Anesthesiology Principles, Pain Management, and Conscious Sedation

Nitrous Oxide

Nitrous oxide provides only partial anesthesia at atmospheric pressure because its MAC is 104% of inspired gas at sea level. Nitrous oxide minimally influences respiration and hemodynamics. In addition, it has low solubility in blood. Therefore, it is often combined with one of the potent volatile agents to permit a lower dose of the potent volatile agent, thus limiting side effects, reducing cost, and facilitating rapid induction and emergence. The most important clinical problem with nitrous oxide is that it is 30 times more soluble than nitrogen and diffuses into closed gas spaces faster than nitrogen diffuses out, thus increasing gas volume and pressure within the closed space. Because of this characteristic, nitrous oxide is contraindicated in the presence of closed gas spaces such as pneumothorax, small bowel obstruction, or middle ear surgery, as well as in retinal surgery in which an intraocular gas bubble is created. Because nitrous oxide gradually accumulates in the pneumoperitoneum, some clinicians prefer to avoid its use during laparoscopic procedures. However, periodic venting can prevent gas accumulation.

The Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA) Trial, reported in 2007, indicated that patients having major surgical procedures lasting more than 2 hours had a higher incidence of postoperative complications and severe postoperative nausea and vomiting (PONV) if they received 70% nitrous oxide as part of their anesthetic regimen compared to patients randomized to not receive nitrous oxide. However, the more recent ENIGMA II Trial, published in 2014, reported that use of nitrous oxide was not associated with an increased incidence of death, cardiovascular complications, or wound infection in high-risk surgical patients. Although the incidence of severe PONV was higher (15% vs. 11%) in patients receiving nitrous oxide compared to controls, the occurrence of PONV in the nitrous oxide group was effectively controlled by antiemetic prophylaxis. A one-year follow-up of ENIGMA II patients did not show an increase in long-term morbidity and mortality with nitrous oxide administration.

Isoflurane

Approved by the U.S. Food and Drug Administration (FDA) in 1979, isoflurane rapidly replaced halothane as the most commonly used potent inhalational agent. Despite the recent release of sevoflurane and desflurane, isoflurane remains commonly used in modern operating rooms, in part because the cost of the now-generic compound is well below that of the newer agents. Isoflurane has several advantages over halothane, including less reduction in cardiac output, less sensitization to the arrhythmogenic effects of catecholamines, and minimal metabolism ( Tables 14.1 and 14.2 ). However, isoflurane-induced tachycardia, a variable response, can increase myocardial oxygen consumption. Careful observation and management of the heart rate are necessary when it is used in patients with coronary artery disease. In concentrations of 1.0 MAC or less, isoflurane causes little increase in cerebral blood flow and intracranial pressure (ICP) and depresses cerebral metabolic activity more than halothane or enflurane does. Its pungent odor virtually precludes use for inhalational induction.

Sevoflurane

Sevoflurane’s relatively low blood solubility facilitates rapid induction and relatively rapid emergence. Sevoflurane is associated with faster emergence than isoflurane is, especially in longer cases, although its slightly faster emergence does not result in earlier discharge after outpatient surgery. Sevoflurane is associated with a lower incidence of postoperative somnolence and nausea in the postanesthesia care unit (PACU) and in the first 24 hours after discharge than isoflurane is. Unlike isoflurane, sevoflurane is pleasant to inhale, thus making it suitable for inhalational induction in children. However, the clinical differences between halothane and sevoflurane are subtle. In premedicated pediatric patients undergoing bilateral myringotomy and tube placement and randomized to receive sevoflurane or halothane, anesthesiologists correctly identified the agent (to which they were blinded) in only 56.6% of cases.

Sevoflurane is clinically suitable for outpatient surgery, mask induction of patients with potentially difficult airways, and maintenance of patients with bronchospastic disease. When sevoflurane, halothane, and isoflurane were compared, all three of the potent agents decreased respiratory resistance in endotracheally intubated nonasthmatics; sevoflurane reduced airway resistance more than halothane or isoflurane did. Another advantage of sevoflurane is that its cardiovascular side effects are minimal.

Considerable metabolic transformation of sevoflurane takes place and results in increases in the serum fluoride ion concentration and, in the presence of soda lime or Baralyme, production of compound A, a metabolite that is nephrotoxic in experimental animals. However, β-lyase, the enzyme responsible for the formation of compound A, has 8 to 30 times greater activity in rat kidney tissue than in human kidney tissue. Therefore, the toxicity of compound A in humans appears to be theoretical and not clinically important.

Desflurane

Desflurane is rapidly taken up and eliminated. After anesthesia lasting more than 3 hours, desflurane was associated with more rapid recovery than isoflurane was. The most volatile and least potent of the volatile anesthetics, desflurane must be administered through specialized electrically heated vaporizers. Its pungent odor precludes inhalational induction. In addition, desflurane is associated with tachycardia and hypertension if the inspired concentration is increased too rapidly.

When exposed to dry CO ₂ absorbent, desflurane, isoflurane, and enflurane are partially converted to carbon monoxide. Desflurane, enflurane, and isoflurane produce more carbon monoxide than halothane or sevoflurane does. Carbon monoxide production is greater with dry CO ₂ absorbent, with Baralyme than with soda lime, at higher temperatures, and at higher anesthetic concentrations. Because continued gas flow in an unused machine will desiccate the CO ₂ absorbent, turning gas flow off in anesthesia machines when they are not in use can reduce carbon monoxide production.

Induction Agents

For most adult patients and many older children, IV induction is preferable to inhalational induction. IV induction is rapid, pleasant, and safe for the vast majority of patients; however, there are situations in which IV induction introduces hazards. Although several agents can be used for IV induction of anesthesia, propofol is the most widely used agent in the United States. Other agents include sodium thiopental, ketamine, methohexital, etomidate, and midazolam ( Table 14.3 ).

Propofol is a short-acting induction agent that is associated with smooth, nausea-free emergence. Small doses are also useful for short-term sedation during brief procedures such as retrobulbar or peribulbar eye blocks, and propofol is commonly used as a continuous infusion during total IV anesthesia and for sedation during less invasive procedures such as gastrointestinal endoscopy. The primary limitations of propofol are pain on injection and blood pressure reduction. Thus propofol should be used with caution in patients who may be hypovolemic or who may tolerate hypotension poorly, such as those with severe coronary artery disease.

Propofol produces excellent bronchodilatation. In asthmatic patients, 0% of those who received propofol wheezed at 2 or 5 minutes after intubation versus 45% of those who received a thiobarbiturate and 26% of those who received an oxybarbiturate. In nonasthmatic patients, three quarters of whom smoked, airway resistance was less after induction with propofol than after induction with thiopental or etomidate. Evidence indicates that the bronchodilatory effects of propofol and ketamine are mediated through blockade of vagus nerve–mediated cholinergic bronchoconstriction.

Ketamine, which produces a dissociative state of anesthesia, is the only IV induction agent that increases blood pressure and heart rate and decreases bronchomotor tone. Usually associated with increased sympathetic tone, ketamine causes direct cardiac depression that may become evident if given to patients with high preanesthetic sympathetic tone, as in patients in hemorrhagic shock. In markedly reduced doses (15%–20% of the usual induction dose), ketamine is an appropriate choice for IV induction of severely hypovolemic patients in whom it causes the least fall in blood pressure of any of the induction agents. Ketamine is an appropriate agent for IV induction of asthmatic patients because it reduces the increase in bronchomotor tone associated with endotracheal intubation. Among the IV induction agents, ketamine also causes the least amount of ventilatory depression and loss of airway reflexes. However, because of the induction of copious oropharyngeal secretions, a drying agent such as glycopyrrolate is generally administered with ketamine.

Ketamine can be used as the sole anesthetic for brief, superficial procedures because it produces profound amnesia and somatic analgesia. It is less useful, however, for abdominal cases or delicate surgery because it produces no muscular relaxation, does not control visceral pain, and may not completely control patient movement. The potent pain-relieving effects of ketamine have been exploited for preemptive analgesia. In patients in whom ketamine was infused continuously before incision and continued through wound closure, postoperative morphine consumption was significantly lower on postoperative days 1 and 2 than in patients who did not receive ketamine.

In patients with coronary artery disease, ketamine is usually avoided because tachycardia and increased blood pressure may cause myocardial ischemia. In patients with increased ICP (e.g., after traumatic brain injury), ketamine may further increase ICP because it is the only IV agent that increases cerebral blood flow. Another clinically important side effect of ketamine is emergence delirium. In adults and older children, supplemental benzodiazepines or volatile agents are generally effective in preventing emergence delirium.

Etomidate is an imidazole compound that produces minimal hemodynamic changes. Because it preserves blood pressure in most patients, etomidate is often chosen as an alternative for induction of patients with cardiovascular disease or severe hypovolemia. Major drawbacks include burning pain on injection, abnormal muscular movements (myoclonus), and adrenal suppression when given as a prolonged infusion for sedation of critically ill patients.

Induction with thiopental, the oldest IV induction agent, is rapid and pleasant. Although the drug is remarkably well tolerated by a wide variety of patients, it is not commonly used in modern anesthetic practice and several clinical situations necessitate caution ( Table 14.3 ). In hypovolemic patients and those with congestive heart failure, thiopental-induced vasodilatation and cardiac depression can lead to severe hypotension unless doses are markedly reduced. In such patients, etomidate or ketamine is an alternative agent. Although thiopental does not directly precipitate bronchospasm, bronchospasm may develop in patients with reactive airway disease in response to the intense airway stimulation produced by endotracheal intubation. Consequently, propofol or ketamine is often chosen as an alternative for induction in patients with reactive airway disease. In the usual doses used for induction of anesthesia, thiopental is associated with rapid emergence because of redistribution of the agent from the brain to peripheral tissues, particularly fat. In higher doses, circulating blood levels increase and the action of thiopental must be terminated by hepatic metabolism, which eliminates only about 10% per hour.

Midazolam is sometimes used for induction because it usually causes minimal cardiovascular side effects and has a much shorter duration of action than diazepam does. Its onset of action is acceptably rapid and, even in smaller doses, induces profound amnesia for painful or anxiety-producing events. Midazolam is frequently selected for induction of patients for cardiovascular surgery. Because midazolam combines powerful anxiolytic and amnesic effects, smaller doses also are commonly used to premedicate anxious patients and as a component of a multidrug anesthetic.

Opioids

Opioids are used in the majority of patients undergoing general anesthesia and are given systemically to a large proportion of patients receiving regional or local anesthesia. As a component of a multifaceted anesthetic, opioids produce profound analgesia and minimal cardiac depression. Their disadvantages include ventilatory depression and inconsistent hypnosis and amnesia, which must usually be provided by other agents.

Several reasons explain the popularity of opioids in anesthetic management. First, they reduce the MAC of potent inhalational agents. For example, fentanyl (3 ng/mL plasma concentration) decreased the MAC of sevoflurane by 59% and reduced MAC _awake (the alveolar concentration at which an emerging patient responds to commands) by 24%. Second, they blunt the hypertension and tachycardia associated with manipulations such as endotracheal intubation and surgical incision. Third, they provide analgesia that extends through the early postemergence interval and facilitates smoother awakening from anesthesia. Fourth, in doses 10 to 20 times the analgesic dose, opioids act as complete anesthetics in a high proportion of patients by providing not only analgesia but also hypnosis and amnesia. This characteristic has prompted their use in cardiac surgery patients, sometimes as sole anesthetic agents and more often as a major component of a multimodal anesthetic. Finally, they are now often added to local anesthetic solutions in epidural and intrathecal blocks to improve the quality of analgesia.

Morphine, hydromorphone, and meperidine are inexpensive, intermediate-acting agents that are less commonly used for maintenance of anesthesia than for postoperative analgesia. Fentanyl, a synthetic opioid that is 100 to 150 times more potent than morphine, is commonly used for maintenance of anesthesia because of its shorter duration of action and rapid onset. Newer synthetic, short-acting opioids, including sufentanil and alfentanil, are also used during anesthesia because they are quickly metabolized and excreted. Remifentanil, an opioid metabolized by serum esterases, is particularly short acting. Remifentanil does not accumulate during prolonged infusions and is therefore often used as part of IV anesthetics. Methadone is a long-acting opioid that is not only a potent μ-opioid receptor agonist but also interacts with N -methyl-D-aspartate (NMDA) receptors and alters the reuptake of serotonin and norepinephrine in the brain. A recent study comparing intraoperative methadone to hydromorphone in patients undergoing posterior spinal fusion showed that methadone administration decreased postoperative opioid requirements, decreased pain scores, and improved patient satisfaction with pain management.

Neuromuscular Blockers

Fifty years ago, anesthesia was typically conducted with single potent inhalational agents that produced all the components of general anesthesia, including the degree of muscle relaxation that was necessary for the conduct of surgery. Among the drawbacks of this approach was the fact that the depth of anesthesia necessary to produce profound muscle relaxation was much deeper than that necessary to provide hypnosis and amnesia. The addition of muscle relaxants afforded the opportunity to deliver only enough of the inhalational and IV agents to achieve hypnosis, amnesia, and analgesia while still providing satisfactory operating conditions.

The two categories of neuromuscular blockers in clinical use are depolarizing (noncompetitive) and nondepolarizing (competitive) agents. The depolarizing agents exert agonistic effects at the cholinergic receptors of the neuromuscular junction, initially causing contractions evident as fasciculations followed by an interval of profound relaxation. The nondepolarizing neuromuscular blockers compete for receptor sites with acetylcholine in the neuromuscular junction, with the magnitude of block dependent on the availability of acetylcholine, the concentration of neuromuscular blocker in the neuromuscular junction, and the affinity of the agent for the receptor.

Succinylcholine, the only depolarizing agent still in clinical use, remains popular for endotracheal intubation because of its rapid onset and short duration of action. However, it is associated with serious hazards, including hyperkalemia and malignant hyperthermia, in a small proportion of patients. The drug can be administered in a relatively high dose for intubation because it is rapidly metabolized by plasma pseudocholinesterase, except in a small fraction of patients with atypical or absent pseudocholinesterase. At high doses, onset of muscle relaxation is rapid (60–90 seconds), which facilitates rapid intubation in patients at risk for aspiration. Because its duration of action is only 5 minutes, a patient who cannot be successfully intubated can be ventilated by mask for a short time until spontaneous respiration resumes. However, a patient who cannot be ventilated by mask after succinylcholine administration will likely not resume spontaneous breathing before the onset of life-threatening hypoxemia.

The side effects of succinylcholine include bradycardia, especially in children, and severe, life-threatening hyperkalemia in patients with burns, paraplegia, quadriplegia, and massive trauma. Succinylcholine, alone or when combined with a volatile agent, is also implicated in triggering malignant hyperthermia in susceptible individuals. Therefore, it is best avoided in patients at risk for malignant hyperthermia, including those with muscular dystrophy or a family history of malignant hyperthermia. Some anesthesiologists avoid succinylcholine in children because masseter spasm is a common occurrence that may presage malignant hyperthermia, but it is usually a benign effect. Because succinylcholine is a depolarizing agent that causes visible muscle fasciculations, it has been implicated in causing postoperative muscle pain, which can be reduced by pretreatment with a small, precurarizing dose of a nondepolarizing agent. As a result of the multiple sporadic problems associated with the use of succinylcholine, some anesthesiologists now reserve its use only for situations in which an airway must be rapidly secured (i.e., rapid-sequence induction). In other situations, nondepolarizing agents, chosen largely on the basis of their mode of excretion and duration of action, are preferable. For instance, cisatracurium is largely metabolized in serum by Hoffman degradation and is suitable for patients with reduced renal function in whom pancuronium and vecuronium would be unsuitable because they are partially eliminated by the kidneys.

Nondepolarizing relaxants are used when succinylcholine is contraindicated as an alternative to succinylcholine for patients in whom easy endotracheal intubation is anticipated and when intraoperative relaxation is required to facilitate surgical exposure. Knowledge of the side effects of individual agents (often related to vagolysis or release of histamine) and routes of metabolism plays a major role in the selection of specific agents for individual cases. Doses required to provide satisfactory operating conditions are summarized in Table 14.4 . Dosing of nondepolarizing agents requires knowledge of several important characteristics. First, the use of neuromuscular blockers prevents movement in response to noxious stimuli. Therefore, chemical paralysis can mask the signs of inadequate anesthesia (or sedation or analgesia in postoperative patients). Medicolegal claims of intraoperative awareness during general anesthesia were more than twice as frequent in patients receiving intraoperative muscle relaxants. Second, higher doses are required to provide satisfactory conditions for intubation than for surgical relaxation. Therefore, if a nondepolarizer is used only after intubation, smaller doses are required. Third, other anesthetic drugs potentiate the actions of nondepolarizing agents. Succinylcholine used for intubation decreases subsequent requirements for nondepolarizers. Potent inhalational agents dose-dependently potentiate the effects of competitive neuromuscular blockers. The newer inhalational agent desflurane potentiates the effects of vecuronium approximately 20% more than isoflurane does. Fourth, individual responses to muscle relaxants vary widely, with patients demonstrating both markedly increased and markedly decreased neuromuscular blockade in comparison to expected levels.

Fifth, and most important, subtle blockade can be difficult to detect and can be associated with postoperative complications. The importance of subtle residual paralysis has recently been quantified by using the train-of-four (TOF) fade ratio, a semiquantitative monitoring technique used to assess the adequacy of neuromuscular blockade and the adequacy of pharmacologic reversal. At the conclusion of anesthesia, a TOF ratio greater than 0.90 has been considered adequate return of neuromuscular function. This ratio means that the fourth of four muscle twitches in response to supramaximal stimuli delivered at 0.5-second intervals to the ulnar nerve is at least 90% of the magnitude of the first twitch. In a 2003 study, at TOF ratios less than 0.90, subjects had diplopia and difficulty tracking objects in all directions. The ability to strongly oppose the incisors did not return until the TOF ratio was higher than 0.90. The authors concluded that satisfactory return of neuromuscular function requires return of the TOF ratio to greater than 0.90 and ideally to 1.0. In patients who received the intermediate-acting neuromuscular blockers atracurium, vecuronium, or rocuronium only for endotracheal intubation, the TOF ratio was lower than 0.9 in 37% of patients 2 hours after receiving the muscle relaxant. More recent studies show that patients with TOF ratios lower than 0.9 have an increased incidence of postoperative respiratory complications and delayed PACU discharge. Thus, it is important to optimize return of neuromuscular function at the end of surgery through judicious use of muscle relaxants and reversal agents.

The use of neuromuscular blocking agents in general and nondepolarizing agents in particular necessitates a strategy to ensure adequate muscular function at the conclusion of anesthesia. Many of the complications associated with neuromuscular blockers relate to inadequate reversal at the conclusion of cases or inadequate assessment of reversal. Historically, nondepolarizing relaxants are generally pharmacologically reversed with an anticholinesterase (neostigmine or edrophonium) accompanied by atropine or glycopyrrolate to counteract the muscarinic effects of the anticholinesterase. However, recovery depends both on the intensity of neuromuscular blockade at the time that reversal is attempted and on the effects of the reversal agent. At the end of anesthesia, profound neuromuscular blockade may preclude reliable antagonism by an anticholinesterase within 5 to 10 minutes. With the longer-acting muscle relaxants, residual blockade can potentially complicate postoperative recovery. In a clinical trial of reversal of muscle relaxation, 691 patients undergoing abdominal, gynecologic, or orthopedic surgery under general anesthesia were randomized to receive pancuronium, vecuronium, or atracurium. After reversal with neostigmine, a higher proportion (26%) of patients who had received pancuronium had residual neuromuscular blockade (TOF <0.70) than did patients who had received vecuronium or atracurium (5.3% combined). Patients who received pancuronium and had a TOF ratio less than 0.70 had a higher incidence of atelectasis or pneumonia on postoperative chest radiographs (16.9% of 59 patients in that category). There was no association between postoperative pulmonary complications and residual blockade with the other two muscle relaxants. However, the development of sugammadex has overcome many of the problems associated with using anticholinesterases to reverse neuromuscular blockade. Sugammadex is a cyclodextrin that directly binds nondepolarizing steroidal neuromuscular blocking agents such as rocuronium and vecuronium. Sugammadex rapidly reverses neuromuscular blockade and avoids the muscarinic side effects associated with use of anticholinesterases. Dosing of sugammadex is based on the depth of neuromuscular blockade. Therefore, monitoring of blockade depth with a twitch monitor is required for optimal reversal of neuromuscular blockade with sugammadex. Nevertheless, comparison of sugammadex to neostigmine for reversal of neuromuscular blockade in patients undergoing abdominal surgery showed that sugammadex administration eliminated residual neuromuscular blockade in the PACU and shortened the time of readiness for discharge from the operating room.

One key factor determining recovery from neuromuscular blockade is the ability to metabolize and excrete the drugs. In patients with renal disease, the half-lives of d -tubocurarine, rocuronium, vecuronium, and pancuronium are prolonged. In such patients, alternative drugs such as cisatracurium, which is metabolized by Hoffman degradation and thus does not have a prolonged half-life in patients with renal dysfunction, should be considered. The sugammadex-neuromuscular blocking agent complex is excreted in the kidney. Therefore, complexes will persist longer in the circulation of patients with renal insufficiency. However, sugammadex binds neuromuscular binding agents irreversibly, so return of neuromuscular blockade is not a concern.