Case Study

An anxious 5-year-old child with chronic otitis media and a history of poorly controlled asthma presents for placement of ventilating ear tubes. General anesthesia is required for this short elective ambulatory surgery procedure. What preanesthetic medication should be administered? Which of the three commonly used anesthetic techniques would you choose to use in this situation: (1) inhalational anesthesia with sevoflurane for induction and maintenance in combination with nitrous oxide, (2) intravenous anesthesia with propofol for induction and maintenance of anesthesia in combination with remifentanil, or (3) balanced anesthesia using propofol for induction of anesthesia followed by a combination of sevoflurane and nitrous oxide for maintenance of anesthesia?

General Anesthetics: Introduction

The physiologic state induced by general anesthetics typically includes analgesia, amnesia, loss of consciousness, inhibition of sensory and autonomic reflexes, and skeletal muscle relaxation. The extent to which any individual anesthetic agent can produce these effects depends on the specific drug, the dosage, and the clinical situation.

An ideal anesthetic drug would induce a smooth and rapid loss of consciousness, while allowing for a prompt recovery after its administration is discontinued. The drug would also possess a wide margin of safety and be devoid of adverse effects. When used as the sole agent, none of the currently available anesthetic agents is capable of achieving all of these desirable effects. The modern practice of anesthesiology most commonly involves the use of combinations of intravenous and inhaled drugs (so-called balanced anesthesia techniques), which take advantage of the favorable properties of each agent while minimizing their adverse reactions.

The choice of anesthetic technique will vary according to the proposed type of diagnostic, therapeutic, or surgical intervention to be performed. For minor superficial surgical procedures, oral or parenteral sedatives are often used in combination with local anesthetics, so-called monitored anesthesia care techniques (see Chapter 26). These techniques provide profound analgesia, but with retention of the patient's ability to maintain a patent airway and to respond to verbal commands. For more extensive surgical procedures, anesthesia frequently includes preoperative benzodiazepines, induction of anesthesia with an intravenous anesthetic (eg, thiopental or propofol), and maintenance of anesthesia with a combination of inhaled (eg, volatile agents, nitrous oxide) and intravenous (eg, propofol, opioid analgesics) drugs.

Types of General Anesthesia

General anesthetics are typically administered by intravenous injection or by inhalation. For many years, inhalation anesthesia was used for all types of surgical procedures. Recently, intravenous anesthesia has become a more widely used technique around the world.

Intravenous Anesthetics

Several different classes of intravenous drugs are used, alone or in combination with other anesthetic and analgesic drugs, to achieve the desired anesthetic state. In addition, some of these drugs are used to sedate ventilator-dependent patients in intensive care units (ICUs). These drugs include the following: (1) barbiturates (eg, thiopental, methohexital); (2) benzodiazepines (eg, midazolam, diazepam); (3) propofol; (4) ketamine; (5) opioid analgesics (morphine, fentanyl, sufentanil, alfentanil, remifentanil); and (6) miscellaneous sedative-hypnotics (eg, etomidate, dexmedetomidine). Figure 25–1 shows the structures of some commonly used intravenous anesthetics.

Inhaled Anesthetics

The chemical structures of the currently available inhaled anesthetics are shown in Figure 25–2. The most commonly used inhaled anesthetics are isoflurane, desflurane, and sevoflurane. These compounds are volatile liquids that are aerosolized in specialized vaporizer delivery systems. Nitrous oxide, a gas at ambient temperature and pressure, continues to be an important adjuvant to the volatile agents. However, concerns about environmental pollution and its ability to increase the incidence of postoperative nausea and vomiting (PONV) have resulted in a significant decrease in its use.

Balanced Anesthesia

Although general anesthesia can be produced using only intravenous or only inhaled anesthetic drugs, modern anesthesia typically involves a combination of intravenous (eg, for induction of anesthesia) and inhaled (eg, for maintenance of anesthesia) drugs. However, volatile anesthetics (eg, sevoflurane) can also be used for induction of anesthesia, and intravenous anesthetics (eg, propofol) can be infused for maintenance of anesthesia. Muscle relaxants are commonly used to facilitate tracheal intubation and optimize surgical conditions during the operation (see Chapter 27). Local anesthetics are frequently administered by tissue infiltration and peripheral nerve blocks to provide perioperative analgesia (see Chapter 26). In addition, potent opioid analgesics and cardiovascular drugs (eg, blockers, ₂ agonists, calcium channel blockers) are used to control transient autonomic responses to noxious (painful) surgical stimuli.

Stages of Anesthesia

The traditional description of the various stages of anesthesia (the so-called Guedel's signs) were derived from observations of the effects of inhaled diethyl ether, which has a slow onset of central action owing to its high solubility in blood. Using these signs, anesthetic effects on the brain can be divided into four stages of increasing depth of central nervous system (CNS) depression:

I. Stage of analgesia: The patient initially experiences analgesia without amnesia. Later in stage I, both analgesia and amnesia are produced.

II. Stage of excitement: During this stage, the patient often appears to be delirious and may vocalize but is definitely amnesic. Respiration is irregular both in volume and rate, and retching and vomiting may occur if the patient is stimulated. For these reasons, efforts are made to limit the duration and severity of this light stage of anesthesia by rapidly increasing the concentration of the agent. This stage ends with the reestablishment of regular breathing.

III. Stage of surgical anesthesia: This stage begins with the recurrence of regular respiration and extends to complete cessation of spontaneous respiration (apnea). Four planes of stage III have been described in terms of changes in ocular movements, eye reflexes, and pupil size, which may represent signs of increasing depth of anesthesia.

IV. Stage of medullary depression: This deep stage of anesthesia includes severe depression of the CNS, including the vasomotor center in the medulla, as well as the respiratory center in the brain stem. Without circulatory and respiratory support, death rapidly ensues.

In current clinical anesthesia practice, the distinctive signs of each of the four stages just described are obscured because of the more rapid onset of action of modern intravenous and inhaled anesthetics (compared with ether), and the fact that the patient's ventilatory function is often controlled during the induction phase to accelerate the process. In addition, the practice of administering preanesthetic medications, as well as intraoperative opioid analgesics, muscle relaxants, and cardiovascular drugs, alters the clinical signs of anesthesia. Anticholinergic drugs (eg, atropine and glycopyrrolate) may be used to decrease oral and airway secretions and to treat bradycardia; however, they can also dilate the pupils. Muscle relaxants reduce muscle tone and prevent purposeful movements, whereas the opioid analgesics exert depressant effects on both the respiratory function and heart rate. The most reliable indication that stage III (ie, surgical anesthesia) has been achieved is loss of purposeful motor and autonomic responses to noxious stimuli (eg, trapezius muscle squeeze) and reestablishment of a regular respiratory pattern. The adequacy of the depth of anesthesia for a specific surgical procedure is assessed by monitoring changes in respiratory and cardiovascular responses to specific surgical stimuli, as well as changes in electroencephalographic, (EEG) based cerebral indices.

Although vital sign monitoring remains the most common method of assessing depth of anesthesia during surgery, newer techniques often involve computer-assisted monitoring of cerebral function using indices of EEG activity. These automated cerebral monitoring techniques use indices derived from EEG signals and include the bispectral index (BIS), auditory evoked potential (AEP), physical state index (PSI), cerebral state index (CSI), and state and response entropy (or irregularity) of EEG waveforms. The application of cerebral monitoring techniques has been shown to reduce the risk of intraoperative awareness (or recall) and decrease the anesthetic requirement, contributing to a more rapid emergence (ie, awakening) from general anesthesia.

Inhaled Anesthetics

Pharmacokinetics

Ensuring an adequate depth of anesthesia depends on achieving a therapeutic concentration of the anesthetic in the CNS. The rate at which an effective brain concentration is achieved (ie, time to induction of general anesthesia) depends on multiple pharmacokinetic factors that influence the brain uptake and tissue distribution of the anesthetic agent. The pharmacokinetic properties of the intravenous anesthetics (Table 25–1) and the physicochemical properties of the inhaled agents (Table 25–2) directly influence the pharmacodynamic effects of these drugs. These factors also influence the rate of recovery when the administration of anesthetic is discontinued.

Uptake & Distribution of Inhaled Anesthetics

The concentration of an inhaled anesthetic in a mixture of gases is proportional to its partial pressure (or tension). These terms are often used interchangeably in discussing the various transfer processes involving anesthetic gases within the body. Achievement of a brain concentration of an inhaled anesthetic necessary to provide an adequate depth of anesthesia requires transfer of the anesthetic from the alveolar air to the blood and from the blood to the brain. The rate at which a therapeutic concentration of the anesthetic is achieved in the brain depends primarily on the solubility properties of the anesthetic, its concentration in the inspired air, the volume of pulmonary ventilation, the pulmonary blood flow, and the partial pressure gradient between arterial and mixed venous blood anesthetic concentrations.

Solubility

One of the most important factors influencing the transfer of an anesthetic from the lungs to the arterial blood is its solubility characteristics (Table 25–2). The blood:gas partition coefficient is a useful index of solubility and defines the relative affinity of an anesthetic for the blood compared with that of inspired gas. The partition coefficients for desflurane and nitrous oxide, which are relatively insoluble in blood, are extremely low. When an anesthetic with low blood solubility diffuses from the lung into the arterial blood, relatively few molecules are required to raise its partial pressure, and therefore the arterial tension rises rapidly (Figure 25–3, top, nitrous oxide). Conversely, for anesthetics with moderate-to-high solubility (eg, halothane, isoflurane), more molecules dissolve before partial pressure changes significantly, and arterial tension of the gas increases less rapidly (Figure 25–3, bottom, halothane). This inverse relationship between the blood solubility of an anesthetic and the rate of rise of its tension in arterial blood is illustrated in Figure 25–4. Nitrous oxide, which possesses low solubility in blood, reaches high arterial tensions rapidly, which in turn results in rapid equilibration with the brain and fast onset of action. A rapid onset of anesthetic action is also characteristic of desflurane and, to a lesser extent, sevoflurane, because these newer volatile anesthetics have lower blood:gas partition coefficients than the traditional agents.

Anesthetic Concentration in the Inspired Air

The concentration of an inhaled anesthetic in the inspired gas mixture has direct effects on both the maximum tension that can be achieved in the alveoli and the rate of increase in its tension in arterial blood. Increases in the inspired anesthetic concentration increase the rate of induction of anesthesia by increasing the rate of transfer into the blood according to Fick's law (see Chapter 1). Advantage is taken of this effect in anesthetic practice with inhaled anesthetics that possess moderate blood solubility (eg, enflurane, isoflurane, and halothane). For example, a 1.5% concentration of isoflurane may be administered initially to increase the rate of rise in the brain concentration; the inspired concentration is subsequently reduced to 0.75–1% when an adequate depth of anesthesia is achieved. In addition, these moderately soluble anesthetics are often administered in combination with a less soluble agent (eg, nitrous oxide) to reduce the time required for loss of consciousness and achievement of a surgical depth of anesthesia.

Pulmonary Ventilation

The rate of rise of anesthetic gas tension in arterial blood is directly dependent on both the rate and depth of ventilation (ie, minute ventilation). The magnitude of the effect also varies according to the blood:gas partition coefficient. An increase in pulmonary ventilation is accompanied by only a slight increase in arterial tension of an anesthetic with low blood solubility (ie, low partition coefficient), but can significantly increase tension of agents with moderate-to-high blood solubility (Figure 25–5). For example, a fourfold increase in ventilation rate almost doubles the arterial tension of halothane during the first 10 minutes of administration but increases the arterial tension of nitrous oxide by only 15%. Therefore, hyperventilation increases the speed of induction of anesthesia with inhaled anesthetics that would normally have a slow onset. Depression of respiration by opioid analgesics slows the onset of anesthesia of inhaled anesthetics unless ventilation is manually or mechanically assisted.

Pulmonary Blood Flow

Changes in blood flow to and from the lungs influence transfer processes of the anesthetic gases. An increase in pulmonary blood flow (ie, increased cardiac output) slows the rate of rise in arterial tension, particularly for those anesthetics with moderate-to-high blood solubility. Increased pulmonary blood flow exposes a larger volume of blood to the anesthetic agent in the alveoli, thereby increasing the blood carrying capacity and decreasing the rate of rise in the anesthetic tension in the blood (and brain). A decrease in pulmonary blood flow has the opposite effect, increasing the rate of rise in the arterial tension of the inhaled anesthetic. In patients with circulatory shock, the combined effects of decreased cardiac output (resulting in decreased pulmonary flow) and increased ventilation will accelerate induction of anesthesia with halothane and isoflurane. However, this effect is much less important with the less soluble agents sevoflurane, nitrous oxide, and desflurane.

Arteriovenous Concentration Gradient

The anesthetic concentration gradient between arterial and mixed venous blood is dependent mainly on uptake of the anesthetic by the tissues, including nonneural tissues. Depending on the rate and extent of tissue uptake, venous blood returning to the lungs may contain significantly less anesthetic than arterial blood. The greater this difference in anesthetic gas tensions, the more time it will take to achieve equilibrium with brain tissue. Anesthetic entry into tissues is influenced by factors similar to those that determine transfer of the anesthetic from the lung to the intravascular space, including tissue:blood partition coefficients, rates of blood flow to the tissues, and concentration gradients.

During the induction phase of anesthesia (and the initial phase of the maintenance period), the tissues that exert greatest influence on the arteriovenous anesthetic concentration gradient are those that are highly perfused (eg, brain, heart, liver, kidneys, and splanchnic bed). These tissues receive over 75% of the resting cardiac output. In the case of volatile anesthetics with relatively high solubility in highly perfused tissues, venous blood concentration will initially be very low, and equilibrium with the arterial blood is achieved slowly.

During maintenance of anesthesia with inhaled anesthetics, the drug continues to be transferred between various tissues at rates dependent on the solubility of the agent, the concentration gradient between the blood and the tissue, and the tissue blood flow. Although muscle and skin constitute 50% of the total body mass, anesthetics accumulate more slowly in these tissues than in highly perfused tissues (eg, brain) because they receive only one-fifth of the resting cardiac output. Although most anesthetic agents are highly soluble in adipose (fatty) tissues, the relatively low blood perfusion to these tissues delays accumulation, and equilibrium is unlikely to occur with most anesthetics during a typical 1- to 3-hour operation.

Elimination

The time to recovery from inhalation anesthesia depends on the rate of elimination of the anesthetic from the brain. Many of the processes responsible for transfer of the anesthetic during the recovery phase are simply the reverse of those that occur during the introduction of the anesthetic agent. One of the most important factors governing rate of recovery is the blood:gas partition coefficient of the anesthetic agent. Other factors controlling rate of recovery include the pulmonary blood flow, the magnitude of ventilation, and the tissue solubility of the anesthetic. Two features of the recovery phase are different from induction of anesthesia. First, transfer of an anesthetic from the lungs to blood can be enhanced by increasing its concentration in inspired air, while the reverse transfer process cannot be enhanced because the concentration in the lungs cannot be reduced below zero. Second, at the beginning of the recovery phase, the anesthetic gas tension in different tissues may be quite variable, depending on the specific agent and the duration of anesthesia. In contrast, at the start of induction of anesthesia the initial anesthetic tension is zero in all tissues.

Inhaled anesthetics that are relatively insoluble in blood (ie, possess low blood:gas partition coefficients) and brain are eliminated at faster rates than the more soluble anesthetics. The washout of nitrous oxide, desflurane, and sevoflurane occurs at a rapid rate, leading to a more rapid recovery from their anesthetic effects compared with halothane and isoflurane. Halothane is approximately twice as soluble in brain tissue and five times more soluble in blood than nitrous oxide and desflurane; its elimination therefore takes place more slowly, and recovery from halothane- and isoflurane-based anesthesia is predictably less rapid.

The duration of exposure to the anesthetic can also have a significant effect on the recovery time, especially in the case of the more soluble anesthetics (eg, halothane and isoflurane). Accumulation of anesthetics in muscle, skin, and fat increases with prolonged exposure (especially in obese patients), and blood tension may decline slowly during recovery as the anesthetic is slowly eliminated from these tissues. Although recovery may be rapid even with the more soluble agents following a short period of exposure, recovery is slow after prolonged administration of halothane or isoflurane.

Clearance of inhaled anesthetics via the lungs is the major route of elimination from the body. However, hepatic metabolism may also contribute to the elimination of some volatile anesthetics. For example, the elimination of halothane during recovery is more rapid than that of enflurane, which would not be predicted from their respective tissue solubilities. However, over 40% of inspired halothane is metabolized during an average anesthetic procedure, whereas less than 10% of enflurane is metabolized over the same period. Oxidative metabolism of halothane results in the formation of trifluoroacetic acid and release of bromide and chloride ions. Under conditions of low oxygen tension, halothane is metabolized to the chlorotrifluoroethyl free radical, which is capable of reacting with hepatic membrane components and on rare occasion has resulted in halothane-induced hepatitis. Isoflurane and desflurane are the least metabolized of the fluorinated anesthetics with only trace concentrations of trifluoroacetic acid appearing in the urine even after prolonged administration.

The metabolism of enflurane and sevoflurane results in the formation of fluoride ion. However, in contrast to the rarely used volatile anesthetic methoxyflurane, renal fluoride levels do not reach toxic levels under normal circumstances. In addition, sevoflurane is degraded by contact with the carbon dioxide absorbent in anesthesia machines, yielding a vinyl ether called "compound A," which can cause renal damage if high concentrations are absorbed. (See Do We Really Need Another Inhaled Anesthetic?) Seventy percent of the absorbed methoxyflurane is metabolized by the liver, and the released fluoride ions can produce nephrotoxicity. In terms of the extent of hepatic metabolism, the rank order for the inhaled anesthetics is methoxyflurane > halothane > enflurane > sevoflurane > isoflurane > desflurane > nitrous oxide (Table 25–2). Nitrous oxide is not metabolized by human tissues. However, bacteria in the gastrointestinal tract may be able to break down the nitrous oxide molecule.

Pharmacodynamics

Mechanism of Action

Both the inhaled and the intravenous anesthetics can depress spontaneous and evoked activity of neurons in many regions of the brain. Older concepts of the mechanism of anesthesia evoked nonspecific interactions of these agents with the lipid matrix of the nerve membrane (the so-called Meyer-Overton principle)—interactions that were thought to lead to secondary changes in ion flux. More recently, evidence has accumulated suggesting that the modification of ion currents by anesthetics results from more direct interactions with specific nerve membrane components. The ionic mechanisms involved for different anesthetics may vary, but at clinically relevant concentrations they appear to involve interactions with members of the ligand-gated ion channel family.

In the past decade, considerable evidence has accumulated that a primary molecular target of general anesthetics is the GABA _A receptor-chloride channel, a major mediator of inhibitory synaptic transmission. Inhaled anesthetics, barbiturates, benzodiazepines, etomidate, and propofol facilitate GABA-mediated inhibition at GABA_A receptor sites. These receptors are sensitive to clinically relevant concentrations of the anesthetic agents and exhibit the appropriate stereospecific effects in the case of enantiomeric drugs. The GABA_A receptor-chloride channel is a pentameric assembly of five proteins derived from several polypeptide subclasses (see Chapter 22). Combinations of three major subunits—, , and —are necessary for normal physiologic and pharmacologic functions. GABA_A receptors in different areas of the CNS contain different subunit combinations, conferring different pharmacologic properties on each receptor subtype. Both inhaled and intravenous anesthetics with sedative-hypnotic properties directly activate GABA_A receptors, but at low concentrations they can also facilitate the action of GABA to increase chloride ion flux. In contrast, benzodiazepines that lack general anesthetic properties (eg, diazepam, lorazepam) facilitate GABA action but have no direct actions on GABA_A receptors even at high concentrations in the absence of GABA.

Reconstitution studies with transfected cells utilizing chimeric and mutated GABA_A receptors reveal that anesthetic molecules do not interact directly with the GABA binding site, but with specific sites in the transmembrane domains of both and subunits. Two specific amino acid residues in transmembrane segments 2 and 3 of the GABA_A receptor ₂ subunit, Ser270 and Ala291, are critical for the enhancement of GABA_A receptor function by volatile anesthetics. One consequence of the interaction of isoflurane with this domain is an alteration in the gating of the chloride ion channel. However, differences occur in the precise binding sites of individual anesthetics. For example, a specific aspartate residue within transmembrane segment 2 of the GABA_A receptor ₂ subunit is required for etomidate activity but is not essential for the activity of barbiturates or propofol.

Ketamine, a unique dissociate anesthetic with analgesic properties, does not produce its effects via facilitation of GABA_A receptor functions; rather its CNS activity appears to be related to antagonism of the action of the excitatory neurotransmitter glutamic acid on the N -methyl-D -apartate (NMDA) channel receptor. This receptor may also be a target for nitrous oxide.

In addition to their action on GABA_A chloride channels, certain general anesthetics have been reported to cause membrane hyperpolarization (ie, an inhibitory action) via their activation of potassium channels. These channels are ubiquitous in the CNS and some are linked to neurotransmitters, including acetylcholine, dopamine, norepinephrine, and serotonin. Electrophysiologic analyses of membrane ion flux in cultured cells have shown that inhaled anesthetics decrease the duration of opening of nicotinic receptor-activated cation channels—an action that decreases the excitatory effects of acetylcholine at cholinergic synapses. Most inhaled anesthetics inhibit nicotinic acetylcholine receptor isoforms, particularly those containing the ₄ subunit, though such actions do not appear to be involved in their immobilizing actions. The strychnine-sensitive glycinereceptor is another ligand-gated ion channel that may function as a target for inhaled anesthetics, which can elicit channel opening directly and independently of their facilitatory effects on neurotransmitter binding.

The neuropharmacologic basis for the CNS effects that characterize the various stages of anesthesia appears to be related to differential sensitivity of specific neurons or neuronal pathways to the anesthetic drugs. Neurons in the substantia gelatinosa of the dorsal horn of the spinal cord are very sensitive to even relatively low concentrations of anesthetic drugs. Interaction with neurons in this region interrupts sensory transmission in the spinothalamic tract, including transmission of nociceptive (pain) stimuli. These effects contribute to stage I analgesia and light or conscious sedation. The disinhibitory effects of general anesthetics (stage II), which occur at higher brain concentrations, result from complex neuronal actions, including blockade of many small inhibitory neurons such as Golgi type II cells, together with a paradoxical facilitation of excitatory neurotransmitters. A progressive depression of ascending pathways in the reticular activating system occurs during stage III of anesthesia; also occurring is suppression of spinal reflex activity, which contributes to muscle relaxation. Neurons in the respiratory and vasomotor centers of the medulla are relatively insensitive to the depressant effects of general anesthetics, but at high concentrations their activity is depressed, leading to cardiorespiratory collapse (stage IV). It remains to be determined whether regional variation in anesthetic actions corresponds to the regional variation in the distribution of GABA_A receptor subtypes within the brain. The differential sensitivity of specific neurons or neuronal pathways to anesthetics could reflect their interactions with other molecules in the fast ligand-gated ion channel family or could represent the existence of other molecular targets that have yet to be characterized.

Dose-Response Characteristics: The Concept of Minimum Alveolar Anesthetic Concentration & the Continuum of CNS Depression

Inhaled (volatile) anesthetics are delivered to the lungs in gas mixtures in which concentrations and flow rates are easy to measure and control. However, dose-response characteristics of volatile anesthetics are difficult to quantify. Although achievement of an anesthetic state depends on the concentration of the anesthetic in the brain (ie, at the effect site), concentrations in the brain tissue are obviously impossible to measure under clinical conditions. Furthermore, neither the lower nor the upper ends of the graded dose-response curve defining the effect on the central nervous system can be ethically determined because at very low gas concentrations awareness of pain may occur. Moreover, at high concentrations there is a high risk of severe cardiovascular and respiratory depression. Nevertheless, a useful estimate of anesthetic potency can be obtained using quantal dose-response principles for both the inhaled and intravenous anesthetics.

During inhalation anesthesia, the partial pressure of the inhaled anesthetic in the brain equals that in the lung when steady-state conditions are achieved. Therefore, at a given level (depth) of anesthesia, measurements of the steady-state alveolar concentrations of different anesthetics provide a comparison of their relative potencies. The volatile anesthetic concentration is the percentage of the alveolar gas mixture, or partial pressure of the anesthetic as a percentage of 760 mm Hg (atmospheric pressure at sea level). The minimum alveolar anesthetic concentration (MAC ) is defined as the median concentration that results in immobility in 50% of patients when exposed to a noxious stimulus (eg, surgical incision). Therefore, the MAC represents one point (the ED₅₀) on a conventional quantal dose-response curve (see Figure 2–16) and is considered a surrogate measure of the anesthetic requirement. Table 25–2 shows MAC values of the inhaled anesthetics, permitting comparison of their relative anesthetic potencies. The MAC value greater than 100% for nitrous oxide demonstrates that it is the least potent inhaled anesthetic. At normal barometric pressure, even 760 mm Hg partial pressure of nitrous oxide (100% of the inspired gas) is still less than 1 MAC; therefore, it must be supplemented with other agents to achieve full surgical anesthesia (see below).

The dose of anesthetic gas that is being administered can be stated in multiples of MAC. A dose of 1 MAC of any anesthetic prevents movement in response to surgical incision in 50% of patients; however, individual patients may require 0.5–1.5 MAC. Unfortunately, MAC gives no information about the slope of the dose-response curve. In general, however, the dose-response relationship for inhaled anesthetics is very steep. Therefore, over 95% of patients may fail to respond to a noxious stimulus at 1.1 MAC.

The measurement of MAC values under controlled conditions has permitted quantitation of the effects of a number of variables on anesthetic requirements. For example, MAC values decrease in elderly patients and with hypothermia, but are not affected greatly by sex, height, and weight. Chronic use of centrally active drugs, alcohol abuse, and pregnancy increase the anesthetic requirement. Of particular importance is the presence of adjuvant drugs, which can change anesthetic requirement significantly. When intravenous drugs (eg, opioid analgesics, sympatholytics, or sedative-hypnotics) are administered as adjuvants to the volatile anesthetics, MAC is decreased in a dose-related fashion. The inspired concentration of anesthetic should be decreased in these situations.

MAC values of the inhaled anesthetics are additive. For example, nitrous oxide (60–70%) can be used as a carrier gas producing 40% of a MAC, thereby decreasing the anesthetic requirement of both volatile and intravenous anesthetics. The addition of nitrous oxide (60% tension, 40% MAC) to 70% of a volatile agent's MAC would yield a total of 110% of a MAC, a value sufficient for surgical anesthesia in most patients.

The intravenous anesthetics produce a similar dose-dependent continuum of CNS depression. At low concentrations of these agents, they produce anxiolytic (ie, reductions in anxiety) and light levels of sedation. As the concentration is increased, they produce a progressively increasing depth of sedation. At deep levels of sedation these sedative-hypnotic drugs produce a state resembling general anesthesia. The slopes of their dose-response curves may vary even within the same drug class. For example, midazolam has a much steeper dose-response curve than diazepam. In addition, the barbiturates, etomidate, and propofol all have steeper dose response curves than the benzodiazepines.

Organ System Effects of Inhaled Anesthetics

Effects on the Cardiovascular System

Halothane, desflurane, enflurane, sevoflurane, and isoflurane all decrease mean arterial pressure in direct proportion to their alveolar concentration. With halothane and enflurane, the reduced arterial pressure appears to be caused by a reduction in cardiac output because there is little change in systemic vascular resistance despite marked changes in individual vascular beds (eg, an increase in cerebral blood flow). In contrast, isoflurane, desflurane, and sevoflurane have a depressant effect on arterial pressure as a result of a decrease in systemic vascular resistance with minimal effect on cardiac output.

Inhaled anesthetics change heart rate either directly by altering the rate of sinus node depolarization or indirectly by shifting the balance of autonomic nervous system activity. Bradycardia can be seen with halothane, probably because of direct vagal stimulation. In contrast, enflurane, and sevoflurane have little effect, and both desflurane and isoflurane increase heart rate. In the case of desflurane, transient sympathetic activation with elevations in catecholamine levels can lead to marked increases in heart rate and blood pressure when high inspired gas concentrations are administered.

All inhaled anesthetics tend to increase right atrial pressure in a dose-related fashion, which reflects depression of myocardial function. In general, enflurane and halothane have greater myocardial depressant effects than isoflurane and the newer, less soluble halogenated anesthetics. Inhaled anesthetics reduce myocardial oxygen consumption, primarily by decreasing the variables that control oxygen demand, such as arterial blood pressure and contractile force (see Chapter 12). Although it produces less depression than the volatile anesthetics, nitrous oxide has also been found to depress the myocardium in a concentration-dependent manner. However, administration of nitrous oxide in combination with the more potent inhaled (volatile) anesthetics can minimize cardiac depressant effects owing to its anesthetic-sparing effect.

Several factors influence the cardiovascular effects of inhaled anesthetics. Surgical stimulation, intravascular volume status, ventilatory status, and duration of anesthesia alter the cardiovascular depressant effects of these drugs. Hypercapnia releases catecholamines, which attenuate the decrease in blood pressure. As a result, the blood pressure decrease after 5 hours of anesthesia is less than it is after 1 hour; however, concomitant use of blockers reduces this adaptive effect. Halothane and, to a lesser extent, isoflurane sensitize the myocardium to circulating catecholamines. Ventricular arrhythmias may occur in patients with cardiac disease who are given sympathomimetic drugs or have high circulating levels of endogenous catecholamines (eg, anxious patients, use of epinephrine-containing local anesthetics, inadequate intraoperative anesthesia or analgesia, and patients with pheochromocytomas). However, the less soluble inhaled anesthetics sevoflurane and desflurane are less likely to produce arrhythmias.

Effects on the Respiratory System

With the exception of nitrous oxide, all inhaled anesthetics in current use cause a dose-dependent decrease in tidal volume and an increase in respiratory rate. However, the increase in respiratory rate is insufficient to compensate for the decrease in volume, resulting in a decrease in minute ventilation. All volatile anesthetics are respiratory depressants, as indicated by a reduced response to increased levels of carbon dioxide. The degree of ventilatory depression varies among the volatile agents, with isoflurane and enflurane being the most depressant. All volatile anesthetics in current use increase the resting level of PaCO₂ (the partial pressure of carbon dioxide in arterial blood).

Volatile anesthetics increase the apneic threshold (PaCO₂ level below which apnea occurs through lack of CO₂-driven respiratory stimulation) and decrease the ventilatory response to hypoxia. The latter effect is especially important because subanesthetic concentrations during the early recovery period can depress the normal compensatory increase in ventilation that occurs during hypoxic states. The respiratory depressant effects of anesthetics are overcome by assisting (or controlling) ventilation mechanically. Furthermore, the ventilatory depressant effects of inhaled anesthetics are counteracted by surgical stimulation.

Inhaled anesthetics also depress mucociliary function in the airway. Thus, prolonged anesthesia may lead to pooling of mucus and then result in atelectasis and postoperative respiratory infections. However, volatile anesthetics possess varying degrees of bronchodilating properties, an effect of value in the treatment of active wheezing and status asthmaticus. The bronchodilating action of halothane and sevoflurane makes them the induction agents of choice in patients with underlying airway problems (eg, asthma, bronchitis, chronic obstructive pulmonary disease). Airway irritation, which may provoke coughing or breath-holding, is rarely a problem with halothane and sevoflurane. However, the pungency of desflurane makes this agent less suitable for induction of anesthesia despite its low blood:gas partition coefficient.

Effects on the Brain

Inhaled anesthetics decrease the metabolic rate of the brain. Nevertheless, the more soluble volatile agents increase cerebral blood flow because they decrease cerebral vascular resistance. The increase in cerebral blood flow is clinically undesirable in patients who have increased intracranial pressure because of a brain tumor or head injury. Volatile anesthetic-induced increases in cerebral blood flow increase cerebral blood volume and further increase intracranial pressure.

Of the inhaled anesthetics, nitrous oxide is the least likely to increase cerebral blood flow. At low concentrations, all of the halogenated agents have similar effects on cerebral blood flow. However, at higher concentrations, the increase in cerebral blood flow is less with the less soluble agents such as desflurane and sevoflurane. If the patient is hyperventilated before the volatile agent is started, the increase in intracranial pressure can be minimized.

Halothane, isoflurane, and enflurane have similar depressant effects on the EEG up to doses of 1–1.5 MAC. At higher doses, the cerebral irritant effects of enflurane may lead to development of a spike-and-wave pattern and mild generalized muscle twitching (ie, myoclonic activity). However, this seizure-like activity has not been found to have any adverse clinical consequences. Seizure-like EEG activity has also been described after sevoflurane, but not desflurane. Although nitrous oxide has a much lower anesthetic potency than the volatile agents, it does possess both analgesic and amnesic properties when used alone or in combination with other agents as part of a balanced anesthesia technique.

Effects on the Kidney

Depending on the concentration, volatile anesthetics decrease the glomerular filtration rate and renal blood flow, and increase the filtration fraction. Since renal blood flow decreases during general anesthesia in spite of well-maintained or even increased perfusion pressures (due to increased renal vascular resistance), autoregulation of renal flow may be impaired by these drugs.

Effects on the Liver

Volatile anesthetics cause a concentration-dependent decrease in hepatic blood flow ranging from 15% to 45% below the preinduction (baseline) value. Despite transient intraoperative changes in liver function tests, permanent changes in liver enzyme function are rare except following repeated exposures to halothane.

Effects on Uterine Smooth Muscle

Nitrous oxide appears to have little effect on uterine musculature. However, the halogenated anesthetics are potent uterine muscle relaxants and produce this effect in a concentration-dependent fashion. This pharmacologic effect can be used to advantage when profound uterine relaxation is required for an intrauterine fetal manipulation or manual extraction of a retained placenta during delivery. However, it can also lead to increased uterine bleeding.

Toxicity

Hepatotoxicity (Halothane)

Postoperative hepatic dysfunction is typically associated with factors such as blood transfusions, hypovolemic shock, and other surgical stresses rather than volatile anesthetic toxicity. However, a small subset of individuals who have been previously exposed to halothane may develop potentially life-threatening hepatitis. The incidence of severe hepatotoxicity following exposure to halothane is in the range of one in 20,000–35,000. Obese patients who have had more than one exposure to halothane during a short time interval may be the most susceptible. There is no specific treatment for halothane hepatitis, and therefore liver transplantation may ultimately be required in the most severe cases.

The mechanisms underlying hepatotoxicity from halothane remain unclear, but studies in animals have implicated the formation of reactive metabolites that either cause direct hepatocellular damage (eg, free radicals) or initiate immune-mediated responses. With regard to the latter mechanism, serum from patients with halothane hepatitis contains a variety of autoantibodies against hepatic proteins. Trifluoroacetylated (TFA) proteins in the liver could be formed in the hepatocyte during the biotransformation of halothane by liver drug-metabolizing enzymes. It is interesting that TFA proteins have also been identified in the sera of patients who did not develop hepatitis after halothane anesthesia.

Nephrotoxicity

Metabolism of methoxyflurane, enflurane, and sevoflurane leads to the formation of fluoride ions, and this has raised questions concerning the potential nephrotoxicity of these three volatile anesthetics. Changes in renal concentrating ability have been observed with prolonged exposure to both methoxyflurane and enflurane but not sevoflurane. Differences between the agents may be related to the fact that methoxyflurane and enflurane (but not sevoflurane) are metabolized in part by renal enzymes (eg, -lyase), generating fluoride ions intrarenally. Sevoflurane degradation by carbon dioxide absorbents in anesthesia machines leads to formation of a haloalkene, compound A, which is metabolized by renal -lyase to form thioacylhalide and causes a proximal tubular necrosis when administered to rats. However, there have been no reports of renal injury in humans receiving sevoflurane anesthesia. Moreover, the anesthetic does not appear to change standard markers of renal function. Renal dysfunction following methoxyflurane is caused by inorganic fluoride released during the extensive metabolism of this anesthetic by hepatic and renal enzymes. As a result, methoxyflurane, though still available, is no longer used in clinical practice.

Malignant Hyperthermia

Malignant hyperthermia is an autosomal dominant genetic disorder of skeletal muscle that occurs in susceptible individuals undergoing general anesthesia with volatile agents and muscle relaxants (eg, succinylcholine). The malignant hyperthermia syndrome consists of the rapid onset of tachycardia and hypertension, severe muscle rigidity, hyperthermia, hyperkalemia, and acid-base imbalance with acidosis that follows exposure to one or more of the triggering agents (see Table 16–4). Malignant hyperthermia is a rare but important cause of anesthetic morbidity and mortality. The specific biochemical abnormality is an increase in free calcium concentration in skeletal muscle cells. Treatment includes administration of dantrolene (to reduce calcium release from the sarcoplasmic reticulum) and appropriate measures to reduce body temperature and restore electrolyte and acid-base balance (see Chapter 27).

Malignant hyperthermia susceptibility is characterized by genetic heterogeneity, and several predisposing clinical myopathies have been identified. It has been associated with mutations in the gene loci corresponding to the skeletal muscle ryanodine receptor (RyRl), the calcium release channel on the sarcoplasmic reticulum. Mutations in the RyRl gene are inherited as mendelian dominant characteristics. Other chromosomal loci for malignant hyperthermia susceptibility include mutant alleles of the gene encoding the ₁ subunit of the human skeletal muscle dihydropyridine-sensitive L-type voltage-dependent calcium channel. However, the genetic loci identified to date account for no more than 50% of malignant hyperthermia-susceptible individuals. Given the degree of genetic heterogeneity, it is premature to use genetic testing methods for malignant hyperthermia susceptibility. Currently, the most reliable test to establish such susceptibility is the in vitro caffeine-halothane contracture test using skeletal muscle biopsy tissue.

Chronic Toxicity

Mutagenicity

Under normal conditions, inhaled anesthetics (including nitrous oxide) are neither mutagens nor carcinogens in patients.

Carcinogenicity

Epidemiologic studies suggested an increase in the cancer rate in operating room personnel who were exposed to trace concentrations of anesthetic agents. However, no study has demonstrated the existence of a causal relationship between anesthetics and cancer. Many other factors might account for the questionably positive results seen after a careful review of epidemiologic data. Most operating rooms now use scavenging systems to remove trace concentrations of anesthetics released from anesthetic machines.

Effects on Reproductive Organs

The most consistent finding reported in surveys conducted to determine the reproductive success of female operating room personnel has been a questionably higher than expected incidence of miscarriages. However, there are several problems in interpreting these studies.

The association of obstetric problems with surgery and anesthesia in pregnant patients is also an important consideration. In the USA, at least 50,000 pregnant women each year undergo anesthesia and surgery for indications unrelated to pregnancy. The risk of abortion is clearly higher following this experience. It is not obvious, however, whether the underlying disease, surgery, anesthesia, or a combination of these factors is the cause of the increased risk.

Hematotoxicity

Prolonged exposure to nitrous oxide decreases methionine synthase activity and theoretically can cause megaloblastic anemia, a potential occupational hazard for staff working in inadequately ventilated dental operating suites.

Clinical Use of Inhaled Anesthetics

Volatile anesthetics are rarely used as the sole agents for both induction and maintenance of anesthesia except in children. Most commonly, they are combined with intravenous agents as part of a balanced anesthesia technique. Of the inhaled anesthetics, nitrous oxide, desflurane, sevoflurane, and isoflurane are the most commonly used in the USA. Use of less soluble volatile anesthetics (especially desflurane and sevoflurane) has increased during the last decade as more surgical procedures are performed on an ambulatory ("short-stay") basis. The low blood:gas coefficients of desflurane and sevoflurane afford a more rapid recovery and fewer postoperative adverse effects than halothane, enflurane, and isoflurane. Although halothane is still used in pediatric anesthesia, sevoflurane is rapidly replacing halothane in this setting. As indicated previously, nitrous oxide lacks sufficient potency to produce surgical anesthesia by itself and therefore is used with volatile or intravenous anesthetics to produce a state of balanced general anesthesia. Despite the obvious advantages of the less soluble inhaled anesthetics, there is reason to believe that better ones might be developed (see Do We Really Need Another Inhaled Anesthetic?).

Intravenous Anesthetics

In the last two decades there has been increasing use of intravenous anesthetics in anesthesia, both as adjuncts to inhaled anesthetics and as part of techniques that do not include any inhaled anesthetics (eg, total intravenous anesthesia). The properties of some of the commonly used intravenous anesthetics are summarized in Table 25–1. Unlike inhaled anesthetics, intravenous agents do not require specialized vaporizer equipment for their delivery or facilities for the disposal of exhaled gases. Intravenous drugs such as thiopental, methohexital, etomidate, ketamine, and propofol have an onset of anesthetic action faster than the most rapid inhaled agents (eg, desflurane and sevoflurane). Therefore, intravenous agents are commonly used for induction of general anesthesia.

Recovery is sufficiently rapid with most intravenous drugs to permit their use for short ambulatory (outpatient) surgical procedures. In the case of propofol, recovery times are similar to those seen with sevoflurane and desflurane. Although most intravenous anesthetics lack antinociceptive (analgesic) properties, their potency is adequate for short superficial surgical procedures when combined with nitrous oxide or local anesthetics, or both. Adjunctive use of potent opioids (eg, fentanyl, sufentanil or remifentanil; see Chapter 31) contributes to improved cardiovascular stability, enhanced sedation, and perioperative analgesia. However, opioid compounds also enhance the ventilatory depressant effects of the intravenous agents and increase postoperative emesis. Benzodiazepines (eg, midazolam, diazepam) have a slower onset and slower recovery than the barbiturates or propofol and are rarely used for induction of anesthesia. However, preanesthetic administration of benzodiazepines (eg, midazolam) can be used to provide anxiolysis, sedation, and amnesia when used as part of an inhalational, intravenous, or balanced anesthetic technique.

Barbiturates

The general pharmacology of the barbiturates is discussed in Chapter 22. Thiopental is a barbiturate commonly used for induction of anesthesia. Thiamylal is structurally almost identical to thiopental and has the same pharmacokinetic and pharmacodynamic profile.

After an intravenous bolus injection, thiopental rapidly crosses the blood-brain barrier and, if given in sufficient dosage, produces loss of consciousness in one circulation time. Similar effects occur with the shorter-acting barbiturate, methohexital. With both of these barbiturates, plasma:brain equilibrium occurs rapidly (< 1 minute) because of their high lipid solubility. Thiopental rapidly diffuses out of the brain and other highly vascular tissues and is redistributed to muscle and fat (Figure 25–6). Because of this rapid removal from brain tissue, a single dose of thiopental produces only a brief period of unconsciousness. Thiopental is metabolized at the rate of only 12–16% per hour in humans following a single dose and less than 1% of the administered dose of thiopental is excreted unchanged by the kidney.

With large doses (or a continuous infusion), thiopental produces dose-dependent decreases in arterial blood pressure, stroke volume, and cardiac output. These hemodynamic effects are due primarily to a myocardial depressant effect and increased venous capacitance; there is little change in total peripheral resistance. Thiopental is also a potent respiratory depressant, producing transient apnea and lowering the sensitivity of the medullary respiratory center to carbon dioxide.

Cerebral metabolism and oxygen utilization are decreased after barbiturate administration in proportion to the degree of cerebral depression. Cerebral blood flow is also decreased, but less than oxygen consumption. Because intracranial pressure and blood volume are not increased (in contrast to the volatile anesthetics), thiopental is a desirable drug for patients with cerebral swelling (eg, head trauma, brain tumors). Methohexital can cause central excitatory activity (eg, myoclonus) and has been useful for neurosurgical procedures involving ablation of seizure foci. However, it also has antiseizure activity and is the drug of choice for providing anesthesia in patients undergoing electroconvulsive therapy (ECT). Given its more rapid elimination, methohexital is also preferred over thiopental for short ambulatory procedures.

Barbiturates reduce hepatic blood flow and glomerular filtration rate, but these drugs produce no adverse effects on hepatic or renal function. Barbiturates can exacerbate acute intermittent porphyria by inducing the production of hepatic -aminolevulinic acid (ALA) synthase (see Chapter 22). On rare occasions, thiopental has precipitated porphyric crisis when used as an induction agent in susceptible patients.

Benzodiazepines

Diazepam, lorazepam, and midazolam are used for preanesthetic medication and as adjuvants during surgical procedures performed under local anesthesia. As a result of their sedative, anxiolytic, and amnestic properties, and their ability to control acute agitation, these compounds are considered to be the drugs of choice for premedication. (The basic pharmacology of benzodiazepines is discussed in Chapter 22.) Diazepam and lorazepam are not water-soluble, and their intravenous use necessitates nonaqueous vehicles, which cause pain and local irritation. Midazolam is water-soluble and is the benzodiazepine of choice for parenteral administration. It is important that the drug becomes lipid-soluble at physiologic pH and can readily cross the blood-brain barrier to produce its central effects.

Compared with the intravenous barbiturates and propofol, benzodiazepines produce a slower onset of CNS depressant effects, which reach a plateau at a depth of sedation that is inadequate for surgical anesthesia. Using large doses of benzodiazepines to achieve deep sedation prolongs the postanesthetic recovery period and can produce a high incidence of anterograde amnesia. Because it possesses sedative-anxiolytic properties and causes a high incidence of amnesia (> 50%), midazolam is frequently administered intravenously before patients enter the operating room. Midazolam has a more rapid onset, a shorter elimination half-life (2–4 hours), and a steeper dose-response curve than the other available benzodiazepines.

The benzodiazepine antagonist flumazenil can be used to accelerate recovery when excessive doses of intravenous benzodiazepines are administered (especially in elderly patients). However, reversal of benzodiazepine-induced respiratory depression is less predictable. The short duration of action (< 90 minutes) of flumazenil may necessitate multiple doses to prevent recurrence of the CNS depressant effects of the longer-acting benzodiazepines (eg, lorazepam, diazepam).

Opioid Analgesics

High doses of opioid analgesics have been used in combination with large doses of benzodiazepines to achieve a general anesthetic state, particularly in patients undergoing cardiac surgery or other major surgery when the patient's circulatory reserve is limited. Although intravenous morphine (1–3 mg/kg) was used many years ago, the high-potency opioids fentanyl (100–150 mcg/kg) and sufentanil (0.25–0.5 mcg/kg IV) have been used more recently in such patients (see Table 31–2). More recently also, remifentanil, a potent and extremely short-acting opioid, has been used to minimize residual ventilatory depression.

Despite the use of high doses of potent opioids for major cardiovascular surgical procedures, awareness during anesthesia and unpleasant postoperative recall can occur. Furthermore, high doses of opioids during surgery can cause chest wall (and laryngeal) rigidity, thereby acutely impairing ventilation, as well as increasing postoperative opioid requirements owing to the development of acute tolerance. Finally, recent studies have suggested that use of high (versus low) dose opioid-based anesthetic techniques may be associated with increased postoperative morbidity (eg, prolonged ventilatory support, gastrointestinal and bladder complications) and even increases in mortality after cardiac surgery. Therefore, lower doses of fentanyl and sufentanil have been used as an adjunct to both intravenous and inhaled anesthetics to provide perioperative analgesia. The shorter-acting alfentanil and remifentanil have been used as co-induction agents with intravenous sedative-hypnotic anesthetics because they have a rapid onset of action. Remifentanil is rapidly metabolized by esterases in the blood (not plasma cholinesterase) and muscle tissues, contributing to an extremely rapid recovery from its opioid effects. The metabolism of remifentanil is not subject to genetic variability, and the drug does not interfere with the clearance of other compounds metabolized by plasma cholinesterase (eg, esmolol, mivacurium, or succinylcholine). Opioid analgesics can also be administered in very low doses by the epidural and subarachnoid (spinal) routes of administration to produce postoperative analgesia. Fentanyl and droperidol (a butyrophenone related to haloperidol) administered together produce analgesia and amnesia and combined with nitrous oxide provide a state referred to as neuroleptanesthesia.

Propofol

Propofol (2,6-diisopropylphenol) has become the most popular intravenous anesthetic. Its rate of onset of action is similar to that of the intravenous barbiturates but recovery is more rapid and patients are able to ambulate earlier after general anesthesia. Furthermore, patients subjectively feel better in the immediate postoperative period because of the reduction in postoperative nausea and vomiting and a sense of well-being. Propofol is used for both induction and maintenance of anesthesia as part of total intravenous or balanced anesthesia techniques, and is the agent of choice for ambulatory surgery. Propofol has become increasingly popular for intravenous sedation in the operating room as part of a monitored anesthesia care technique and in diagnostic suites for procedural sedation. The drug is also effective in producing prolonged sedation in patients in critical care settings (see Sedation & Monitored Anesthesia Care). When administered by prolonged infusion for sedation or ventilatory management in the ICU, cumulative effects can lead to delayed arousal. In addition, prolonged administration of conventional emulsion formulations can elevate serum lipid levels. Prolonged use of high-dose propofol infusions for the sedation of critically ill young children has led to severe acidosis in the presence of respiratory infections and to possible neurologic sequelae upon withdrawal.

After intravenous administration of propofol, the distribution half-life is 2–8 minutes, and the redistribution half-life is approximately 30–60 minutes. The drug is rapidly metabolized in the liver at a rate ten times faster than that of thiopental. Propofol is excreted in the urine as glucuronide and sulfate conjugates, with less than 1% of the parent drug excreted unchanged. Total body clearance of the anesthetic is greater than hepatic blood flow, suggesting that its elimination includes extrahepatic mechanisms in addition to metabolism by liver enzymes. This property can be useful in patients with impaired ability to metabolize other sedative-anesthetic drugs.

Effects on respiratory function are similar to those of thiopental. At the usual anesthetic doses, propofol produces dose-related depression of central ventilatory drive and transient apnea. However, propofol causes a marked decrease in blood pressure during induction of anesthesia through decreased peripheral arterial resistance and venodilation. In addition, propofol has greater direct negative inotropic effects than other intravenous anesthetics. Pain at the site of injection is the most common adverse effect of bolus administration. Muscle movements, hypotonus, and (rarely) tremors have also been reported after prolonged use. Clinical infections due to bacterial contamination of the propofol emulsion have led to the addition of antimicrobial adjuvants (eg, ethylenediaminetetraacetic acid [EDTA] and sodium metabisulfite). Newer formulations of propofol have been developed that contain less lipid for prolonged administration (eg, Ampofol). However, pain on injection is increased when the lipid content is reduced. Admixture or pretreatment with lidocaine (20–50 mg) is the most effective approach to minimizing the pain on injection of propofol. A water-soluble prodrug of propofol, fospropofol, has recently been approved. This agent may ameliorate some of the problems associated with administration of propofol.

Etomidate

Etomidate is a carboxylated imidazole that can be used for induction of anesthesia in patients with limited cardiovascular reserve. Its major advantage over other intravenous anesthetics is that it causes minimal cardiovascular and respiratory depression. Etomidate produces a rapid loss of consciousness, with minimal hypotension even in elderly patients with poor cardiovascular reserve. The heart rate is usually unchanged, and the incidence of apnea is low. The drug has no analgesic effects, and coadministration of opioid analgesics is required to decrease cardiac responses during tracheal intubation and to lessen spontaneous muscle movements. Following an induction dose, initial recovery from etomidate is less rapid (< 10 minutes) compared with recovery from propofol.

Distribution of etomidate is rapid, with a biphasic plasma concentration curve showing initial and intermediate distribution half-lives of 3 and 29 minutes, respectively. Redistribution of the drug from brain to highly perfused tissues appears to be responsible for the relatively short duration of its anesthetic effects. Etomidate is extensively metabolized in the liver and plasma to inactive metabolites, with only 2% of the drug excreted unchanged in the urine.

Etomidate causes a high incidence of pain on injection, myoclonic activity, and postoperative nausea and vomiting. The involuntary muscle movements are not associated with electroencephalographic epileptiform activity. Etomidate may also cause adrenocortical suppression via inhibitory effects on steroidogenesis, with decreased plasma levels of cortisol after a single dose. Prolonged infusion of etomidate in critically ill patients may result in hypotension, electrolyte imbalance, and oliguria because of its adrenal suppressive effects.

Ketamine

Ketamine is a racemic mixture of two optical isomers, S (+) and R (–) ketamine. The drug produces a dissociative anesthetic state characterized by catatonia, amnesia, and analgesia, with or without loss of consciousness (hypnosis). The drug is an arylcyclohexylamine chemically related to phencyclidine (PCP), a drug with a high abuse potential owing to its psychoactive properties. The mechanism of action of ketamine may involve blockade of the membrane effects of the excitatory neurotransmitter glutamic acid at the NMDA receptor subtype (see Chapter 21). Ketamine is a highly lipophilic drug and is rapidly distributed into well-perfused organs, including the brain, liver, and kidney. Subsequently ketamine is redistributed to less well perfused tissues with concurrent hepatic metabolism followed by both urinary and biliary excretion.

Ketamine is the only intravenous anesthetic that possesses both anesthetic and analgesic properties, as well as the ability to produce dose-related cardiovascular stimulation. Heart rate, arterial blood pressure, and cardiac output can be significantly increased above baseline values. These variables reach a peak 2–4 minutes after an intravenous bolus injection, then slowly decline to normal values over the next 10–20 minutes. Ketamine produces its cardiovascular effects by stimulating the central sympathetic nervous system and, to a lesser extent, by inhibiting the reuptake of norepinephrine at sympathetic nerve terminals. Increases in plasma epinephrine and norepinephrine levels occur as early as 2 minutes after an intravenous bolus of ketamine and return to baseline levels in less than 15 minutes.

Ketamine markedly increases cerebral blood flow, oxygen consumption, and intracranial pressure. Similar to the volatile anesthetics, ketamine is a potentially dangerous drug when intracranial pressure is elevated. Although ketamine decreases the respiratory rate, upper airway muscle tone is well maintained and airway reflexes are usually preserved.

Use of ketamine has been associated with postoperative disorientation, sensory and perceptual illusions, and vivid dreams (so-called emergence phenomena). Diazepam (0.2–0.3 mg/kg) or midazolam (0.025–0.05 mg/kg), as well as propofol (0.5–1 mg/kg IV), given before the administration of ketamine reduce the incidence of these adverse effects. Because of the high incidence of postoperative psychic phenomena associated with its use in high doses for induction of anesthesia (1–2 mg/kg IV), clinical use of ketamine fell into disfavor. However, use of low doses of ketamine (0.1–0.25 mg/kg IV) in combination with other intravenous and inhaled anesthetics has become an increasingly popular alternative to opioid analgesics to minimize ventilatory depression. In addition, ketamine is very useful for poor-risk geriatric patients and high-risk patients in cardiogenic or septic shock because of its cardiostimulatory properties. It is also used in low doses for outpatient anesthesia in combination with propofol (eg, as part of a monitored anesthesia care technique, see Sedation & Monitored Anesthesia Care) and in children undergoing painful procedures (eg, dressing changes for burns). In an effort to enhance ketamine's efficacy and reduce its side-effect profile, investigators separated the isomers and demonstrated that the S(+) ketamine possessed greater anesthetic and analgesic potency. However, even the S(+) isomer of ketamine possesses psychotomimetic side effects. Ketamine has also been compounded for topical use and this preparation is purportedly useful for some types of arthritic pain.

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References