General Anesthesia - Katzung Review

IV: 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).

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

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 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 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

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

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

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

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

Recovery:

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.

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.

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. 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. One of the possible new inhaled anesthetics that could be developed for clinical use in the future is xenon. However, the high cost of this novel drug may preclude its use in routine clinical practice.

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 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).

MAC values of the inhaled anesthetics are additive.

REgions

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.

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.

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 PaCO_2.

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.

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.

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. Seizure-like EEG activity has also been described after sevoflurane, but not desflurane.

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

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.

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.

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.

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.

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

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.

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.

OPIOIDs: 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.

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.

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 (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.

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).

Many diagnostic and minor therapeutic surgical procedures can be performed without general anesthesia using sedation-based anesthetic techniques. In this setting, regional or local anesthesia supplemented with midazolam or propofol and opioid analgesics (or ketamine) may be a more appropriate and safer approach than general anesthesia for superficial surgical procedures. This anesthetic technique is known as monitored anesthesia care. The technique typically involves the use of intravenous midazolam for premedication (to provide anxiolysis, amnesia, and mild sedation) followed by a titrated, variable-rate propofol infusion (to provide moderate to deep levels of sedation), and a potent opioid analgesic or ketamine (to minimize the discomfort associated with the injection of local anesthesia and the surgical manipulations).

Another approach, used primarily by nonanesthesiologists, is called conscious sedation. This technique refers to drug-induced alleviation of anxiety and pain in combination with an altered level of consciousness associated with the use of smaller doses of sedative medications. In this state the patient retains the ability to maintain a patent airway and is responsive to verbal commands. A wide variety of intravenous anesthetic drugs have proved to be useful drugs in conscious sedation techniques (eg, diazepam, midazolam, propofol). Use of benzodiazepines and opioid analgesics (eg, meperidine, fentanyl) in conscious sedation protocols has the advantage of being reversible by the specific receptor antagonist drugs (flumazenil and naloxone, respectively).

A specialized form of conscious sedation is occasionally required in the ICU, when patients are under severe stress and require mechanical ventilation for prolonged periods. In this situation, sedative-hypnotic drugs or low doses of intravenous anesthetics, neuromuscular blocking drugs, and dexmedetomidine may be combined. Dexmedetomidine is an ₂ agonist with sedative and analgesic effects. It has a half-life of 2–3 hours and is metabolized in the liver and excreted mainly as inactive urinary metabolites.

Deep sedation is similar to a light state of general (intravenous) anesthesia involving decreased consciousness from which the patient is not easily aroused. Because deep sedation is often accompanied by a loss of protective reflexes, an inability to maintain a patent airway, and lack of verbal responsiveness to surgical stimuli, this state may be indistinguishable from intravenous anesthesia. Intravenous agents used in deep sedation protocols include the sedative-hypnotics thiopental, methohexital, midazolam, or propofol, the potent opioid analgesics, and ketamine.

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.

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. investigators separated the isomers and demonstrated that the S(+) ketamine possessed greater anesthetic and analgesic potency