raises the blood pressure. Nitrous oxide, although not potent enough to use alone, provides partial anesthesia and allows a second agent to be used in smaller doses, reducing side effects.

Minimum alveolar concentration (MAC) is a measure of anesthetic potency. It is the ED₅₀ of an inhaled agent (i.e., the dose required to block a response to a painful stimulus in 50% of subjects). The higher the MAC, the less potent an agent is. The potency and speed of induction of inhaled agents correlate with their lipid solubility, and this is known as the Meyer-Overton rule. Nitrous oxide has a low solubility and is a weak anesthetic agent, but has the most rapid onset and offset. The “potent” gases (e.g., desflurane, sevoflurane, enflurane, and halothane) are more soluble in blood than nitrous oxide and can be given in lower concentrations, but have longer induction and emergence characteristics.

Sevoflurane and desflurane are the two most recently introduced inhalational agents in common use. Because of their relatively lower tissue and blood solubility, induction and recovery are more rapid than with isoflurane or enflurane.

All of the potent inhalational agents (e.g., halothane, isoflurane, enflurane, sevoflurane, and desflurane), as well as the depolarizing agent succinylcholine, are triggering agents for malignant hyperthermia. Table 46-3 lists the advantages and disadvantages of each agent.

Local Anesthetics

Local anesthetics are divided into two groups based on their chemical structure: the amides and the esters. In general, the amides are metabolized in the liver, and the esters are metabolized by plasma cholinesterases, which yield metabolites with slightly higher allergic potential than the amides (Table 46-4).

Amides

Lidocaine, bupivacaine, mepivacaine, prilocaine, and ropivacaine have in common an amide linkage between a benzene ring and a hydrocarbon chain that, in turn, is attached to a tertiary amine. The benzene ring confers lipid solubility for penetration of nerve membranes, and the tertiary amine attached to the hydrocarbon chain makes these local anesthetics water soluble. Lidocaine has a more rapid onset and is shorter acting than bupivacaine; however, both are widely used for tissue infiltration, regional nerve blocks, and spinal and epidural anesthesia. Ropivacaine is the most recently introduced local anesthetic. It is clinically similar to bupivacaine in that it has a slow onset and a long duration, but is less cardiotoxic. All amides are 95% metabolized in the liver, with 5% excreted unchanged by the kidneys.

Esters

Cocaine, procaine, chloroprocaine, tetracaine, and benzocaine have an ester linkage in place of the amide linkage mentioned earlier in the Amides section. Unique among local anesthetics, cocaine occurs in nature, was the first used clinically, produces vasoconstriction (making it useful for topical application, e.g., for intranasal surgery), releases norepinephrine from nerve terminals resulting in hypertension, and is highly addictive. Cocaine is a Schedule II drug. Procaine, synthesized in 1905 as a nontoxic substitute for cocaine, has a short duration and is used for infiltration. Tetracaine has a long duration and is useful as a spinal anesthetic for lengthy operations. Benzocaine is for topical use only. The esters are hydrolyzed in the blood by pseudocholinesterase. Some of the metabolites have a greater allergic potential than the metabolites of the amide anesthetics, but true allergies to local anesthetics are rare.

The common characteristic of all local anesthetics is a reversible block of the transmission of neural impulses when placed on or near a nerve membrane. Local anesthetics block nerve conduction by stabilizing sodium channels in their closed state, preventing action potentials from propagating along the nerve. The individual local anesthetic agents have different recovery times based on lipid solubility and tissue binding, but return of neural function is spontaneous as the drug is metabolized or removed from the nerve by the vascular system.

Toxicity of local anesthetics results from absorption into the bloodstream or from inadvertent direct intravascular injection. Toxicity manifests first in the more sensitive CNS and then the cardiovascular system.

Central Nervous System Toxicity

As plasma concentration of local anesthetic rises, symptoms progress from restlessness to complaints of tinnitus. Slurred speech, seizures, and unconsciousness follow. Cessation of the seizure via administration of a benzodiazepine or thiopental and maintenance of the airway are the immediate treatment. If the seizure persists, the trachea must be intubated with a cuffed endotracheal tube to guard against pulmonary aspiration of stomach contents.

Cardiovascular System Toxicity

With increasingly elevated plasma levels of local anesthetics, progression to hypotension, increased P-R intervals, bradycardia, and cardiac arrest may occur. Bupivacaine is more cardiotoxic than other local anesthetics. It has a direct effect on ventricular muscle, and because it is more lipid soluble than lidocaine, it binds tightly to sodium channels (it is called the fast-in, slow-out local anesthetic). Patients who have received an inadvertent intravascular injection of bupivacaine have experienced profound hypotension, ventricular tachycardia and fibrillation, and complete atrioventricular heart block that is extremely refractory to treatment. The toxic dose of lidocaine is approximately 5 mg/kg; that of bupivacaine is approximately 3 mg/kg.

Calculation of the toxic dose before injection is imperative. It is helpful to remember that for any drug or solution, 1% = 10 mg/mL. For a 50-kg person, the toxic dose of bupivacaine would be approximately 3 mg/kg, or 3 × 50 = 150 mg. A 0.5% solution of bupivacaine is 5 mg/mL, so 150 mL/5 mg/mL = 30 mL as the upper limit for infiltration. For lidocaine in the same patient, the calculation is 50 kg × 5 mg/mL = 250 mg toxic dose. If a 1% solution is used, the allowed amount would be 250 mg/10 mg/mL = 25 mL.

Additives to Local Anesthetics

Epinephrine has one physiologic and several clinical effects when added to local anesthetics. Epinephrine is a vasoconstrictor, and by reducing local bleeding, molecules of the local anesthetic remain in proximity to the nerve for a longer time period. Onset of the nerve block is faster, the quality of the block is improved, the duration is longer, and less local anesthetic will be absorbed into the bloodstream, thereby reducing toxicity. Although epinephrine 1:200,000 (5 g/mL) added to a local anesthetic for infiltration will greatly lengthen the time of analgesia, epinephrine-containing solutions should not be injected into body parts with end-arteries, such as toes or fingers, as vasoconstriction may lead to ischemia or loss of a digit. When added to the local anesthetic, sodium bicarbonate will raise the pH, favoring the nonionized uncharged form of the molecule. This speeds the onset of the block, especially in local anesthetics that are mixed with epinephrine. The pH of such solutions is around 4.5; therefore, the addition of sodium bicarbonate results in a relatively large increase in pH.¹⁶

Regional Anesthesia: Peripheral vs. Central

Peripheral Nerve Blocks

Local anesthetic can be injected peripherally, near a large nerve or plexus, to provide anesthesia to a larger region of the body. Examples include the brachial plexus for surgery of the arm or hand, blockade of the femoral and sciatic nerves for surgery of the lower extremity, ankle block for surgery of the foot or toes, intercostal block for analgesia of the thorax postoperatively, or blockade of the cervical plexus, which is ideal for carotid endarterectomy. Risks of peripheral regional nerve blocks are dependent on their location. For example, nerve blocks injected into the neck risk puncture of the carotid or vertebral arteries, intercostal nerves are in close proximity to the vascular bundle and have a high rate of absorption of local anesthetic, and nerve blocks of the thorax run the risk of causing pneumothorax. All peripheral nerve blocks may be supplemented intraoperatively with IV sedation and/or analgesics.

Central Nerve Blocks: Spinal and Epidural

Local anesthetic injected centrally near the spinal cord—spinal or epidural anesthesia—provides anesthesia for the lower half of the body. This is especially useful for genitourinary, gynecologic, inguinal hernia, or lower extremity procedures. Spinal and epidural anesthesia block the spinal nerves as they exit the spinal cord. Spinal nerves are mixed nerves; they contain motor, sensory, and sympathetic components. The subsequent block will cause sensory anesthesia, loss of motor function, and blockade of the sympathetic nerves from the level of the anesthetic distally to the lower extremities. Subsequent vasodilation of the vasculature from sympathetic block may result in hypotension, which is treatable with IV fluids and/or pressors.

Spinal Anesthesia

Local anesthetic is injected directly into the dural sac surrounding the spinal cord. The level of injection is usually below L1 to L2, where the spinal cord ends in most adults. Because the local anesthetic is injected directly into the cerebrospinal fluid surrounding the spinal cord, only a small dose is needed, the onset of anesthesia is rapid, and the blockade is thorough. Lidocaine, bupivacaine, and tetracaine are commonly used agents of differing durations; the block wears off naturally via drug uptake by the cerebrospinal fluid, bloodstream, or diffusion into fat. Epinephrine as an additive to the local anesthetic will significantly prolong the blockade.

Possible complications include hypotension, especially if the patient is not adequately prehydrated; high spinal block requires immediate airway management; and postdural puncture headache sometimes occurs. Spinal headache is related to the diameter and configuration of the spinal needle and can be reduced to approximately 1% with the use of a small 25- or 27-gauge needle.

Cauda equina syndrome is injury to the nerves emanating distal to the spinal cord resulting in bowel and bladder dysfunction and lower extremity sensory and motor loss. It has mainly been seen in cases in which indwelling spinal microcatheters and high (5%) concentrations of lidocaine were used. Indwelling spinal catheters are no longer used.

Epidural Anesthesia

Epidural anesthesia could also be called extradural anesthesia, because local anesthetics are injected into the epidural space surrounding the dural sac of the spinal cord. Much greater volumes of anesthetic are required than with spinal anesthesia, and the onset of the block is longer—10 to 15 minutes. As in spinal anesthesia, local anesthetic bathes the spinal nerves as they exit the dura; the patient achieves analgesia from the sensory block, muscle relaxation from blockade of the motor nerves, and hypotension from blockade of the sympathetic nerves as they exit the spinal cord. Note that regional anesthesia, whether peripheral or central, provides only two of the three major components of anesthesia—analgesia and muscle relaxation. Anxiolysis, amnesia, or sedation must be attained by supplemental IV administration of other drugs (e.g., the benzodiazepines or propofol infusion).

Complications are similar to those of spinal anesthesia. Inadvertent injection of local anesthetic into a dural tear will result in a high block, manifesting as unconsciousness, severe hypotension, and respiratory paralysis requiring immediate aggressive hemodynamic management and control of the airway. Indwelling catheters are often placed through introducers into the epidural space, allowing an intermittent or continuous technique, as opposed to the single-shot method of spinal anesthesia. By necessity, the epidural-introducing needles are of a much larger diameter (17- or 18-gauge) than spinal needles, and accidental dural puncture more often results in a severe headache that may last up to 10 days if left untreated.

Preoperative Evaluation and Preparation

The ASA has adopted basic standards for the evaluation of patients before surgery. These standards require the anesthesiologist to determine the medical status of the patient by developing a plan of anesthetic care and to discuss this plan with the patient and/or legal guardian.

The preoperative visit results in a summary of all pertinent findings, including a detailed medical history, current drug therapy, complete physical examination, and laboratory and specific testing results. Based on these findings, the anesthesiologist may find that the patient is not in optimal medical condition to undergo elective surgery. These findings and opinions are then discussed with the patient’s primary physician, and the surgery may be delayed or cancelled until the patient’s medical condition is further tested and optimized.

The detailed medical history obtained at the preoperative visit should include the patient’s previous exposure and experience with anesthesia, as well as any family history of problems with anesthesia. History of atopy (medication, foods, or environmental) is an important aspect of this evaluation in that it may predispose patients to form antibodies against antigens that may be represented by agents administered during the perioperative period. A careful review of major organ systems and their function also should be performed.

The physical examination is targeted primarily at the CNS, cardiovascular system, lungs, and upper airway. Specific areas to investigate are shown in Table 46-5.

Concurrent medications must be fully explored, and adverse interactions with agents administered during the perioperative period need to be considered. However, concurrent medications that produce desired effects (i.e., β-blockade, antihypertensive, and antiasthma medications) can and should be continued throughout the perioperative period; patients should be counseled to continue these medications up to and including the morning of surgery. Careful documentation will allow the anesthesiologist to make informed decisions about the perioperative selection of drugs and therapy as well as monitoring techniques.

Preoperative laboratory data and specific testing for elective surgery should be patient and situation specific. Examples include serum potassium for a patient on diuretics, glucose in a diabetic patient, or hemoglobin concentration in any surgery with a high risk of blood loss. Coagulation tests are not necessary if the patient is not receiving anticoagulants or has no signs or symptoms of abnormal clotting. Otherwise healthy patients usually do not need preoperative laboratory testing, and tests performed within the previous 6 months are usually sufficient.¹⁷ Other tests that should be generated by history and physical examination include chest radiograph if there is evidence of chest disease and pulmonary function tests in patients who are morbidly obese, severe asthmatics, or patients undergoing pulmonary resection surgery. An electrocardiogram should be performed in all symptomatic patients and in asymptomatic men age 45 years or older and asymptomatic women age 50 years or older. Urine pregnancy testing should be performed on the day of surgery in all women of childbearing age.

Risk Assessment

An integral part of the preoperative visit is for the anesthesiologist to assess patient risk. Risk assessment encompasses two major questions: (a) Is the patient in optimal medical condition for surgery? and (b) Are the anticipated benefits of surgery greater than the surgical and anesthetic risks associated with the procedure?

Research into quantifying preoperative factors that correlate with the development of postoperative morbidity and mortality has recently gained great interest. Originally designed as a simple classification of a patient’s physical status immediately before surgery, the ASA physical status scale is one of the few prospective scales that correlate with the risk of anesthesia and surgery (Table 46-6).

Criticism of the ASA scale is primarily due to its exclusion of age and difficulty of intubation (discussed later in this ­chapter). Cullen and associates examined 1095 patients undergoing total hip replacement, prostatectomy, or cholecystectomy, and found that both age and ASA scale accurately ­predict postoperative morbidity and mortality¹⁸ (Table 46-7). The ASA scale remains useful and should be applied to all patients during the preoperative visit.

Evaluation of the Airway

The airway examination is an effort to identify those patients in whom management of the airway and conventional endotracheal intubation may be ­difficult. It is vitally important to recognize such patients before administering medications that induce apnea.

Mallampati Classification

The amount of the posterior pharynx one can visualize preoperatively is important and correlates with the difficulty of intubation. A large tongue (relative to the size of the mouth) that also interferes with visualization of the larynx on laryngoscopy will obscure visualization of the pharynx. The Mallampati classification (Fig. 46-2, Table 46-8) is based on the structures visualized with maximal mouth opening and tongue protrusion in the sitting position.

Other predictors of difficult intubation include obesity, immobility of the neck, interincisor distance <4 cm in an adult, a large overbite, or the inability to shift the lower incisors in front of the upper incisors. The thyromental distance (i.e., the distance from the thyroid cartilage to the mentum [tip of the chin]) should be >6.5 to 7 cm.

Consideration of Patients with Comorbidities

A thorough knowledge of the pathophysiology of concurrent medical conditions regardless of the reason for surgery is essential for optimal perioperative care. Optimal anesthesia extends beyond pharmacology and technical procedures. Specifically, ischemic heart disease, renal dysfunction, pulmonary disease, metabolic and endocrine disorders, CNS diseases, and diseases of the liver and biliary tract can have major impact on the management of anesthesia.

Ischemic Heart Disease

Ischemic heart disease is the result of the heart demanding more oxygen (O₂) than its supply can provide. A supply problem may be due to many factors, including hypoxia, anemia, hypotension and coronary artery atherosclerosis, thrombosis, or spasm. Additionally, the problem may be an increase in myocardial O₂ demand (tachycardia). In the vast majority of cases, the most responsible lesion is a reduction in the luminal area of coronary arteries due to atherosclerosis.

An estimated 14 million people in the United States have ischemic heart disease. Of these, as many as 4 million have few or no symptoms and are unaware that they are at risk for angina pectoris, myocardial infarction, or sudden death.

An important goal of the preoperative visit is for the anesthesiologist to ascertain the patient’s severity, progression, and functional limitations induced by ischemic heart disease. Furthermore, this visit can elucidate the possibility of previously undiagnosed ischemic heart disease. A thorough investigation of risk factors for ischemic heart disease is essential during the preoperative visit. The risk of perioperative death due to myocardial infarction in patients without ischemic heart disease is approximately 1%.¹⁹ In contrast, the risk in patients with known or suspected ischemic heart disease is approximately 3%,¹⁹ and in patients undergoing surgery for peripheral vascular disease, the combined risk of death due to cardiac causes is 29%.²⁰

Major Risk Factors for Coronary Artery Disease

The risk of hypercholesterolemia is proportional to the increased serum level of low-density lipoprotein cholesterol. Reduction achieved via decreased dietary fat or pharmacotherapy reduces risk.

Hyperlipidemia may be familial and thus may account for the fact that a strong family history of premature CAD is a significant risk factor. High-density lipoprotein cholesterol is protective.

Although definitely a risk factor, hypertension alone probably does not cause plaques. Rather, it may act synergistically with hypercholesterolemia by first causing mechanical wall stress and damage.

Smoking causes endothelial damage, and therefore promotes plaque thrombosis. Cessation greatly reduces the risk of CAD.

Diabetes mellitus is a strong independent risk factor. A hypothesis is that glycosylation products cause release of growth factors that stimulate smooth muscle proliferation.

Other Risk Factors

Hyperhomocysteinemia is becoming an established independent risk factor, but is still under evaluation. Reduction of levels by folate therapy may be beneficial.

Advanced age, male sex, obesity, and a sedentary lifestyle can also put a person at risk for developing ischemic heart ­disease.²¹

Drugs used for the medical management of patients with ischemic heart disease should be continued throughout the perioperative period. Withdrawal of an antihypertensive drug or suspension of β-blockade can induce unwanted increases in sympathetic nervous system activity.¹² Induction of anesthesia in patients with ischemic heart disease can be safely accomplished with a number of IV drugs. As many as 45% of patients have been shown to have myocardial ischemia during the stress of tracheal intubation, and direct laryngoscopy should be used for the shortest time possible to minimize the magnitude of stimulation.²²

The intraoperative anesthetic technique should allow for the prompt control of hemodynamic variables; the maintenance of the balance between myocardial O₂ delivery and myocardial O₂ demand is probably the single most important factor in managing patients with ischemic heart disease. In this regard, muscle relaxants with minimal to no effects on heart rate and blood pressure, such as vecuronium and rocuronium, are attractive choices for neuromuscular blockade. Additionally, controlled myocardial depression using a volatile anesthetic in patients with a normal left ventricular ejection fraction may help to minimize the stimulation of the sympathetic nervous system and subsequent increases in myocardial O₂ requirements. In patients with impaired left ventricular function, continued myocardial depression with volatile anesthetics may not be tolerated; the addition of short-acting opioids such as fentanyl is beneficial. In cardiac surgical patients, it is not uncommon for high-dose opioids to be used as the predominant anesthetic.

Pulmonary Disease

Chronic pulmonary disease has developed into a worldwide public health problem. Chronic ­obstructive pulmonary disease (COPD), distinguished from asthma, which is characterized by reversible airway smooth muscle constriction, is a progressive disease that leads to the destruction of the lung parenchyma.

Infection, noxious particles, and gases can exacerbate COPD. Historically, certain lung function parameters (i.e., significantly abnormal spirometry or arterial blood gas analysis) were once considered contraindications for anesthesia. However, anesthetic techniques have improved, and it has been shown that patients with severe lung disease can safely undergo anesthesia.²³ Zollinger and Pasch found no specific parameters of lung function that were predictive of postoperative lung complications. The highest predictive parameter found was upper abdominal surgery and thoracic surgery.²⁴

General anesthesia can be performed safely in patients with pulmonary disease.²⁵ Inhaled anesthetics are often used due to their bronchodilating properties.²⁶ Some authors have advocated pretreatment with salbutamol, a long-acting β-agonist, which may prevent bronchoconstriction during anesthetic induction.^27,28

Regional and local anesthesia have the benefit of avoiding tracheal irritation and stimulating bronchospasm. However, patients with COPD may become hypoxic while lying strictly supine, and sensory levels of anesthetic above T10 are associated with the impairment of respiratory muscle activity necessary for patients with COPD to maintain adequate ventilation.¹²

Intraoperatively, mechanical ventilation using a slow breathing rate (at eight breaths per minute) should be used to allow for passive exhalation in the presence of increased airway resistance. This slow breathing, facilitated by high inspiratory flow rate, may allow for improved maintenance of normal partial pressure of arterial oxygen (Pao₂) and partial pressure of arterial carbon dioxide (CO₂) levels. Patients should also be well hydrated during the procedure with adequate crystalloid/colloid volume therapy, which may allow for less viscous pulmonary secretions following surgery.

Renal Disease

Five percent of the adult population may have pre-existing renal disease that could contribute to perioperative morbidity.²⁹ In addition, the risk of acute renal failure is increased by certain events or patient characteristics independent of pre-existing renal disease, such as hypovolemia and obstructive vascular disease. Ischemic tubular damage (i.e., acute tubular necrosis) is the most likely cause of acute renal failure in the perioperative period, reflecting events that cause an imbalance of O₂ supply to O₂ demand in the medullary ascending tubular cells.

Virtually all anesthetic drugs and techniques are associated with decreases in renal blood flow, the glomerular filtration rate, and urine output, reflecting multiple mechanisms such as decreased cardiac output, altered autonomic nervous system activity, neuroendocrine changes, and positive pressure ventilation. Renal blood flow (15%–25% of the cardiac output) far exceeds renal O₂ needs, but ensures optimal clearance of wastes and drugs. Prehydration and the depth of anesthesia may influence the renal response to anesthesia.

Management of anesthesia in patients with chronic renal disease requires attention to intraoperative fluid management and tight control of ventilation, as respiratory alkalosis will shift the oxyhemoglobin dissociation curve, and respiratory acidosis could raise serum potassium to dangerous levels. Because of decreased excretion by the kidney, doses of opioids and neuromuscular blocking agents must be attenuated.

Hepatobiliary Disease

Management of anesthesia for the patient with liver disease requires an understanding of the many physiologic functions of the liver: synthesis of albumin and coagulation factors, metabolism of drugs, glucose homeostasis, and the production of bilirubin. Data from the 1970s suggested that approximately 1 in every 700 adult patients who are scheduled for elective surgical procedures has unknown liver disease or is in the prodromal phase of viral hepatitis. Severe hepatic necrosis following surgery and anesthesia is most often due to decreased hepatic O₂ delivery rather than the anesthetic.

Regional anesthesia may be useful in patients with advanced liver disease, assuming coagulation status is acceptable. When general anesthesia is selected, administration of modest doses of volatile anesthetics with or without nitrous oxide or fentanyl often is recommended. Selection of nondepolarizing muscle relaxants should consider clearance mechanisms for these drugs. For example, patients with hepatic cirrhosis may be hypersensitive to mivacurium because of the lowered plasma cholinesterase activity. Perfusion to the liver is maintained by administering fluids (guided by filling pressures) and maintaining adequate systemic pressure and cardiac output.

The coexisting presence of liver disease may influence the selection of volatile anesthetics. Halothane is the anesthetic most studied regarding possible hepatotoxicity. Halothane hepatitis occurs rarely (approximately 1:25,000 patients) and may have an immune-mediated mechanism stimulated by repeated exposures to halothane.³⁰ Halothane, enflurane, isoflurane, and desflurane all yield a reactive oxidative trifluoroacetyl halide and may be cross-reactive, but the magnitude of metabolism of the volatile anesthetics is a probable factor in the ability to cause hepatitis.³¹ Halothane is metabolized 20%, enflurane 2%, isoflurane 0.2%, and desflurane 0.02%; desflurane probably has the least potential for liver injury. Sevoflurane does not yield any trifluoroacetylated metabolites and is unlikely to cause hepatitis. An estimated 15 to 20 million adults in the United States have biliary tract disease. Treatment of gallbladder disease by open or laparoscopic cholecystectomy is most often performed with general anesthesia supplemented with muscle relaxants. Complete biliary tract obstruction could interfere with the clearance of some muscle relaxants dependent on liver metabolism, such as vecuronium and pancuronium. Anesthetic considerations for laparoscopic cholecystectomy are similar to those for other laparoscopic procedures. Insufflation of the abdominal cavity with CO₂ results in increased intra-abdominal pressure that may interfere with the ease of ventilation and venous return. During laparoscopic cholecystectomy, placement of the patient in the reverse Trendelenburg position favors movement of abdominal contents away from the operative site and may improve ventilation. However, this position may further interfere with venous return and reduce cardiac output, emphasizing the need to maintain intravascular fluid volume. Mechanical ventilation of the lungs is recommended to ensure adequate ventilation in the presence of increased intra-abdominal pressure and to offset the effects of systemic absorption of CO₂ used during insufflation of the abdominal cavity. High intra-abdominal pressure may increase the risk of passive reflux of gastric contents. Tracheal intubation with a cuffed tube is advised to minimize the risk of pulmonary aspiration.

Metabolic and Endocrine Disease

Metabolic and endocrine disorders encompass a wide range of diseases. These diseases may be the primary reason for surgery or can exist in patients requiring surgery for other unrelated disorders. Preoperative evaluation of endocrine function consists of relevant medical history, glucose or protein in the urine, vital signs, history of fluctuations in body weight, survey of sexual function, and concomitant medications. The three metabolic and endocrine conditions that are most prevalent in patients undergoing surgery are diabetes mellitus, hypothyroidism, and obesity. The prevalence of all three conditions, either alone or in combination, in the general population has been steadily rising throughout the world for the past 20 to 30 years.^12,32 The aging population and changes in the diagnostic criteria for diabetes mellitus are sure to continue this trend.^12,33

Patients with diabetes are at an increased risk for perioperative myocardial ischemia, stroke, renal dysfunction or failure, and increased mortality.³⁴ Increased wound infections and impairment of wound healing also are associated with the preexistence of diabetes in patients undergoing surgery.³⁵

The stress response to surgery is associated with hyperglycemia in nondiabetic patients due to increased secretion of catabolic hormones and a combination of reduced insulin secretion and increased insulin resistance.^36,37 Improved glycemic control in diabetic patients undergoing major surgery has been shown to improve perioperative morbidity and mortality; avoidance of hypoglycemia and hyperglycemic events is the standard of care in these patients.^33,38,39,40

Anesthetic techniques in the diabetic patient can modulate the secretion of catabolic hormones.⁴¹ However, regional anesthesia may carry greater risks to the diabetic patient with autonomic neuropathy, and the hypotension associated with regional anesthesia may be deleterious to the diabetic patient with coexisting CAD.³³ There is no evidence that regional anesthesia or general anesthesia, either alone or in combination, offers any benefit to the diabetic surgical patient in terms of morbidity or mortality.³³

Hypothyroidism is a deficiency in the secretion of the thyroid hormones, thyroxine and 3,5′,3-triiodothyronine, by the thyroid gland. More than 5 million Americans have this common medical condition, and as many as 10% of women may have some degree of thyroid hormone deficiency. Controlled clinical trials have not shown an increase in risk when patients with mild to moderate hypothyroidism undergo surgery.⁴² Nevertheless, close monitoring of these patients for adverse effects of anesthesia, including delayed gastric emptying, adrenal insufficiency, and hypovolemia, is warranted.⁴³

The prevalence of significant obesity continues to rise both in developed and developing countries and is associated with an increased incidence of a wide spectrum of medical and surgical pathologies⁴⁴ (Table 46-9). In the United States, one-third of people have a body weight more than 20% above their ideal weight.⁴⁵ Body mass index (BMI) is calculated by dividing the weight in kilograms by the square of the height in meters. In the United States, the prevalence of a BMI >25 kg/m² is 59.4% for men, 50.7% for women, and 54.9% for adults overall. Patients with a BMI >28 kg/m² have increased perioperative morbidity over the general population.

Anesthetic management of the obese patient is problematic, and tasks such as establishing IV access, applying monitoring equipment, managing the airway, and transporting the patient are more difficult. Ventilation may be a particular ­problem because of obstructive sleep apnea or because obesity itself imposes a restrictive ventilatory state with decreased expiratory reserve and vital capacity.¹² Induction of anesthesia is particularly challenging in the obese patient, as there is increased risk of pulmonary aspiration, and the increased mass of soft tissue about the head and neck makes establishing and maintaining a patent airway difficult.

The impact of obesity on the pharmacokinetics of anesthetic drugs is variable. For example, blood volume is often increased in obese patients, which can decrease predicted concentrations of drugs, but adipose tissue has low blood flow, which could elevate blood concentrations of these agents. It is prudent to calculate the first dose of anesthetic based on ideal body weight and to base subsequent dosages on the patient’s responsiveness.^12,46

Central Nervous System Disease

Diseases of the CNS present unique situations for the anesthesiologist and require an understanding of the relationship between intracranial pressure (ICP), cerebral blood flow (CBF), and cerebral metabolic rate of O₂ consumption (CMRO₂). Preoperative assessment of ICP is difficult, as symptoms of headache, nausea, and vomiting are nonspecific, and signs of retinal changes do not occur acutely. A midline shift on computed tomography scanning or magnetic resonance imaging may indicate an expanding lesion in the brain.

Provision of anesthesia for intracranial procedures must balance hemodynamic factors such as fluid volume, mean arterial pressure, ICP, and CBF. For intracranial tumors, the mass effect of the tumor makes control of ICP and CBF critical. In intracranial aneurysm surgery, the goal of the anesthetic is to prevent sudden increases in systemic blood pressure that could rupture the aneurysm, especially during the stress of laryngoscopy and endotracheal intubation. The relationship between mean arterial pressure, ICP, and CBF is affected by pharmacologic agents. Inhalational agents in high concentrations (>0.6 MAC) cause dilation of the cerebral vasculature, decreasing cerebral vascular resistance. CBF is therefore increased in a dose-dependent fashion, despite decreases in CMRO₂.¹²

Propofol decreases CBF, ICP, and CMRO₂.⁴⁷ Propofol may also decrease systemic blood pressure, resulting in a decrease in cerebral perfusion pressure; however, propofol does not alter the autoregulation of CBF.⁴⁸ Etomidate is a potent cerebral vasoconstrictor that reduces CBF and ICP and should be used with caution in patients with epilepsy due to its excitatory effects seen on electroencephalograms.⁴⁹

Opioids decrease CBF and may also decrease ICP under certain conditions. However, Sperry and associates have reported increases in ICP with the administration of fentanyl in head trauma patients.⁵⁰ Additionally, opioids have a depressant effect on consciousness and ventilation that may increase ICP if accompanied by an increase in partial pressure of arterial CO₂; opioids should be used with caution in head trauma patients.

Regardless of the drugs or technique selected, maintenance of stable hemodynamics is optimal. Recovery from anesthesia should be smooth, avoiding pain, coughing, and straining, all of which can increase blood pressure and ICP and cause bleeding at the surgical site.

Fluid therapy can increase cerebral edema and ICP when administered in large quantities, resulting in hypervolemia. Euvolemia should be the goal in head trauma patients, whereas hypervolemia may be beneficial for patients with intracranial aneurysms to reduce vasospasm.

Induction of Anesthesia

During induction of anesthesia, the patient becomes unconscious and rapidly apneic, myocardial function is usually depressed, and vascular tone abruptly changes. The induction of general anesthesia is the most critical component of practicing anesthesia, as the majority of catastrophic anesthetic complications occur during this phase. There are several different techniques used for the induction of general anesthesia, each with significant advantages and disadvantages (Fig. 46-3). Each patient must be carefully evaluated during the preoperative period to ensure that the most efficacious and safe technique is used.

IV induction, used primarily in adults, is smooth and is associated with a high level of patient satisfaction. The addition of opioids will blunt the response of laryngoscopy and intubation to avoid hypertension and tachycardia.

In a patient with a full stomach, the standard induction technique may result in vomiting and pulmonary aspiration of stomach contents. The goal of rapid sequence induction is to achieve secure protection of the airway with a cuffed endotracheal tube while preventing vomiting and aspiration.

Rapid sequence induction is performed as follows:

• Proceed only after evaluation of the airway predicts an uncomplicated intubation.

• Preoxygenate the patient.

• Rapidly introduce an IV induction agent (e.g., propofol).

• An assistant to the anesthesiologist presses firmly down on the cricoid cartilage to block any gastric contents from being regurgitated into the trachea, a muscle relaxant is injected, and the trachea is quickly intubated.

• The assistant is instructed not to release pressure on the cricoid cartilage until the cuff of the endotracheal tube is inflated and the position of the tube is confirmed.

Patients undergoing inhalation induction progress through three stages: (a) awake, (b) excitement, and (c) surgical level of anesthesia. Adult patients are not good candidates for this type of induction, as the smell of the inhalation agent is unpleasant and the excitement stage can last for several ­minutes, which may cause hypertension, tachycardia, laryngospasm, vomiting, and aspiration. Children, however, progress through stage 2 quickly and are highly motivated for inhalation induction as an alternative to the IV route. The benefit of postinduction IV cannulation is the avoidance of many presurgical anxieties, and inhalation induction is the most common technique for ­pediatric surgery.

Management of the Airway

After induction of anesthesia, the airway may be managed in several ways, including by face mask, with a laryngeal mask airway (LMA), or, most definitively, by endotracheal intubation with a cuffed endotracheal tube. Nasal and oral airways can help establish a patent airway in a patient being ventilated with a mask by creating an air passage behind the tongue (Fig. 46-4).

The LMA is a cuffed oral airway that sits in the oropharynx. It is passed blindly, and the cuff is inflated to push the soft tissues away from the laryngeal inlet. Because it does not pass through the vocal cords, it does not fully protect against aspiration. It should not be used in patients with a full stomach (Fig. 46-5; lower left). The accurate placement of an endotracheal tube requires skill and proper equipment and conditions. Usually, the patient is unconscious and immobile (including paralysis of the muscles of respiration). Intubation is typically performed under direct visualization by looking through the mouth with a laryngoscope directly at the vocal cords (direct laryngoscopy) and watching the endotracheal tube pass through the cords into the trachea. To obtain a direct line of sight, the patient is placed in the sniffing position. The neck is flexed at the lower cervical spine and extended at the atlanto-occipital joint. This flexion and extension are amplified during laryngoscopy. Laryngoscope handles contain batteries and can be fitted with curved (Macintosh) or straight (Miller) blades (see Fig. 46-5, top row).

Some patients have physical characteristics or a history suggesting difficulty in placing an endotracheal tube. A short neck, limited neck mobility, small interincisor distance, short thyromental distance, and Mallampati class IV may all represent a challenge to endotracheal intubation. Several devices have been developed to assist in management of the difficult airway. The Bullard rigid fiberoptic laryngoscope is a self-contained device that can be passed through a mouth with a narrow opening (Fig. 46-6). The head and neck also can be kept in a neutral position, as a direct line of sight needed with a standard laryngoscope is not necessary. Another new intubating device is the Glidescope, which allows visualization of the vocal cords on a screen (Fig. 46-7)

The intubating laryngeal mask airway (ILMA) is an advanced form of LMA designed to maintain a patent airway as well as facilitate tracheal intubation with an endotracheal tube. The ILMA can be placed in anticipated or unexpectedly difficult airways as an airway rescue device and as a guide for intubating the trachea. An endotracheal tube can be passed blindly through the ILMA into the larynx, or the ILMA can be used as a conduit for a flexible fiberoptic scope (Fig. 46-8).

The flexible fiberoptic intubation scope is the gold standard for difficult intubation. It is indicated in difficult or compromised airways where neck extension is not desirable or in cases with risk of dental damage. The scope is constructed of fiberoptic bundles and cables encased in a sheath. The cables permit manipulation of the tip of the scope by adjustments made at the operating end of the device. There is a port for suction and/or insufflation of O₂. The scope gives excellent visualization of the airway with minimal hemodynamic stress when used properly. It can be used nasally or orally in an awake, spontaneously ventilating patient whose airway has been treated with topical anesthetic. It requires skill for proper use, is expensive, and requires careful maintenance (Fig. 46-9).

The ASA has developed algorithms for management of the difficult airway (Figs. 46-10 and 46-11).⁵¹

Fluid Therapy

Numerous preparations of IV fluid are available for the replacement of perioperative fluid losses in patients undergoing surgery. Different fluid preparations may influence clinical parameters (e.g., platelet function) and may also affect postoperative outcome.

Traditionally, IV fluids have been classified according to whether they are crystalloid or colloid in nature. Crystalloid fluids comprise electrolyte solutions with or without a bicarbonate precursor such as acetate or lactate. The colloids contain a complex sugar or protein suspended in an electrolyte solution. A further distinction between IV fluid types may be based on the nature of the solution. Normal saline-based (0.9% sodium chloride) preparations (crystalloid or colloid) contain no electrolytes other than sodium and chloride. In contrast, balanced salt-based fluids such as lactated Ringer’s solution contain other electrolytes, with or without a bicarbonate precursor.

Several types of colloids are available, but three are most commonly used—hydroxyethyl starch (HES), gelatin, and albumin. The HES preparations differ from one another according to their concentration, molecular weight, and extent of hydroxyethylation or substitution, with resultant varying physiochemical properties. HES solutions most often are described according to their weight-averaged mean molecular weight in kilodaltons (kDa): high molecular weight (450 kDa), middle molecular weight (200 kDa, 270 kDa), and low molecular weight (130 kDa, 70 kDa). HES 450 kDa solutions are available in a normal saline solution (HES 450/NS) and in a lactated, balanced salt solution (HES 450/BS). Although all of these colloids are used in Europe, gelatins are not available in the United States, and the only HES preparations approved by the U.S. Food and Drug Administration are the 6% high molecular weight (450 kDa) formulations.

The administration of a large volume of any type of IV fluid will cause dilution of platelets and coagulation factors and may lead to coagulopathy (i.e., dilutional coagulopathy). In addition, fluids can have a direct impact on blood clotting through effects on circulating components of the coagulation cascade or by altering platelet function.

Recent evidence suggests that the nature of the solution itself may influence coagulation and bleeding. HES 450/NS may be associated with more bleeding than other fluids. HES 450 in a balanced salt solution appears to be equivalent to 5% albumin with respect to bleeding outcomes.^52,53,54 Waters and colleagues reported that patients undergoing abdominal aortic aneurysm repair who received lactated Ringer’s solution received smaller volumes of platelets and had less blood product exposure than those treated with normal saline.⁵⁵

It is possible that certain fluids may induce hypercoagulability that may be reflected not only by less bleeding, but also by an increased incidence of postoperative thrombotic complications (e.g., deep vein thrombosis and cerebrovascular accident). There are laboratory data⁵⁶ to suggest that IV fluid administration may induce a hypercoagulable state, but the clinical significance of this remains unclear. The type of fluid administered intraoperatively to a patient can have a significant impact on renal function. The administration of HES/NS or ­normal saline to critically ill patients or elderly patients undergoing major surgery was associated with the development of renal ­dysfunction.^57,58,59

The administration of adequate IV fluids during the perioperative period results in a lower incidence of nausea, vomiting, and antiemetic use after minor or day case surgery.⁶⁰ In major noncardiac surgical patients, the administration of HES 450 (in a balanced salt or normal saline solution, or a combination of balanced crystalloid and colloid) has been associated with less postoperative nausea, vomiting, and antiemetic use and earlier return of postoperative bowel function, as reflected by first consumption of solid food, than the administration of 5% albumin, lactated Ringer’s solution, or normal saline alone.⁶¹ Studies of patients undergoing ambulatory surgery have shown that perioperative IV fluid administration decreases the incidence of dizziness, drowsiness, thirst, and headache.⁶² In a randomized crossover study of healthy volunteers, subjective deterioration in mental status (lassitude and difficulty in abstract thinking) was reported only by individuals who received 0.9% sodium chloride and not by those who received lactated Ringer’s solution.⁶³ The possible effect of different IV fluid preparations on CNS function has not yet been fully explored.

The relative impact of crystalloids and/or colloids on pulmonary function has been the subject of long-standing debate. No difference in postoperative pulmonary function was seen in cardiac surgery patients, orthopedic patients, or urologic surgery patients treated intraoperatively with different colloids.^57,64,65 In a number of studies in major surgical patients that compared crystalloid (lactated Ringer’s solution) with colloid (HES 130/NS, HES 450/NS, 5% albumin/BS),^66,67,68 no difference was seen in the incidence or duration of mechanical ventilation or other indices of respiratory function. These findings suggest that the intraoperative administration of crystalloids does not have a detrimental effect on pulmonary function compared with the administration of colloids.

Transfusion of Red Blood Cells

ABO Blood Groups

There are four different ABO groups, which are determined by whether or not an individual’s red blood cells (RBCs) carry the A antigen, the B antigen, both A and B antigens, or neither. From early in childhood, normal healthy individuals make antibodies against A or B antigens that are not expressed on their own cells. People who are group A have anti-B antibodies in their plasma, people who are group B have anti-A antibodies, people who are group O have anti-A and anti-B antibodies, and people who are group AB have neither of these antibodies. These naturally occurring antibodies are mainly immunoglobulin M that attack and rapidly destroy RBCs. Anti-A antibodies attack RBCs of group A (or AB), and anti-B antibodies attack RBCs of group B (or AB).

ABO-Incompatible Red Cell Transfusion

If RBCs of the wrong group are transfused, in particular if group A RBCs are infused into a recipient who is group O, the recipient’s anti-A antibodies bind to the transfused cells. This activates the complement pathways, which damages the red cell membranes and lyses the RBCs. Hemoglobin released from the damaged RBCs is toxic to the kidneys, while the fragments of ruptured cell membranes activate the blood-clotting pathways. The patient suffers acute renal failure and disseminated intravascular coagulation.

Basics of Red Blood Cell Compatibility

Ensuring that the right blood group is transfused is imperative. It is essential to ensure that no ABO-incompatible RBC transfusion is ever given. This avoidable accident is likely to kill or harm the patient. Procedures in which compatibility is determined by establishing both transfusion recipient and donor blood ABO types via crossmatch analysis have evolved over years of clinical and laboratory experience to minimize the risk of this disastrous error. These procedures will continue to evolve as improved computerized systems are introduced to help staff avoid errors in blood administration.

Rhesus D Antigen and Antibody

In a white population, about 15% will lack the Rhesus D (Rh D) antigen and are termed Rh D negative. Antibodies to Rh D antigen occur only in individuals who are Rh D negative and as a consequence of transfusion or pregnancy. Even small amounts of Rh D–positive cells entering the circulation of an Rh D–negative person can stimulate the production of antibodies to Rh D, usually immunoglobulin G.

Physiologic Response and Tolerance of Anemia

O₂ is carried in blood in two distinct forms: bound to hemoglobin (Hb) within the RBC and dissolved in the plasma. The actual oxygen content of arterial blood (Cao₂) is determined by the concentration of Hb in the blood, the arterial oxygen saturation of Hb (Sao₂), the O₂-binding capacity of Hb, the Pao₂, and the O₂ solubility of plasma. These variables are interrelated and can be expressed in the following equation:

Adult Hb consists of four protein chains, each carrying one heme group. One mole of Hb is able to bind to a maximum of 4 moles of O₂. O₂-binding capacity per gram of Hb is 1.39 g/mL. The relationship between Pao₂ and Hb O₂ saturation is shown in Fig. 46-12. The steep part of this curve (partialpressure of oxygen [Po₂] 20–40 mmHg) facilitates O₂ release from Hb. Tissue Po₂ values of different organs are also shown in Fig. 46-12 and lie on this steep part of the curve, facilitating O₂ release from Hb.

Hemodilution and Critical Hematocrit

The intentional dilution of blood volume often is referred to as acute normovolemic hemodilution (ANH) anemia. ANH is a technique in which whole blood is removed from a patient, while the circulating blood volume is maintained with acellular fluid. Blood is collected via central lines with simultaneous infusion of crystalloid or colloid solutions. Collected blood is reinfused after major blood loss has ceased, or sooner, if indicated. Blood units are reinfused in the reverse order of collection. Under conditions of ANH, the increased plasma compartment becomes an important source of O₂, which is delivered to the tissues.

Oxygenation is maintained by increased cardiac output and increased O₂ extraction by the tissues, and when these compensatory mechanisms fail to match the O₂ needs of the tissues, the “critical hematocrit” is said to have been reached. The critical hematocrit has been a source of debate for many years. A theoretical model was developed that describes the relation between hematocrit, myocardial O₂ demand, and the required coronary blood flow during progressive hemodilution.⁶⁹ Using this model, the determinants of critical hematocrit and the limits of ANH can be calculated based on the limits of coronary reserve. Because the critical hematocrit varies with O₂ consumption and degree of CAD, a fixed critical hematocrit as a transfusion trigger is not appropriate in most patients. Rather, the indication for blood transfusions must individually take into account the specific circumstances of the patient, such as expected blood loss and required O₂ transport capacity reserves, hemodynamic stability, CAD, and systemic O₂ consumption.

Reversal of Neuromuscular Blockade

The elimination of neuromuscular blocking agents from the body and subsequent resumption of neuromuscular transmission takes a considerable amount of time, even with drugs such as vecuronium that have relatively short half-lives. Additionally, it is time consuming to wait for complete spontaneous recovery at the end of a surgical procedure. Therefore, it has become routine to antagonize the neuromuscular block pharmacologically with the use of reversal agents. Reversal agents raise the ­concentration of the neurotransmitter acetylcholine to a higher level than that of the neuromuscular blocking agent. This is accomplished by the use of anticholinesterase agents, which reduce the breakdown of acetylcholine. The most commonly used agents are neostigmine, pyridostigmine, and edrophonium.

The common side effects of these three anticholinesterase agents are bradycardia, bronchial and intestinal smooth muscle contractions, and excessive secretions from salivary and bronchial glands. These effects are primarily mediated by effects on muscarinic receptors, which are effectively blocked by the concomitant use of antimuscarinic drugs such as atropine or glycopyrrolate. To ensure adequate ventilation postoperatively, it is important that the neuromuscular blocking agents are fully reversed, as assessed by monitoring twitch strength with a nerve stimulator and clinically correlating this with signs such as grip strength or 5-second head lift.

The Postanesthesia Care Unit

It is of primary importance that all patients awakening from anesthesia are followed in a recovery room, as approximately 10% of all anesthetic accidents occur in the recovery period. As more serious surgeries are performed on older and sicker patients, the number of patients requiring postoperative ventilation and medications to support their circulation increases with age. The new trend for postoperative pain control with continuous epidural administration of local anesthetics and narcotics demands close observation, because respiratory depression can occur. In most hospitals, the number of intensive care beds is too small to accommodate the increasing number of these patients. What originally began as the recovery room now must function as an intensive care unit setting for short stays. The name “recovery room” has been changed to postanesthetic care unit (PACU). A variety of physiologic disorders that can affect different organ systems need to be diagnosed and treated in the PACU during emergence from anesthesia and surgery. Postoperative nausea and vomiting (PONV), airway support, and hypotension requiring pharmacologic support have been observed to be the most frequent complications in the PACU.⁷⁰ Abnormal bleeding, hypertension, dysrhythmia, myocardial infarction, and altered mental status are not uncommon.⁷⁰

Postoperative Nausea and Vomiting

PONV typically occurs in 20% to 30% of surgical cases,⁷¹ with considerable variation in frequency reported between studies (range, 8%–92%).⁷² PONV is generally considered a transient, unpleasant event carrying little long-term morbidity; however, aspiration of emesis, gastric bleeding, and wound hematomas may occur with protracted or vigorous retching or vomiting. Troublesome PONV can prolong recovery room stay and hospitalization and is one of the most common causes of hospital admission following ambulatory surgery. Published evidence suggests that prophylactic administration of antiemetics is not cost-effective in the surgical setting.⁷³ Recent consensus guidelines using data from systematic reviews, randomized trials and studies, and logistic regression models have been published (Fig. 46-13).⁷³

Agents usually administered for PONV are the serotonin receptor antagonists (e.g., ondansetron, dolasetron, granisetron, and tropisetron). The safety and efficacy of the compounds, when given at the end of surgery, are virtually identical.^73,74 Metoclopramide (not a true antiemetic), when used in the standard dose of 10 mg, is ineffective for PONV.⁷⁵ Although some studies have shown higher doses (20 mg) to have some effect on PONV, most evidence suggests that the serotonin receptor antagonists are the most efficacious choice.

Pain: The Fifth Vital Sign

Analgesic research methodology has been enhanced since the 1960s through the use of graduated and visual analog scales, tools that permit the standardization of pain scores. One frequently used graduated scale is a four-point measure of pain intensity (0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe pain) and a five-point measure of relief (0 = no relief, 1 = a little relief, 2 = some relief, 3 = a lot of relief, and 4 = complete relief).

Acute postoperative pain and its treatment (or prophylaxis) are significant challenges for the healthcare professional. Despite the recent development of new nonnarcotic analgesics and a better understanding of the side effects associated with pain medication of all types, acute postoperative pain remains a significant concern for patients and represents an extremely negative experience for patients undergoing surgery. Many patients experience pain in the postoperative period despite the use of potent techniques such as patient-controlled analgesia, epidural analgesia, and regional anesthesia. The culture of acceptance of postoperative pain is changing. The American Pain Society has advocated the assessment of pain as the fifth vital sign, along with temperature, pulse, blood pressure, and respiratory rate. The four vital signs provide a quick snapshot of a patient’s general condition, but pain management advocates claim the picture is not complete without including pain as the fifth vital sign.

This approach may improve the efficacy of pain treatment. Many departments of anesthesiology support an active pain service and provide consultation for postoperative pain relief, including the administration of nerve blocks.

Opioids, long the staple of postoperative pain management, reduce pain by acting on the μ-receptor. Analgesia is accompanied by unwanted side effects also promulgated by the μ-receptor (e.g., sedation, nausea and vomiting, constipation, respiratory depression). Reducing opioid use and those side effects by the addition of nonopioid analgesics is called multimodal analgesia.⁷⁶ Analine derivatives (IV acetaminophen),⁷⁷ NSAIDs like celecoxib⁷⁸ and ketorolac,⁷⁹ steroids (dexamethasone),⁸⁰ and anticonvulsants (gabapentin and pregabalin)^81,82 have all been used as opioid-sparing methods to attenuate postoperative pain. The best mixture of drugs is yet to be found; continued work is necessary to find the idea combination.⁸³

Regional analgesia, (i.e., nerve blocks) is an effective method for reducing postoperative pain while minimizing opioid consumption. Nerve blocks can be of the upper or lower extremities, truncal, epidural, or paravertebral (Fig. 46-14).

The transversus abdominal plane (TAP) block is truncal regional analgesia that results in analgesia to the anterior abdominal wall and has rapidly gained popularity. Pain secondary to any transgression of the abdominal wall can be attenuated by a TAP block, including laparoscopic procedures⁸⁴; vertical or Pfannenstiel incisions; inguinal,⁸⁵ incisional, or umbilical hernia repair; hysterectomy; cholecystectomy; and appendectomy (Figs. 46-15–46-18).^86,87,88

Somatic nerves supplying the abdominal wall travel in the plane between the internal oblique muscle and the transversus abdominis muscle (Fig. 46-19). Injection of local anesthetic into this plane under ultrasound guidance results in pain relief for 8 to 12 hours (Fig. 46-20,46-21,46-21).

Malignant hyperthermia (MH) is a hereditary, life-threatening, hypermetabolic acute disorder, developing during or after receiving general anesthesia.⁸⁹ The clinical incidence of MH is about 1:12,000 in children and 1:40,000 in adults. A genetic predisposition and one or more triggering agents are necessary to evoke MH. Triggering agents include all volatile anesthetics (e.g., halothane, enflurane, isoflurane, sevoflurane, and desflurane) and the depolarizing muscle relaxant succinylcholine. Volatile anesthetics and/or succinylcholine cause a rise in the myoplasmic calcium concentration in susceptible patients, resulting in persistent muscle contraction.

MH is an autosomal dominant disorder associated with several gene loci, predominantly the ryanodine receptor gene RYR1. MH can be diagnosed with the caffeine-contracture halothane test (which requires muscle biopsy). Genetic testing is helpful after the fact; there is no simple reliable blood screening test yet available.

The classic MH crisis entails a hypermetabolic state, tachycardia, and the elevation of end-tidal CO₂ in the face of constant minute ventilation. Respiratory and metabolic acidosis and muscle rigidity follow, as well as rhabdomyolysis, arrhythmias, hyperkalemia, and sudden cardiac arrest. A rise in temperature is often a late sign of MH. Treatment must be aggressive and begin as soon as a case of MH is suspected:

• Call for help.

• Stop all volatile anesthetics and give 100% O₂.

• Hyperventilate the patient up to three times the calculated minute volume.

• Give bicarbonate to treat acidosis if dantrolene is ­ineffective.

• Treat hyperkalemia with insulin, glucose, and calcium.

• Avoid calcium channel blockers

• Begin infusion of dantrolene sodium, 2.5 mg/kg IV. Repeat as necessary, titrating to clinical signs of MH. Repeat dantrolene at 1 mg/kg every 6 to 8 hours at least twice, and monitor the patient in an intensive care unit setting for 24 hours or more for possible recrudescence.

• Call the MH hotline to report the case and get advice: 1-888-274-7899.

The general mantra of “gene therapy is the future of medicine” must be more specifically related to how those genes create, shape, and regulate proteins. The study of how proteins manifest their activity and/or concentration is called proteomics (from proteome—a fusion of “protein” and “genome”).

As the technology advances to biologically identify individual proteins, studies of individual levels of proteomes will allow the study of disease processes on the molecular level, directly aiding diagnosis and therapeutics.⁹⁰

Specifically to the field of anesthesiology, the technology of proteomics will be used to elucidate the actual mechanism of action of our anesthetic drugs and how these drugs have differing effects on different individuals. There will be a day when a buccal swab in the preoperative clinic will become routine, with the results telling us which opioids carry the fewest side effects for that particular patient, for example, or which antiemetics are most effective, or which postoperative analgesics to use—a tailored anesthetic.

Recent studies in mice have examined the α5 subunit of the GABA receptor, which appears to regulate memory. The human genome is polymorphic for the α5 gene; because each variant may manifest in different amounts of memory/amnesia, proteomics may someday lead to tests that determine the propensity of a particular patient to experience awareness and allow us to tailor the anesthetic even further.⁹¹

Genetic testing for cytochrome P450 deficiencies is now commercially available.⁹² As the number of enzymes able to be tested increases, we will be able to choose the most appropriate match between drug and patient.