The most useful definition of dose for inhaled anesthetics is the partial pressure in alveoli, which can be monitored in end-tidal gases.
All halogenated anesthetics decompose when they contact desiccated alkaline chemicals in CO2 adsorbents, producing carbon monoxide (CO) and heat. Proper use and maintenance of anesthesia equipment and less-alkaline CO2 adsorbents reduce potential harm to patients.
The rate at which the alveolar anesthetic concentration (FA or Palv) approaches the inspired (circuit) concentration (FI or Pcirc) depends on FI (the concentration effect), minute alveolar ventilation (increased ventilation accelerates equilibration), cardiac output (increased output slows equilibration), and the anesthetic blood-gas partition coefficient (high solubility slows equilibration).
Nitrous oxide (N2O) diffuses into air-filled spaces in the body, causing expansion, increased pressure, or both.
The minimum alveolar concentration (MAC) is the alveolar concentration of inhaled anesthetic that blocks movement in half of subjects in response to a surgical incision. MAC is influenced by age, pharmacologic, physiologic, and genetic factors.
MAC-awake is the alveolar concentration of anesthetic causing loss of response to verbal commands in half of subjects. Amnesia is produced by inhalational anesthetic concentrations lower than MAC-awake.
Awareness and explicit recall of intraoperative events are attributable to inadequate delivery of anesthetics for the patient’s needs. Without preventive measures, awareness during anesthesia occurs in about 1 of 750 patients, and about 1% of patients are at high risk for this complication. Intraoperative awareness may cause psychological disturbances leading to post-traumatic stress disorder.
All potent volatile anesthetics in current use decrease mean arterial pressure in a dose-dependent manner. Severe cardiovascular and respiratory depression can occur even at low volatile anesthetic concentrations in elderly, hypovolemic, or critically ill patients. Avoidance of these toxicities requires vigilant monitoring and anticipation of anesthetic requirements.
Volatile anesthetics all attenuate baroreceptor reflex control to a varying degree and may increase heart rate, by both indirect and direct vagolytic effect on the heart.
Volatile anesthetics tend to increase the respiratory rate and decrease tidal volume and blunt ventilatory responses to hypercapnia and hypoxia.
Desflurane is very pungent and associated with airway irritability, bronchoconstriction, and laryngospasm when used for induction. Among volatile anesthetics, sevoflurane causes the least amount of airway irritation.
Volatile anesthetics inhibit cerebrovascular autoregulation by vasodilating vessels, increasing blood flow and potentially intracranial pressure. Cerebrovascular responses to altered Pco2 are maintained. Cerebral metabolic oxygen consumption is reduced by volatile anesthetics and increased by N2O.
Halothane undergoes the most hepatic metabolism of the inhaled agents. Whereas enflurane, isoflurane, and sevoflurane are also metabolized in the liver, desflurane and nitrous oxide are minimally metabolized. The oxidative metabolism of halothane and other volatile agents can induce severe immune-mediated hepatitis.
All potent volatile agents may trigger malignant hyperthermia in susceptible individuals.
Preclinical evidence suggests that volatile anesthetics exert neurotoxic effects that may impair cognitive development in the very young or accelerate cognitive decline in the elderly. However, definitive clinical evidence of significant sequelae remains absent, while ongoing prospective trials are expected to clarify the risks.
Experimentation with inhalation of gases and vapors for the purpose of obtunding the distress associated with surgery began in the nineteenth century. The administration of inhaled anesthetics spread rapidly after the successful public demonstration of ether anesthesia by William TG Morton on October 16, 1846, at Massachusetts General Hospital in Boston.
Inhaled agents were the sole means of reliably inducing general anesthesia until the development of intravenous (IV) delivery techniques and drugs. Inhalants continue to be used in a large fraction of general anesthetics because of their ease of use and predictable effects. The inhalational route of administration is almost always available, and the same route is used for drug removal, requiring no metabolic clearance (indeed, inhaled anesthetic metabolism is associated with toxicity). Modern equipment for administration of inhaled anesthetics is simple and robust, providing an elegant method for inducing, maintaining, and reversing general anesthesia. Furthermore, monitoring inhaled anesthetic concentrations in end-tidal gases provides an estimate of drug concentrations in the circulating blood and central nervous system (CNS). This ability to assess drug concentrations in the body reduces pharmacokinetic uncertainty when determining how much inhaled vapor to administer.
PURPOSE AND SCOPE OF THIS CHAPTER
This chapter describes the chemical and biophysical properties of commonly used inhaled anesthetics and relates these properties to their clinical pharmacology. Physicochemical properties of inhaled drugs influence their stability, rate of pulmonary uptake, distribution to various body compartments, elimination, and metabolism (pharmacokinetics), as well as clinically important differences among their therapeutic actions and toxicities (pharmacodynamics). Understanding these pharmacologic relationships is crucial for the safe and effective delivery of inhaled anesthetics. An understanding of inhaled anesthetic pharmacology must begin with clear definitions of both the drug amount (dosage) and important effects (response).
ANESTHETIC DOSE-RESPONSE CONCEPTS
The “dosage” of an inhaled anesthetic can be a confusing concept. The dosage of an inhaled anesthetic documented in an anesthetic record is frequently the delivered gaseous concentration (in percentage of total gas) in the vaporizer outflow (ie, fresh gas). Dosage may also be defined as the inspired concentration of inhaled anesthetic in the breathing circuit or, analogous to injected drugs, as the amount absorbed by the body via the lungs. However, these definitions are of limited use because several factors, including ambient atmospheric pressure, fresh gas flow (FGF) rate, minute ventilation, and the rate of uptake into the blood via the lungs, determine how these various “doses” affect patients. The most informative and practical definition of dosage for inhaled anesthetic drugs is the partial pressure in alveolar gas, which is approximated in end-expiratory gas. The partial pressure of an inhaled drug is directly proportional to its fractional concentration in a gas mixture (Dalton’s law) and is measured on an absolute scale of pressure (see the section Biophysical Properties of Inhaled Anesthetics).
The common effects that all general anesthetics reversibly induce are hypnosis (loss of perceptive awareness), amnesia (anterograde loss of memory), and ablation of movement in response to pain (inhibition of nociceptive reflexes).1 These therapeutic actions, which define the state of general anesthesia, are all mediated by the CNS (brain and spinal cord). Some anesthetics can provide additional therapeutic actions, such as analgesia, attenuation of autonomic reflexes, and protection of the heart and brain from ischemia and reperfusion. In addition, the nontherapeutic effects of anesthetics (side effects) must be considered because these often influence the choice of anesthetic drug and dosage, depending on the specific clinical setting.
CHEMICAL AND PHYSICAL PROPERTIES OF INHALED ANESTHETICS
The structures of various inhaled anesthetics, in three chemical categories, are depicted in Figure 34-1. Three inhaled anesthetics (nitrous oxide [N2O], diethyl ether, and chloroform) were used in the nineteenth century. In the early twentieth century, more inhaled anesthetics were identified, including ethylene, ethyl chloride, and cyclopropane. Of these, only N2O remains in use. The other early inhaled anesthetics in use up to 1950 were combustible, occasionally resulting in catastrophic outcomes for both patients and caregivers.2 The chemical and physical properties of the gaseous and volatile anesthetics currently available for clinical use (N2O, isoflurane, enflurane, halothane, desflurane, and sevoflurane) are summarized for comparison in Table 34-1.
Structures of inhaled anesthetics. Of note, three different classes of inhaled anesthetics were identified in the nineteenth century.
Table 34-1Physicochemical Properties of Inhaled Anesthetics ||Download (.pdf) Table 34-1 Physicochemical Properties of Inhaled Anesthetics
|Property ||N2O ||Isoflurane ||Enflurane ||Halothane ||Desflurane ||Sevoflurane |
|Molecular weight ||44 ||184.5 ||184.5 ||197.4 ||168 ||200.1 |
|Boiling point (°C/°F) ||88.5/–127.3 ||48.5/119.3 ||56.5/133.7 ||50.2/122.4 ||22.8/74.3 ||58.6/137.5 |
|Density (g/mL) ||1.84 × 10–3 (gas) ||1.5 ||1.52 ||1.86 ||1.45 ||1.50 |
|Vapor pressure at 20°C (mm Hg) ||43 879 (gas) ||238 ||175 ||243 ||664 ||157 |
|Oil-gas partition coefficient at 37°C ||1.3 ||90.8 ||96.5 ||197 ||19 ||47–54 |
Nitrous oxide is an inorganic gas at normal ambient temperature and pressure. N2O has no odor or taste. The boiling point of N2O is –88.5°C. At room temperature (25°C), N2O condenses into a liquid at 745 psi (50 atm), enabling economical storage and transport of large quantities in pressurized cylinders. A room temperature cylinder will display a pressure near 745 psi as long as liquid N2O remains. The pressure will decrease if the temperature of the liquid drops or if the tank is completely depleted of liquid and nearly empty. Pressure within the cylinder may decrease during rapid delivery of N2O as vaporization absorbs heat, cooling the tank and its contents. The amount of N2O remaining in the cylinder can only be determined by its weight, not by a pressure reading. The use of N2O during surgery with electrocautery or lasers can support combustion of ignited flammable materials.
Nitrous oxide produces analgesia, yet it has low potency as an anesthetic. It must be delivered at nearly 0.7 atm (530 mm Hg) to ablate awareness in half of patients, and preventing movement during an incision would require more than 1 atm in most patients. Therefore, N2O is frequently used in combination with other inhaled or intravenous anesthetic agents.
In the midtwentieth century, efforts to develop safer inhaled anesthetics focused on reducing flammability by adding halogens (bromine, chlorine, and fluorine) to alkanes and ethers.3 Halothane is a halogenated alkane (CF3CHBrCl) that entered clinical use in 1956. It has a pleasant, nonpungent odor and is tolerated well during inhalation. Halothane is a liquid at room temperature and 1 atm pressure. Clinically used concentrations of halothane are not flammable, but higher concentrations (in anesthesia machines) can ignite. Halothane is slightly unstable, decomposing in the presence of light and oxygen. To prevent photooxidative breakdown, halothane is stored in dark glass bottles containing 0.01% thymol. Halothane undergoes significant metabolism in the liver (Table 34-2).
Table 34-2Biophysical and Pharmacokinetic and Pharmacodynamic Properties of Inhaled Anesthetics ||Download (.pdf) Table 34-2 Biophysical and Pharmacokinetic and Pharmacodynamic Properties of Inhaled Anesthetics
|Property ||N2O ||Isoflurane ||Enflurane ||Halothane ||Desflurane ||Sevoflurane |
|λblood/gas at 37°Ca ||0.47 ||1.4 ||1.8 ||2.5 ||0.45 ||0.65 |
|Blood Veff (L)b ||2.4 ||7.5 ||9.0 ||12.5 ||2.3 ||3.3 |
|λbrain/blood at 37°Ca ||1.1 ||1.6 ||1.4 ||1.9 ||1.3 ||1.7 |
|Brain Veff (L)b ||1.5 ||2.2 ||2.0 ||2.7 ||1.8 ||2.4 |
|τbrain/blood (min)c ||2.1 ||3.0 ||2.6 ||3.5 ||2.4 ||3.2 |
|λmuscle/blood at 37°Ca ||1.2 ||2.9 ||1.7 ||3.4 ||2 ||3.1 |
|Muscle Veff (L)b ||36 ||87 ||51 ||102 ||60 ||93 |
|τmuscle/blood (min)c ||62 ||147 ||87 ||174 ||103 ||159 |
|λfat/blood at 37°Ca ||2.3 ||45 ||36 ||51 ||27 ||48 |
|Fat Veff (L)b ||29.7 ||580 ||464 ||658 ||348 ||619 |
|τfat/blood (min)c ||126 ||2470 ||1976 ||2800 ||1482 ||2635 |
|MACd (% mm–1 Hg–1) in O2 ||105/800 ||1.28/9.7 ||1.58/12.0 ||0.75/5.7 ||6.0/45.6 ||2.05/15.6 |
|MACd (% mm–1 Hg–1) in 70%N2O/30%O2 ||— ||0.56/4.26 ||0.57/4.33 ||0.29/2.20 ||2.5/19 ||0.66/5.02 |
|MAC-awakee (% mm–1 Hg–1) ||71/540 ||0.43/3.27 ||0.51/3.88 ||0.41/3.21 ||2.4/19 ||0.63/4.79 |
|Metabolism (%) ||0 ||0.2 ||2.4 ||20 ||0.02 ||2-5 |
Enflurane and its structural isomer isoflurane were introduced to clinical practice in the 1970s. They are halogenated ethers that undergo much less metabolism and have faster onset and offset compared with halothane.
Enflurane (CHFClCF2OCHF2), while more pungent than halothane, is well tolerated for inhalation induction. It is a clear liquid with a vapor pressure of 175 mm Hg at 20°C.
Isoflurane (CF3CHClOCHF2) is a clear liquid with a vapor pressure of 238 mm Hg at 20°C. It is pungent and frequently stimulates coughing when inhaled.
Desflurane and sevoflurane, introduced in the 1990s, are ethers that are halogenated exclusively with fluorine. Both are less potent and less blood soluble than other halogenated anesthetics. Low blood solubility provides rapid pulmonary uptake and elimination, which is highly desirable in clinical settings where rapid onset and emergence from anesthesia are valued.
Desflurane (CF3CHFOCHF2) is extremely resistant to biodegradation. Desflurane has a high vapor pressure at 20°C (664 mm Hg) and boils at 22.8°C (73°F). To prevent boiling, desflurane is stored in special bottles with valves that only open when fitted into the filling port of a unique vaporizer. The desflurane vaporizer heats the anesthetic to 39°C to control its vapor pressure and delivery rate.4 Desflurane vapor is extremely pungent, frequently causing coughing and autonomic stimulation. Thus, inhalational induction with desflurane is best avoided.
Sevoflurane [(CF3)2CHOCH2F] is a clear liquid with a vapor pressure of 157 mm Hg at 20°C. Sevoflurane has a pleasant odor and low pungency, making it the current standard anesthetic for inhalational induction, particularly in infants and children.
BIOPHYSICAL PROPERTIES OF INHALED ANESTHETICS
The concepts of partial pressure and partition coefficients are central to understanding how gases distribute among various compartments in the body.
Partial pressure is the pressure exerted by one component of a gas mixture, in which the sum of all the partial pressures equals the total pressure (Dalton’s law). For example, air contains about 79% nitrogen (fraction of N2 = FN2 = 0.79) and 21% oxygen (FO2 = 0.21), so when barometric pressure is 1 standard atmosphere (PBar = 1 atm = 760 mm Hg), the partial pressure of N2, PN2 = 0.79 atm = 600 mm Hg and PO2 = 0.21 atm = 160 mm Hg. Near sea level, where atmospheric pressure is near 1 atm, the partial pressure (in atm) of a gas and its fractional concentration in a gas mixture can be used interchangeably. At high altitudes, where ambient pressure is lower, the partial pressures of nitrogen and oxygen in the air are reduced relative to those at sea level, while their fractional concentrations are the same. For example, in Denver (PBar = 630 mm Hg), PN2 = 500 mm Hg and PO2 = 130 mm Hg. Similarly, when used at high altitudes, gaseous anesthetics such as N2O exert a lower partial pressure (and have a reduced anesthetic effect) relative to the same fractional concentration at sea level.
Volatile anesthetic vapor pressure is the gaseous partial pressure at the liquid-gas interface, such as that in a vaporizer. Vapor pressure is a property of the anesthetic agent and rises with temperature but is independent of total ambient pressure. Thus, in relation to carrier gases, the fractional concentration of saturated volatile anesthetic in a vaporizer increases with altitude (Figure 34-2). When working at ambient pressures that differ significantly from sea level, anesthetists must adjust the delivered oxygen concentrations and vaporizer settings appropriately.
Vapor pressure, partial pressure, and concentration of inhaled anesthetics: The impact of atmospheric pressure on vaporizer output. Top. Variable bypass vaporizers are calibrated at 20°C and 1 atm (standard temperature and pressure). The partial pressure of isoflurane in the vaporization chamber is its vapor pressure, 238 mm Hg. Isoflurane vapor adds to the carrier gases (O2 and nitrous oxide [N2O]), and the sum of the partial pressures equals atmospheric pressure (~760 mm Hg at sea level) at all points in the flow path. With fresh gas flow of 3 L/min and the vaporizer set at 2.0%, the carrier flow through the vaporization chamber is 134 mL. About 61 mL/min of isoflurane vapor (0.34 mL/min liquid) is added to the carrier gases so that the output of the vaporizer after dilution is 3061 mL/min at 2.0% isoflurane (Piso = 15.2 mm Hg). Bottom. With the same flow and vaporizer settings in Denver (5280 ft elevation; ambient pressure, 630 mm Hg), isoflurane comprises a larger portion of the carrier gas mixture, and after dilution, the output of the vaporizer is 3081 mL/min at about 2.6% isoflurane. Thus, in Denver, the delivered concentration of isoflurane is 30% higher than that at sea level. However, the delivered partial pressure of isoflurane in Denver is 16.7 mm Hg, only 10% higher than that at sea level. Similarly, liquid isoflurane is vaporized at 0.37 mL/min in Denver, about 10% more than that at sea level. Because its partial pressure directly determines the uptake and effect of isoflurane on patients, only minor changes in vaporizer settings are required at high altitudes. Partial pressures of N2O and O2 carrier gases in Denver are about 17% lower than those at sea level. Thus, at similar carrier gas flows, N2O has a significantly reduced anesthetic action in Denver versus sea level. Moreover, the inspired O2 concentration in Denver should be increased to reduce the risk of hypoxia, so increasing the N2O concentration may not be possible.
Partial pressure is the driving force for the diffusion of gases across permeable barriers into other gases, liquids, or tissues. At equilibrium, the partial pressure of any gas is equal in all intercommunicating compartments within a closed system. In the operating room, intercommunicating compartments include the anesthesia machine, the breathing circuit, and the patient’s body, which is further compartmentalized. The partial pressure of an inhaled anesthetic is directly proportional to its concentration in certain compartments that may be liquid phase (eg, blood) or tissue (eg, brain), where concentration is usually defined as the weight, volume, or moles of drug per volume of liquid or tissue. Importantly, various liquids (eg, blood or cerebrospinal fluid) and tissues may contain vastly different anesthetic concentrations at the same partial pressure, depending on the solubility of the anesthetic gas in each liquid or tissue. This is quantitatively expressed by Henry’s law Cg = KH × Pg, where Cg is the concentration of a gas, KH is its solubility constant, and Pg is the partial pressure of the gas.
A partition coefficient is defined as the ratio of concentrations of an anesthetic in one compartment (gas, blood, or tissue) versus another intercommunicating compartment at equilibrium (ie, when anesthetic partial pressure is equal in both compartments). Partition coefficients therefore have no units. Another useful concept is that the partition coefficient represents the number of volumes of the reference phase (eg, gas) that contains the same amount of anesthetic as the second phase (eg, blood), which we call the effective volume (or relative volume) of the second phase (Figure 34-3; Table 34-2). The effective volume concept is similar to the distribution volume of injected drugs when calculating metabolic or renal clearance and helps illustrate why drug equilibration in different tissues takes vastly different amounts of time. Both blood-gas partitioning and tissue-blood partitioning (see Table 34-2) determine the distribution of inhaled anesthetics within the body.
Blood-gas partitioning of isoflurane. After equilibrating a sealed container containing blood and isoflurane in air, a sample of blood will contain 1.5 times the amount of isoflurane as an equal volume of air.
The blood solubility of inhaled anesthetics is another term for the blood-gas partition coefficient (λb/g). At equilibrium, the concentration (eg, volume of drug per volume of gas, liquid, or tissue = v/v) of halothane, enflurane, or isoflurane is higher in blood than in surrounding gases. That is, λb/g is greater than 1 (Table 34-2). In contrast, sevoflurane, desflurane, and N2O have low blood solubility, and λb/g values are lower than 1. Blood-gas partitioning varies depending on temperature, hematocrit, and the lipid content of blood. The solubility in liquids of most gases, including all the inhaled anesthetics, increases as temperature decreases.5 Blood cells and plasma contain protein and lipids, which bind anesthetics and increase their solubility. Thus, the blood solubility of inhaled anesthetics is reduced by hemodilution (decreased cell mass) and increased by hyperlipidemia after a fatty meal.6
In general, the solubility of inhaled anesthetics in tissues depends on the fractional lipid content7 because most anesthetics are highly lipophilic. Thus, the more potent volatile anesthetics, which are also the most oil soluble (based on the Meyer-Overton correlation), tend to partition avidly into fatty tissues (Table 34-2).
PHARMACOKINETICS: INHALED ANESTHETIC UPTAKE AND DISTRIBUTION
A MULTICOMPARTMENTAL KINETIC MODEL
The inflows and outflows between the anesthesia machine circuit and the patient’s lungs, blood, and tissues can be depicted as a cyclical multicompartmental system wherein the anesthetic partial pressure in upstream compartments drives anesthetic into or out of downstream compartment(s) (Figure 34-4). These compartments have different biophysical phases: gas in the anesthetic circuitry and airspace of the lung, liquid in blood, and mixed liquid and solid in organs and tissues.8 The model depicted in Figure 34-4 is complex and requires a computer to calculate how the anesthetic partial pressure in the various compartments changes over time (for details, see the legend of Figure 34-4). It is, however, relatively easy to understand how an anesthetic moves between a single upstream compartment and a downstream compartment (a two-compartment system).
A model for uptake and distribution of inhaled anesthetics. The schematic depicts the flow of anesthetic gas from the vaporizer to the breathing circuit, its transfer into blood via the lungs, and distribution to various tissues. The sizes of tissue compartments are drawn in general proportion to their effective volumes (Veff = Vanatomic × λtissue/blood), and arrows of different width indicate relative blood flows. A variety of mathematical models have been devised to quantitatively illustrate anesthetic flow and distribution, and most are elaborations on the model introduced in 1963 by Mapleson.254 The model shown here is not intended to replicate reality, although it approximates it and serves as a simple way of illustrating how the various input parameters (fresh gas flow [FGF], type of agent, vaporizer setting, minute ventilation, and cardiac output) affect the rate of gas uptake. The following differential equations were used to generate the uptake and clearance data displayed in figures throughout this chapter (V̇ is minute ventilation, Q̇ is cardiac output, and q̇ is tissue perfusion).
Transfer of anesthetic gas from one compartment to another (eg, from a vaporizer to the breathing circuit) is proportional to both the bulk carrier flow (FGF in this example) and the partial pressure difference (eg, Pdelivered – Pcircuit). As more anesthetic gas is transferred, the partial pressure difference between the compartments lessens, and the transfer rate slows. The time it takes a downstream compartment to equilibrate with its upstream anesthetic partial pressure is determined by its volume (or effective volume) and the bulk flow carrying anesthetic between the compartments.
Equilibration between upstream and downstream compartments is quantitatively described by an exponential equation (Eq. 34-1), characterized by a time constant (τ). After a period equal to a single time constant, the difference between upstream and downstream concentrations is reduced by about 63%. A general equation describing this is
(34-1) Pdownstream = Pupstream × (1 – e–t/τ)
where t is the elapsed time measured from when the anesthetic flow began. The time constant (τ) is directly proportional to the downstream compartment volume (V): If the volume of the receiving compartment doubles, τ doubles, and it takes twice as long for equilibration to occur. is inversely proportional to carrier flow (F): If the delivery flow doubles, τ halves and equilibration occurs twice as fast.
After five time constants elapse, anesthetic concentrations in upstream and downstream compartments differ by less than 1%. At this equilibrium state, the compartments have the same partial pressure of anesthetic, and no net anesthetic transfer between compartments occurs even though carrier flow continues.
Equilibration time is independent of the source partial pressure if it is low (however, see the discussion of the concentration effect that follows). The time, however, to reach a target partial pressure in the downstream compartment (eg, to reach a specific depth of anesthesia) will be shorter if the upstream partial pressure is higher. A common practice is to deliver potent volatile anesthetics at two to three times the target partial pressure (overpressure) to reduce the induction time. When the desired depth of anesthesia has been achieved, the vaporizer is reset to deliver a lower concentration to prevent overdosage.
THE INSPIRED PARTIAL PRESSURE OF ANESTHETIC GAS
The two-compartment equilibration model predicts how long it takes to “prime” a breathing circuit with anesthetic when preparing for a single-breath induction. The upstream source is the fresh gas output from a vaporizer (Pdelivered), the drug carrier is FGF, and the downstream compartment is the breathing circuit volume (Vcirc). The delivery of anesthetic is the product of the FGF and Pdelivered. The time needed to equilibrate the breathing circuit with the fresh gas mixture is determined by the ratio of Vcirc to FGF. High FGFs and low circuit volume in open-circuit delivery systems enable rapid control of the anesthetic concentration inhaled by the patient (Figure 34-5).
The impact of fresh gas flow (FGF) on the anesthetic concentration in the breathing circuit. A. The rise of anesthetic partial pressure follows a single exponential when there is only a single downstream compartment (the circuit). Anesthetic clearance from the circuit follows the same time course as its rise, depending on FGF. B. The rise of the inspired anesthetic (isoflurane in this example) partial pressure is slowed by uptake into the patient.
The most common breathing circuit configuration is a circle system that allows rebreathing of exhaled anesthetic gases while removing carbon dioxide. These circuits have total gas volumes of 6 to 8 L. If Vcirc is 6 L and FGF is 6 L/min, then τ = 1 minute, and about 5 minutes is needed to equilibrate the anesthetic concentration in the circuit with the vaporizer output. At FGF = 1 L/min, τ = 6 minutes, and a half hour is needed to fully equilibrate the circuit (Figure 34-5A).
We must further consider what happens if a patient is breathing the circuit gases when the vaporizer is turned on. In this case, uptake of anesthetic into the patient’s body reduces the rate of rise of anesthetic partial pressure in the breathing circuit (Figure 34-5B). These examples illustrate why a high FGF is most useful when rapid changes in inspired anesthetic concentration are needed, such as during induction and emergence. After the induction period, the rate of uptake of anesthetic into the patient slows, and if a rebreathing circuit is used, FGF can be reduced, usually in the range of 1 to 2 L/min. After FGF is reduced, modestly increasing the delivered anesthetic concentration helps maintain drug delivery to match the uptake of anesthetic into the body (Figure 34-6). Reducing FGF has economic, environmental, and medical benefits. Lower FGF results in lower usage of inhaled gases, reducing costs and adverse environmental effects. The patient’s airway humidity is also maintained, improving the clearance of bronchopulmonary secretions.
Lowering fresh gas flows (FGFs) after induction. After the initial rapid uptake of anesthetic, FGF may be dropped, reducing both drug delivery and waste. The decrease in anesthetic concentration that results is larger for highly soluble agents.
The extreme of low FGF is “closed-circuit” anesthesia, wherein almost all inhaled gases are rebreathed and fresh gas is delivered with only sufficient oxygen to replace that metabolized by the patient (about 0.25 L/min for a typical normothermic 70-kg adult), and anesthetic vapor is added to match uptake and maintain the level of anesthesia. The practice of closed-circuit anesthesia increases the risk of delivering a hypoxic gas mixture and should be based on detailed knowledge of anesthetic gas uptake into patients.9,10
THE ALVEOLAR PARTIAL PRESSURE OF ANESTHETIC GAS
The alveolar anesthetic partial pressure (Palv) is important because it is the upstream driving pressure that rapidly equilibrates with the blood, brain, and other highly perfused tissues (see following discussion) and because its level can be monitored in end-expired gases. Thus, Palv represents the most useful definition of inhaled anesthetic “dose.”
The anesthetic partial pressure in the breathing circuit:
(34-3) dPcirc/dt = FGF/ Vcirc × (Pdel – Pcirc) –V./Vcirc × (Pcirc – Palv)
The anesthetic partial pressure in alveolar gas:
(34-4) dPalv/dt = V̇/Vlung × (Pcirc – Palv) – (Q̇ × λb/g)/ Vlung × (Palv – Pmv)
Uptake into a specific tissue (i):
(34-5) dPi/dt = q̇1/(Vi × λi/b) × (Palv – Pi)
The anesthetic partial pressure in mixed venous blood:
VRG, vessel-rich group, including brain, heart, liver, kidneys.
Transfer of Anesthetic From the Breathing Circuit to Alveoli
The transfer of inhaled anesthetic from the breathing circuit into the airspace of the lungs depends on the minute alveolar ventilation rate (MV) and the partial pressure difference between the circuit (Pcirc) and the lung (Palv). Thus, hyperventilation speeds equilibration between the breathing circuit and alveoli. The impact of varying minute alveolar ventilation is illustrated in Figure 34-7.
The impact of minute ventilation on the alveolar anesthetic concentration. A. The rise of Palv is shown in the traditional manner, normalized to inspired concentration (Pcirc), which is constant only with very high fresh gas flows (FGFs) and no rebreathing. Increased minute ventilation (MV) accelerates the rise of Palv and increases clearance after delivery stops. B. Palv is shown normalized to the constant delivered anesthetic concentration. This illustration better reflects the rise of Palv during a typical induction when rebreathing occurs (FGF = 6 L/min).
It is traditional to illustrate uptake with Palv normalized to constant Pcirc (inspired), which represents the case of high-flow open-circuit anesthesia, wherein Pcirc ≈ Pdelivered. However, with a rebreathing circuit, as we have described, Pcirc/Pdelivered is not constant (Figure 34-5). In this instance, a more realistic illustration of how Palv varies over time is obtained by normalizing to Pdelivered, which is held constant in our uptake model calculations. The difference between open-circuit versus rebreathing models is illustrated in Figure 34-7. Comparing the two panels, it is apparent that Palv increases more slowly with moderate FGF using a rebreathing circuit, but the impact of changing minute ventilation is similar in both cases. For simplicity, we have adopted the traditional open-circuit model to illustrate the impact of other physiologic variables on anesthetic uptake (for washout in these figures, we have normalized to either Pdelivered or Pcirc just before the agent is turned off).
Anesthetic Uptake Into Pulmonary Blood
Alveolar anesthetic gases rapidly diffuse into pulmonary blood. The uptake into blood depends on blood solubility (the blood-gas partition coefficient, λb/g), the rate of pulmonary blood flow (usually similar to cardiac output), and the difference between Palv and that of mixed venous blood entering the lung (PMV). The highly blood-soluble anesthetics produce a slower rise of Palv relative to the inspired concentration (Pcirc) because more anesthetic needs to be transferred into blood before the blood compartment is “filled” (Figure 34-8). Stated another way, the effective volume of blood is larger for the more soluble anesthetics (see Table 34-2).
The impact of blood solubility on the alveolar anesthetic concentration. During induction, high blood solubility (high λb/g) results in a slow rise of Palv because a large fraction of alveolar anesthetic is taken up into blood. Conversely, low blood solubility results in rapid equilibration between alveolar and inspired anesthetic concentrations. The impact of λb/g on anesthetic clearance mirrors that on uptake. Des, desflurane; Enf, enflurane; Hal, halothane; Iso, isoflurane.
Increased cardiac output (pulmonary blood flow) slows the rise in Palv by more rapidly removing the anesthetic agent from alveolar gases, and decreasing cardiac output will accelerate the rise in Palv. This effect is most significant for the highly blood-soluble anesthetics because their greater uptake into blood more effectively reduces Palv. Changes in cardiac output cause smaller changes in the rate of rise of Palv for the less blood-soluble anesthetics, such as N2O and desflurane (Figure 34-9).
The impact of cardiac output (CO) on the alveolar anesthetic concentration. During induction, increased CO (pulmonary blood flow) results in a slower rise of Palv because uptake from the alveoli into pulmonary blood is accelerated. The dependence of the Palv rate of rise on CO is greatest for highly soluble anesthetics and minimal for insoluble drugs like nitrous oxide. The impact of CO on anesthetic clearance is similar to that on uptake.
The role of cardiac output in inhaled anesthetic uptake (and therefore inhalation induction) can seem counterintuitive. Increased cardiac output results in a more rapid delivery of anesthetic to the major sites of action in the nervous system, suggesting that anesthesia induction might be faster, not slower. The key to untangling this conundrum is to understand that during inhalation induction, Palv is the driving force for rapid anesthetic drug entry into the blood and nervous system. Because Palv increases more slowly when cardiac output increases, anesthetic partial pressures in the brain and spinal cord also increase more slowly. What happens to the “extra” anesthetic that is taken up via the lung when cardiac output rises? Muscle, which typically takes hours to equilibrate with Palv, receives most of the increased blood flow and absorbs most of the additional anesthetic agent.
In summary, the rate of equilibration between the alveolar partial pressure (Palv) and the inspired anesthetic partial pressure (Pcirc) depends on three factors we have reviewed so far: (1) minute alveolar ventilation (as minute ventilation increases, the lung more rapidly equilibrates with the circuit); (2) cardiac output (as cardiac output increases, uptake into the blood and tissues from alveoli slows the rate at which Palv rises); and (3) blood-gas partitioning (high λb/g increases uptake into blood, removing a larger fraction of anesthetic from the pulmonary airspace and slowing the rate at which Palv increases). A fourth factor is the inspired fraction of anesthetic (Fi): A very high anesthetic concentration can speed the rate of rise of Palv (FA/FI; see the Concentration Effect section that follows).
DISTRIBUTION OF INHALED ANESTHETICS IN BODY TISSUES
Mixed venous blood entering the pulmonary capillary bed rapidly equilibrates with the alveolar partial pressure of an inhaled anesthetic (Palv), so blood exiting from the pulmonary vein has a partial pressure close to Palv. Anesthetic is then distributed to various tissues via systemic arterial blood. Delivery of anesthetic to each tissue is determined by its blood flow, its anatomic volume, and its tissue-blood partition coefficient (Table 34-2). The effective volume (Veff) for uptake of anesthetic in a given tissue is the product of its anatomic volume and λtissue/blood. The time required for anesthetic partial pressure equilibration between blood and a given tissue decreases when tissue perfusion is high and increases when Veff is large (see Eq. 34-2).
Highly perfused tissues include the brain, spinal cord, kidney, liver, and heart, together comprising less than 10% of an adult’s body mass while receiving about 70% of the cardiac output at rest. Highly perfused tissues equilibrate within a few minutes with the arterial (alveolar) anesthetic partial pressure (Figure 34-10, Table 34-2). As a result, Palv, estimated in end-tidal gas concentration, is close to the partial pressures in brain and spinal cord, except when the anesthetic concentration in alveolar gas is changing rapidly.
Uptake of anesthetics into different tissues. The partial pressure of isoflurane in different tissue beds is depicted during induction with fresh gas flow (FGF) = 6 L/min, V. = 5 L/min, and Q̇ = 5 L/min. Note that the isoflurane partial pressure in highly perfused tissues (brain) closely matches that in alveoli except when Palv is changing very rapidly. Also note that the partial pressure of anesthetic in fat continues to rise after discontinuing isoflurane delivery, as long as Palv is greater than Pfat. V., minute alveolar ventilation; Q̇, cardiac output.
Muscle represents a large anatomic volume (average, 35%-40% of body mass), and the muscle-blood partition coefficient for all inhaled agents ranges from 1.2 to 3.1. Because muscle normally receives about 15% of cardiac output at rest, the anesthetic partial pressure in muscle rises slowly, and equilibration with Palv takes hours for most clinically used anesthetics (Table 34-2).
Fat receives less than 10% of cardiac output and represents about 25% of body mass in the average adult, with considerable variation. Potent volatile agents partition highly into fat (λfat/blood; range, 27-51), so the effective volume for uptake of volatiles into fat is extremely large (Table 34-2). Consequently, uptake of volatile anesthetics into fat is so slow that equilibration with Palv never occurs under normal clinical conditions. The only commonly used inhaled anesthetic with a low fat solubility is N2O (λfat/blood = 2.3), for which the equilibration time constant is about 2 hours.
The vessel-poor group of tissues include skin, ligaments, tendons, cartilage, and cortical bone. These represent about 14% of the average adult’s body mass, and they receive less than 2% of cardiac output. As a result, their contribution to anesthetic uptake is negligible.
OTHER FACTORS AFFECTING THE UPTAKE AND DISTRIBUTION OF INHALED ANESTHETICS
Intrapulmonary right-to-left shunts may be physiological or iatrogenic due to endobronchial intubation and one-lung ventilation. The resulting perfused but nonventilated lung regions do not participate in anesthetic uptake. These shunts slow the rate of uptake into blood, allowing Palv to increase more quickly, especially for highly blood-soluble anesthetics. At the same time, pulmonary shunting of mixed venous blood combines with blood from gas-exchanging lung regions entering the arterial circulation. As the fraction of pulmonary blood flow passing through right-to-left shunts increases, Part, the direct upstream anesthetic source for the nervous system, decreases relative to Palv. For the highly soluble anesthetics, the increased Palv somewhat compensates for admixing, and Part increases only slightly slower than normal (Figure 34-11). With less-soluble agents, the impact of a shunt on uptake from the lung (Palv) is smaller, and there is less compensation for admixing, more profoundly slowing the increase of Part.
The impact of pulmonary right-to-left shunting on alveolar and arterial anesthetic concentrations. The impact of a 30% right-to-left shunt was calculated using a modified model from Figure 34-4. Pulmonary right-to-left shunting reduces alveolar uptake, increasing Palv, and mixing of shunted blood results in a lower Part. However, the increased Palv compensates for admixing, so compared with the zero-shunt model, Part is only about 10% reduced by the 30% shunt.
Systemic arteriovenous (left-to-right) shunting causes the anesthetic partial pressure in mixed venous blood to increase rapidly, slowing the uptake of anesthetic agent from alveolar gas. Palv therefore increases more rapidly, compensating for the reduced uptake rate. Overall, arteriovenous shunting modestly increases the rate of increase of anesthetic partial pressures in alveoli and in highly perfused tissues.
Cardiac or systemic right-to-left shunting is rare and, overall effects on anesthetic uptake are influenced by shunt location, flow, and compensatory increases in cardiac output.
Anatomic and physiologic dead space (ventilated but nonperfused lung regions) effectively reduces alveolar ventilation relative to minute ventilation. This slows anesthetic uptake into blood, particularly for highly soluble drugs. However, the lack of anesthetic uptake from dead space results in a faster increase in Palv, partially compensating for reduced uptake.
Anesthetic-induced changes in cardiac and respiratory function affect the rate of anesthesia induction with volatile anesthetics. When spontaneous ventilation is maintained, the uptake of inhaled drug is reduced as anesthetic is absorbed, and minute ventilation decreases. Anesthetic depression of cardiac output is another dynamic factor altering both uptake and distribution of anesthetic, as discussed previously.
CONCENTRATION EFFECT AND SECOND GAS EFFECT
Nitrous oxide represents a special case in clinical anesthesia because it is often the major constituent of the inhaled gas mixture. When the inspired N2O concentration is high, the initial uptake of N2O from the alveolar gas is rapid. As large volumes of N2O move from the alveolar space into blood, alveolar volume diminishes and additional gas mixture is drawn into the lung from the breathing circuit, effectively increasing alveolar ventilation. The higher the inspired N2O concentration, the more rapidly the alveolar N2O concentration equilibrates with that inspired. This is known as the concentration effect. In addition, as alveolar gas volume drops, the other inspired gases, such as oxygen and volatile anesthetic become more concentrated, accelerating their uptake into blood.11 This is known as the second gas effect. Consider a single breath of a gas mixture of 70% N2O, 29% O2, and 1% isoflurane near the start of an anesthetic when mixed venous blood does not contain N2O (Figure 34-12). When half of the alveolar N2O is taken up into blood, the remaining alveolar gas volume will be 65% of the original volume, with relative concentrations of 35 N2O:29 O2:1 Iso = 54% N2O:45% O2:1.5% Iso. Despite the uptake of half its volume, the alveolar N2O concentration (and partial pressure) remains at more than half its original concentration. The high N2O concentration therefore maintains the pressure gradient for uptake. The second gas effect is also evident in this example. The reduced alveolar gas volume due to rapid uptake of N2O increases the alveolar concentrations of both oxygen and isoflurane, accelerating their uptake into blood (Figure 34-12).12
The concentration and second gas effects. When nitrous oxide (N2O) is inspired at high concentrations, transfer from the lung into pulmonary blood causes the volume of alveolar gas to decrease, drawing in more of the gas mixture and concentrating the remaining gases. This concentration effect on N2O itself results in a sustained alveolar driving pressure and more rapid uptake. The alveolar concentrations of other gases, such as isoflurane and oxygen, become higher than the inspired concentrations, which increases their uptake as well—the second gas effect.
NITROUS OXIDE UPTAKE INTO AIR SPACES IN THE BODY
Inhalation of N2O at high concentrations leads to important effects on airspaces within the body. Airspaces usually contain mostly nitrogen (79% of air), which has very low solubility in blood (λb/g = 0.015), so that bulk transfer of trapped nitrogen gas cannot occur on the timescale of most anesthetics. N2O (λb/g = 0.45) is delivered to airspaces 30 times faster than nitrogen leaves. As N2O diffuses into the preexisting airspace, the volume or pressure in the airspace increases. In most cases, both airspace volume and pressure increase, but examples in which one or the other effect dominates are useful for illustration.
A compliant airspace, such as a small air embolus or pneumothorax, can increase its volume with minimal pressure change. It continues to expand until the partial pressure of N2O within the airspace equals that in surrounding blood. Theoretically, at 50% inspired N2O, the volume of a gas bubble can double (half of its gas volume will then consist of N2O). Similarly, 67% N2O could triple and 75% N2O could quadruple airspace volume (Figure 34-13). Small venous air emboli may thus not only become easier to detect with Doppler and echocardiographic monitors but also create more physiologic problems by obstructing blood vessels.13,14 A small pneumothorax could also expand to compress mediastinal structures and impair oxygenation or create hemodynamic compromise. The rate of airspace expansion depends on the volume, geometry, and compliance of the airspace as well as the blood flow delivering N2O to it. Small venous air emboli may expand within seconds, and a pneumothorax can expand toward equilibrium in less than an hour; airspaces in the bowel may take considerably longer to expand.
Expansion of venous air emboli by nitrous oxide. Nitrous oxide (N2O) enters air pockets far faster than nitrogen leaves (because of low blood nitrogen-carrying capacity), causing airspace expansion. Expansion continues until the partial pressure of N2O inside the air bubble matches that in surrounding blood. Thus, at 50% N2O (PN2O = 0.5 atm), air emboli can double in volume, and at 67% N2O (PN2O = 0.67 atm), they can triple in volume. Expansion of small venous air emboli can lead to occlusion of pulmonary capillaries, compromising both blood flow and gas exchange.
Diffusion of N2O into noncompliant airspaces can also create clinical problems. If volume does not change, total pressure will increase as N2O enters. For example, after intravitreal injection of sulfur hexafluoride (SF6) or perfluoropropane (C3F8) gases, N2O administration can result in rapid increases of intraocular pressure, compromising retinal blood flow.15,16 Intracranial air bubbles (after craniectomy or pneumoencephalography) and the inner ear also represent airspaces in noncompliant body compartments.
Other common inhaled anesthetics also diffuse into airspaces, but their low concentrations in clinical settings result in negligible impact on airspace volume and pressure. Xenon is an experimental anesthetic used at high concentrations (60%-70%) and, like N2O, is associated with airspace expansion.17
ELIMINATION OF INHALED ANESTHETICS VIA VENTILATION
The removal of inhaled anesthetics via the lungs is essentially the reverse of uptake, and many of the factors affecting induction also affect elimination rates. High FGF promotes faster washout of anesthetic from the circuit, enhancing the gradient for removal from the lung (Figure 34-5). High minute ventilation clears alveolar anesthetic, reducing Palv and providing a gradient for movement of anesthetic from the blood to the alveoli (Figure 34-7). Highly blood-soluble anesthetics are retained longer than insoluble drugs because the effective volume of blood is higher as λb/g increases (Figure 34-8). Similarly, increasing the cardiac output retards recovery (Figure 34-9).
Some aspects of anesthetic elimination do not mirror the uptake during anesthetic induction. The use of overpressure to accelerate anesthetic induction has no parallel during recovery because the delivered concentration or partial pressure of anesthetic agent cannot fall below zero. Also, before induction, whereas the inhaled anesthetic partial pressure in all tissues is zero, different tissues will typically have reached different partial pressures when anesthetic delivery is discontinued. In particular, the partial pressures in muscle and fat may be far lower than Palv after a brief anesthetic. Because anesthetic continues to distribute from blood into tissue as long as Palv is greater than Ptissue, these compartments can continue to absorb drug after delivery via the lungs stops. This effect is illustrated in Figure 34-10, where fat continues to take up isoflurane from blood long after delivery is discontinued, until Palv is less than Pfat. This uptake helps reduce the anesthetic partial pressure in the highly perfused tissues and can shorten emergence time.
The longer anesthesia is maintained, the more drug is absorbed into muscle and fat, which are characterized by slow uptake and release of agent. Thus, clearance of inhaled anesthetics is context sensitive: the longer the anesthetic is maintained, the slower the clearance. Theoretical modeling suggests that after 4 hours at one times the minimum alveolar concentration (MAC) of various anesthetics, 99.9% brain elimination takes 33 hours for desflurane, 52 hours for sevoflurane, and 71 hours for isoflurane, and that significant amounts of these drugs remain in the body for days after discontinuation of anesthetic delivery.18 If fat and muscle reach high partial pressures (after many hours for most potent agents), recovery from anesthesia may be significantly delayed. Obese patients and those with a higher-than-normal muscle mass are therefore at risk for slowed emergence after long exposures to soluble anesthetics. Uptake and redistribution models indicate that following prolonged inhalational anesthesia, if hyperventilation is used to rapidly decrease Palv and achieve awakening, subsequent hypoventilation may result in “reanesthetization” through return of anesthetic from muscle into blood and then into the CNS.19,20
Washout of high concentrations of N2O can result in “diffusion hypoxia” (also known as the Fink effect), which is the reverse of the second gas effect. Immediately after discontinuing its administration at high concentrations, rapid N2O diffusion from blood into alveoli increases airspace volume, diluting O2 and CO2. This can lead to hypoxemia and reduced respiratory drive. Supplemental O2 should always be administered when discontinuing N2O.
PHARMACODYNAMICS OF INHALED ANESTHETICS
THERAPEUTIC EFFECTS AND ANESTHETIC DEPTH
Although general anesthesia results in a multitude of physiologic alterations, there is no consensus among clinicians and researchers regarding which actions are essential to the state of general anesthesia.21 Our view is that the desired therapeutic effects of all general anesthetics are hypnosis (loss of awareness), amnesia (loss of memory), and immobility (suppression of movement in response to pain). Some include analgesia as an essential component.22 Modulation of pain is unquestionably a critical consideration in perioperative care, but the potent sedative-hypnotic effects of most general anesthetics confound the assessment of pain. The cellular and molecular targets for volatile anesthetics are in the CNS. Hypnosis and amnesia are produced via drug effects on neural networks within the brain, and immobility is primarily mediated by the spinal cord. Beneficial and toxic effects of inhaled anesthetics on other physiologic systems (eg, cardiovascular function, respiration) can be regarded as secondary. In this section, we discuss various measurements of anesthetic effects in the nervous system, as well as their limitations.
Because general anesthesia is defined as the loss of normal responses to environmental stimuli, anesthetic depth is most rigorously defined by stimulus-response testing using stimuli that range from benign (eg, spoken commands) to noxious (eg, laryngoscopy or surgical incision).23 In addition, certain consistent pharmacologic effects of anesthetics that are stimulus independent are useful signs of anesthetic depth. Traditionally, both desired and undesired clinical effects have been associated with the various stages and planes of anesthesia introduced by Snow (1847)24 and modified by Guedel (1937).25 These descriptions (Table 34-3) were developed during the era of ether and chloroform anesthesia and are therefore not fully applicable to modern practice.
Table 34-3Classic Stages and Planes of Inhalational Anesthesia ||Download (.pdf) Table 34-3 Classic Stages and Planes of Inhalational Anesthesia
Stage 1 is defined as the time between the normal waking state and the loss of consciousness (hypnosis) caused by an anesthetic agent. There is also mild analgesia in stage 1 anesthesia.
Stage 2 is associated with loss of awareness and recall (amnesia). Stage 2 is associated with the undesired effects of cardiovascular instability, excitation, dysconjugate ocular movements, and emesis.
Stage 3 is defined as surgical anesthesia, a state during which movement in response to pain is suppressed. Various planes of anesthesia were described by Guedel25 based on additional physiological signs:
Plane 1 is associated with deep respiration, coordinated thoracic and diaphragmatic muscular activity, and pupillary constriction.
Plane 2 is associated with diminished respiration, as well as fixed midline and dilated pupils.
Plane 3 is associated with continued diaphragmatic movement, diminished thoracic movement, and further pupillary dilation.
Plane 4 is associated with thoracic immobility and diminished diaphragmatic movement.
Stage 4 is associated with cessation of spontaneous respiration and medullary cardiac reflexes and may lead to death.
MINIMUM ALVEOLAR CONCENTRATION, MINIMUM ALVEOLAR CONCENTRATION AWAKE, AND MINIMUM ALVEOLAR CONCENTRATION BAR
Minimum Alveolar Concentration
In 1965, Eger introduced the concept of MAC as a stimulus-response measure of anesthetic potency.26,27 MAC is the alveolar concentration of inhaled anesthetic that prevents movement in half (ie, an ED50) of subjects in response to a standardized surgical incision. When different noxious stimuli (eg, varying point pressures or electric shocks) are tested, MAC increases with stimulus intensity.28 Thus, MAC is most useful for comparing potency (inversely related to MAC) among different inhaled agents under the same conditions. When measuring MAC, equilibrium between Palv and the CNS must be established, and other drugs that modulate awareness (eg, benzodiazepines), pain sensation (eg, opioids), or movement (eg, muscle relaxants) must be absent. MAC defined as a fraction of an inspired gas mixture depends on atmospheric pressure, but if expressed as a partial pressure, it is independent of ambient pressure. The MAC values of common inhaled agents in oxygen (Table 34-2) show that N2O is least potent, followed by desflurane, sevoflurane, enflurane, isoflurane, and halothane. By definition, an exclusively inhalational anesthetic to a level of one times the MAC will prevent movement in only 50% of patients. The ED95, which is roughly 1.3 times the × MAC, may be a more clinically useful value.
The MAC is affected by age and physiologic, genetic, and pharmacologic factors. MAC is highest within the first year of life (age 6-12 months) and decreases with age, by about 6%-10%/decade (Figure 34-14).29,30 Standard MAC values are those for patients around age 40 years.
Minimum alveolar concentration (MAC) varies with age. MAC is maximal in the first year of life and decreases with age. The figure shows the relationship on a semilogarithmic scale. The equation of the line is MAC/MAC40 = 1.32 × 10-0.00303Age, or a 6.7% decrease in MAC per decade.26
Physiologic factors such as body temperature influence MAC. For each decrease in core temperature by 1°C, MAC decreases by 5%. Other physiologic extremes that affect CNS function (eg, hypoxia [Pao2 < 40 mm Hg], hypercapnia [Paco2 > 90 mm Hg], acidosis, hypotension [mean arterial pressure, MAP, < 40 mm Hg]) also decrease MAC.
Whether MAC is affected by gender is controversial. Elderly women require 26% less xenon than age-matched men. In young men and women, however, MAC for desflurane does not significantly differ.31 MAC is reduced in parturient women.32 Increases in either progesterone or endogenous opiates (endorphins) during pregnancy have been proposed to account for this decreased anesthetic requirement, but these theories have not been substantiated by experiment.
Genetic factors play a role in determining MAC. Mice of varying genomic backgrounds are differentially susceptible to volatile anesthetics such as halothane, isoflurane, and sevoflurane.33 In humans, patients with naturally red hair have a significantly higher desflurane MAC than other patients (Figure 34-15).34 Of the redheads tested, 90% had mutations reducing expression of the melanocortin-1 receptor gene. Genetically altered (knockout) mice lacking the melanocortin-1 receptor gene also display a modest increase in MAC for desflurane, isoflurane, sevoflurane, and halothane.35
Minimum alveolar concentration (MAC) values are increased in natural redheads. The figure depicts data reported by Liem et al.31 On average, redheads require about 20% higher alveolar concentrations of desflurane to prevent movement. Columns represent averages, and error bars represent standard deviations.
Pharmacologic factors alter MAC. The addition of 70% N2O reduces the anesthetic requirements of other inhaled agents by 55% to 70% (Table 34-2). MAC is an additive phenomenon when two or more inhaled agents are combined.36 Adjunct opiate or benzodiazepine administration reduces MAC. Whereas acute alcohol intoxication reduces MAC, chronic intake of alcohol or sedatives can increase MAC, a phenomenon known as cross-tolerance.37
In animal models, MAC has been shown to be primarily dependent on anesthetic effects on the spinal cord and not the brain.38,39 Anesthetic-induced immobility is likely attributable to suppression of spinal motor neuron function, observed as a diminished Hoffmann’s reflex (H reflex) and F-wave amplitudes.40,41 Suppression of movement and H-reflex amplitude by sevoflurane follow similar dose-response relationships in humans.42
Minimum Alveolar Concentration—Awake
MAC-awake is the concentration of inhaled anesthetic that inhibits appropriate responses to spoken commands in half of patients.29 The ratio of MAC-awake to MAC is not consistent among inhaled agents. It is fairly constant for the halogenated volatiles (roughly 0.35 × MAC), and significantly higher for N2O,43 which likely reflects their different mechanisms of action (see Chapter 33).
Recovery of consciousness from anesthesia depends on MAC-awake for the specific agent as well as its elimination kinetics. Therefore, the time required to awaken after an anesthetic, especially a long one, depends on what concentration of the anesthetic was used relative to its MAC-awake. If the inhaled concentration was two times the × MAC-awake, then only a 50% reduction in Palv will be needed before the patient awakens, which is usually rapidly achieved for most agents. If higher concentrations were used, then emergence may be more than proportionately slowed because the slower phases of agent elimination will have a more dominant effect (see Elimination of Inhaled Anesthetics via Ventilation).
Similar to MAC, MAC-awake is reduced in elderly adults, by hypothermia and by the presence of other drugs with hypnotic activity (ethanol, benzodiazepines, anticonvulsants, antidepressants).29 MAC-awake is also reduced by neuraxial blockade (spinal or epidural) despite intact cranial nerve function.44-47 This may be due to diminished ascending spinal signaling that stimulates cortical arousal via the brainstem. MAC-awake is decreased by high doses of opiates, but this reduction is smaller than that of MAC.48
Anesthetic-induced hypnosis is thought to be mediated through actions in the cerebral cortex. Gamma-range (25- to 100-Hz) electroencephalographic (EEG) signals from different cortical regions become desynchronized during the transition from conscious to unconscious states.49,50 Synchrony in specific cortical networks, particularly the thalamocortical network, is believed to be associated with consciousness, and its interruption produces unconsciousness.51 Loss of “functional connectivity” among various cortical networks during anesthesia has been demonstrated by functional brain imaging studies.52-54
Memory is inhibited at lower concentrations of inhaled anesthetics than awareness.43 When inhaled agents are given at MAC-awake, only a small fraction of “aware” experimental subjects (those responding to spoken commands) can recall events.55 Amnesia is likely caused by effects on the limbic network, including the amygdala and hippocampus. Lesions in the basolateral amygdala produce resistance to the amnestic effects of sevoflurane in animals.56 Volatile anesthetics both attenuate hippocampal activity and inhibit long-term potentiation of hippocampal synapses that is associated with memory formation.57
Minimum Alveolar Concentration for Blockade of Autonomic Responses
The minimum alveolar concentration for blockade of autonomic responses (MAC-BAR) is the alveolar anesthetic concentration that suppresses cardiovascular responses to surgical incision in half of patients.58 MAC-BAR is typically greater than MAC. For example, MAC-BAR for desflurane is 1.66 × MAC. Similar to MAC and MAC-awake, MAC-BAR is reduced by opiates.23
Limitations on Traditional Anesthetic Depth Measurements
Stimulus-response testing is usually impractical in clinical settings. Neuromuscular blocking drugs ablate motor responses to both painful (MAC) and benign (MAC-awake) stimuli. Techniques for maintaining motor response capability are laborious, so autonomic signs like blood pressure, heart rate, diaphoresis, tearing, and pupillary responses are often used to assess adequacy of anesthesia. These signs are unreliable guides to anesthetic depth, especially when confounded by drugs and diseases that affect cardiac or autonomic nervous system functions.
Numerous factors affect anesthetic sensitivity (including unknown genetic factors), resulting in widely varying individual anesthetic requirements. Too little anesthetic puts patients at risk for intraoperative awareness (see discussion that follows). Conversely, deep anesthesia for all patients is neither feasible nor advisable. Deep inhalational anesthesia in patients with cardiac disease, hypovolemia, and other critical illnesses predictably causes profound hypotension and organ hypoperfusion. Healthy patients may tolerate deep anesthesia, but this results in slow emergence and a high incidence of side effects such as postoperative nausea and vomiting (PONV).59 Research has suggested that excessively deep general anesthesia may increase the incidence of delirium,60 may accelerate the pathogenesis of neurodegenerative diseases such as Alzheimer dementia,61,62 and may be associated with increased late mortality.63 Clinical studies, including a prospective multinational trial, are being conducted to further investigate whether anesthesia depth influences patient outcomes.64 The delivery of sufficient but not excessive anesthesia while providing optimal surgical conditions represents a central challenge for anesthetists.
ELECTROENCEPHALOGRAPHIC MEASUREMENT OF ANESTHETIC DEPTH
General anesthetic drugs are frequently coadministered with neuromuscular blockers to produce immobility, narcotics to provide analgesia, and other drugs to control autonomic activity. In such cases, the essential therapeutic effects of general anesthetics are reduced to hypnosis and amnesia, two brain functions that are difficult to assess clinically. Clinical monitors that analyze electrical signals from the brain can provide anesthetists with more data to individually titrate drug dosage for the desired depth of general anesthesia. Titration to individual needs has been shown to reduce anesthetic dosage, resulting in faster emergence and reduced PONV in some settings.65,66
A number of techniques based on EEG have been developed and used. Fourier transformation of raw EEG data enables the derivation of median power and spectral edge frequencies.67 Other EEG analyses include bispectral phase relationships, burst suppression, and entropy. The bispectral index (BIS; of the Bispectral Index Sensor™, Covidien, Boulder, CO) is a proprietary algorithm based on burst suppression, near-burst suppression, β-band power, and phase relationships between δ- and θ-waves.68 The Sedline monitor (Masimo Corp., Irvine, CA) derives another proprietary scalar, the patient state index.69 Similar technology is employed in entropy monitors (eg, S/5, General Electric [Datex-Ohmeda], Helsinki, Finland) that analyze randomness in frequency and phase relationships using both EEG and frontal electromyography (EMG).70 For most patients, EEG indices such as BIS and spectral entropy correlate with the alveolar concentration of volatile anesthetics (Figure 34-16).71 Monitors based on stimulus-response have also been developed for clinical use. Auditory evoked potentials can be used to assess anesthetic-induced unconsciousness and may be used in conjunction with other EEG parameters.72 Transcranial magnetic stimulation has been used in conjunction with EEG to detect loss of consciousness.73 Nonetheless, all currently available monitors have considerable limitations. Recent research based on the theory that consciousness requires information flow between many cortical regions has led to novel EEG analysis approaches that may improve the depth of anesthesia monitoring.74,75
Correlation between processed electroencephalographic (EEG) parameters and volatile anesthetic concentration. A. Time course of state entropy (SE), response entropy (RE), bispectral index (BIS), and burst suppression ratio (BSR) of a single patient. Each symbol represents an EEG parameter of a 5-s epoch. B. End-tidal sevoflurane concentration (Cet) and calculated effect site concentration (Ceff) during the same time course in the same patient. [Reproduced with permission from Ellerkmann RK, Liermann VM, Alves TM, et al. Spectral entropy and bispectral index as measures of the electroencephalographic effects of sevoflurane. Anesthesiology. 2004 Dec;101(6):1275-1282.]
INTRAOPERATIVE AWARENESS AND RECALL
Inadequate anesthesia can result in awareness and explicit recall of intraoperative events, a problem that is a subject of clinical, public, and scientific attention.76
INCIDENCE OF AWARENESS WITH RECALL DURING GENERAL ANESTHESIA
Large studies in both Sweden77 and the United States78 have used multiple postoperative interviews (eg, Table 34-4) to investigate intraoperative awareness. In a combined total of 31,360 patients, 40 cases of “definite” and “probable” awareness with recall were identified, an incidence of 0.13%. Given that 30 to 50 million general anesthetics are administered in the United States, the number of patients experiencing awareness with recall is estimated at around 50,000 per year.
Table 34-4The Modified Brice Interview ||Download (.pdf) Table 34-4 The Modified Brice Interview
What is the last thing you remember before anesthesia?
What is the first thing you recall after waking up?
Do you recall anything in between?
Did you have any dreams during surgery?
What was the worst thing about your surgery and anesthesia?
PATIENT REPORTS AND POST-TRAUMATIC STRESS DISORDER AFTER INTRAOPERATIVE AWARENESS
Spontaneous reports by patients of intraoperative awareness are rare, highlighting the need to use a structured interview that probes for these events.79,80 Patients report a variety of intraoperative experiences after general anesthesia. A high proportion of these experiences are vague and dreamlike, but others are explicit recollections of intraoperative events. Explicit recollections may include hearing conversations among operating room personnel; pain associated with intubation or surgery; and extreme anxiety, particularly in paralyzed patients. These experiences can lead to postoperative psychological problems, including post=traumatic stress disorder (PTSD). PTSD is characterized by recurrent episodes of anxiety, irritability, anger, and vigilance, often associated with flashbacks or nightmares, avoidance of cues related to the trauma, and sleep disturbances.81 The incidence of PTSD after intraoperative awareness is not known, but it likely depends on the duration of the awareness episode and the presence of pain, anxiety, and preexisting psychological problems. In surveys of postawareness adult patients, more than 50% develop symptoms of PTSD.82,83 Interestingly, children rarely develop PTSD, even though they report intraoperative awareness more often than adults. However, their limited understanding of general anesthesia may influence children’s responses to awareness surveys.84
RISK FACTORS FOR AWARENESS DURING GENERAL ANESTHESIA
Factors that contribute to intraoperative awareness include the use of muscle relaxants, high individual requirements for anesthetics, surgical situations during which “light” anesthesia is typically used, and errors by the anesthesia care team (Figure 34-17).85 Awareness with recall has been reported in patients who were anesthetized without muscle relaxants, but the incidence was much higher when muscle relaxants were given. Furthermore, severe psychological problems seem to develop primarily in patients who experience “awake paralysis” with anxiety and pain.86 Patients receiving chronic therapy with sedatives, opiates, and some anticonvulsants can develop tolerance (resistance) to anesthetic drugs and require higher-than-normal anesthetic doses. Pharmacogenomic factors are likely to play a role, and patients with either a personal or a family history of awareness during general anesthesia are at increased risk.87 In contrast to the association between natural red hair and MAC, there is no significant association between red hair and recovery time, postoperative pain, or intraoperative awareness outcomes.88
Causes and consequences of awareness during anesthesia.
Surgical procedures associated with high incidences of intraoperative awareness include major trauma, thoracoabdominal, and cardiac surgery. In these settings, hemodynamic instability often precludes the use of deep general anesthesia, resulting in incidences of awareness ranging from 1% up to 40%.89,90 Caesarean section under general anesthesia, during which a “light” anesthetic is often used to reduce drug effects on the newborn, is also associated with a high incidence of maternal awareness (0.4%).91 Inadequate dosing, misuse of equipment, and other human errors can also lead to patient awareness during general anesthesia. Many cases of awareness appear to occur during prolonged attempts at airway intubation when the hypnotic effect of intravenous induction agents wears off while patients remain paralyzed with a muscle relaxant. Other reports have described awareness when anesthetic vaporizers were empty or when infusion pumps were not delivering intended doses of hypnotic agents. Reviews of awareness during general anesthesia incidents reported that most cases were preventable.92
MONITORING AND PREVENTION OF INTRAOPERATIVE AWARENESS
Two monitoring strategies have been shown effective at reducing the incidence of intraoperative awareness when inhaled anesthetics are used. These are based on measurements of either the EEG-derived BIS or end-tidal anesthetic partial pressures.
The BIS is the only EEG-based monitoring technique that has been extensively evaluated for its ability to reduce the incidence of awareness. Myles et al93 conducted a prospective, randomized, double-blinded, multicenter trial (the B-AWARE trial) of 2463 patients at high risk of awareness with recall who were assigned to either “standard care” or BIS-guided anesthesia groups and assessed with postoperative interviews. The incidence of awareness with recall in the BIS-guided group (0.16%) was much lower than in the control group (0.9%). Of note, use of the BIS monitor in B-AWARE did not reduce the incidence of patient-reported intraoperative experiences judged as “possible awareness” or “no awareness.”
A number of confounding factors can also affect the BIS, reducing its ability to accurately gauge depth of anesthesia. These include electrical artifact from electrocautery devices, physiologic alterations such as hypoglycemia, low-voltage EEG caused by genetic variation or drugs, and neurologic abnormalities such as Alzheimer disease.94 A factor that frequently degrades EEG waveform analysis is EMG (muscle) activity, which can be reduced with neuromuscular blockade.95,96 Appropriate interpretation and intervention are also required for effective use of these monitors. Finally, the value of BIS monitoring has been validated only for propofol and volatile anesthetics. When ketamine and N2O are present, the relationship between BIS value and perceptive awareness can be significantly altered.97
End-tidal anesthetic gas (ETAG) monitoring, which is available in most modern anesthesia systems, is also useful for reducing the incidence of intraoperative awareness. Avidan et al conducted a prospective randomized trial that assessed explicit awareness in high-risk patients (the B-UNAWARE trial).98 The incidence of explicit awareness was similarly low (0.2%) in patients whose anesthesia was guided using BIS and a comparison patient group who received ETAG-guided anesthesia (0.7 to 1.3 × Age-adjusted MAC). However, there was no “standard care” control group included in this study. Subsequent large prospective trials also found anesthesia guided by either BIS or ETAG to be equivalent in preventing awareness with recall in high-risk patients and typical adult surgical patients.99-101 Of course, ETAG is not applicable for patients receiving total intravenous anesthesia or a combination of intravenous infusions and inhaled anesthetic agents.
MANAGEMENT OF INTRAOPERATIVE AWARENESS
Prevention of intraoperative awareness with recall begins with recognizing and addressing known risk factors. Caregivers must be familiar with their equipment and its proper use. Amnestics, such as benzodiazepines, can reduce the incidence of awareness with recall and should be considered as premedication for most patients and when “light” anesthesia is unavoidable. Muscle relaxants should be used judiciously to provide adequate relaxation for surgery or avoided whenever possible. N2O-relaxant anesthesia should be supplemented with volatile anesthetics or intravenous hypnotic agents to maintain adequate hypnosis (~2 × MAC-awake). When intubation is delayed or multiple attempts are required, consideration should be given to supplementing the induction bolus with additional inhaled or intravenous hypnotic agents.
All patients should be routinely informed of the risk of awareness during general anesthesia. High-risk patients should be monitored using ETAG or an EEG-based monitor when feasible. If adjunct monitoring is used, it should be used according to the manufacturer’s guidelines, and indications of potentially inadequate anesthesia on the monitor should be treated with an increased dose of hypnotic agents unless other circumstances make this inadvisable.
Ideally, in the postoperative period, all patients should be interviewed and asked specific questions (Table 34-4) to assess for intraoperative awareness. When awareness is detected, the patient should be treated for this occurrence like any other complication that results in harm or potential harm. A thorough debriefing of the patient is warranted, and the details of the patient’s experiences should be documented in the medical record. All involved care team members should be informed and asked if they can corroborate patient recollections of intraoperative events. The incident should also be reported to the departmental quality assurance committee and possibly to the institutional legal counsel.
Patients reporting awareness during anesthesia should be reassured that their experience is valid and provided with an explanation of why and how the intraoperative awareness occurred. Expressing sympathy for the patient’s suffering and apologizing if indicated can help maintain a therapeutic relationship, and the patient should be offered professional psychological evaluation and therapy if uncomfortable psychological symptoms are present. Maintaining contact with the patient to monitor the patient’s status may facilitate recovery and can reduce malpractice risk.
SYSTEMIC ACTIONS OF INHALED ANESTHETICS
In this section, we summarize both the therapeutic and toxic secondary effects of inhaled anesthetics on important physiologic systems.
Cerebrovascular and Metabolic Effects
The effects of anesthetics on cerebral metabolism and vascular tone are summarized in Table 34-5. Normal cerebral blood flow (CBF) is tightly autoregulated and coupled with cerebral metabolic demands. Volatile anesthetics interrupt this autoregulation by acting as direct vasodilators of the cerebral vasculature.102 Volatile anesthetics dose-dependently increase middle cerebral artery blood flow velocity, with sevoflurane causing less vasodilation than isoflurane or desflurane.103,104 Both K+ channels105 and neuronal nitric oxide synthase106 have been linked to these direct actions of anesthetics.
Table 34-5Inhaled Anesthetic Effects on Central Nervous System Physiology ||Download (.pdf) Table 34-5 Inhaled Anesthetic Effects on Central Nervous System Physiology
|Effect ||Nitrous Oxide ||Desflurane ||Sevoflurane ||Isoflurane ||Halothane |
|Cerebral blood flow ||⇑ ||⇑ ||⇑ ||⇑ ||⇑ |
|Cerebral perfusion pressure ||⇓ ||⇓ ||⇓ ||⇓ ||⇓ |
|Intracranial pressure ||⇑ ||⇔/⇑ ||⇔/⇑ ||⇔/⇑ ||⇔/⇑ |
|Metabolic demands ||⇑ ||⇓ ||⇓ ||⇓ ||⇓ |
|CO2 reactivity ||⇔ ||⇔ ||⇔ ||⇔ ||⇔ |
Halothane, isoflurane, sevoflurane, and desflurane decrease the cerebral metabolic rate (CMR) of oxygen consumption dose dependently.102,107 The extent to which blood flow and metabolism are altered depends on the agent. Halothane may increase CBF by almost 200% while reducing the CMR by only 10%.108 Isoflurane increases CBF by about 20% while reducing CMR by 45%.109 Volatile agents also partially uncouple flow-metabolism relationships and carbon dioxide reactivity.110,111 These agents do not increase intracranial pressure (ICP) in normocapnic adults undergoing supratentorial brain tumor resection without a preoperative midline shift.112 In children, isoflurane, sevoflurane, and desflurane have all been shown to increase ICP.113 N2O is distinguished from the potent volatile anesthetics in that it increases CBF and CMR and may increase ICP.114,115 This is partly attributable to its sympathomimetic effects.116
Volatile anesthetics alter EEG signals, decreasing high-frequency (γ-band) activity and increasing slower frequencies. Quantitative EEG analysis demonstrates that power shifts anteriorly.50 In comparison, N2O has little effect or increases the frequency of the EEG.117 Indeed, EEG-based monitors do not reliably detect the hypnotic effects of N2O alone or in combination with other anesthetics.118,119 Deep volatile anesthesia (1.5-2 × MAC) leads to burst-suppression or isoelectric EEG patterns. Although all volatile anesthetics have been used to suppress seizures, both enflurane and sevoflurane induce epileptiform EEG patterns in both patients with epilepsy and those without.120-122 This activity is frequently seen in children during inhalation induction with high concentrations (6% to 8%) of sevoflurane.123 Enflurane and sevoflurane are thus potentially useful during cortical mapping of seizure foci but should otherwise be avoided in patients with seizure disorders.
Emergence Delirium/Emergence Agitation
Emergence delirium is an acute postoperative complication defined by waxing and waning confusion and inability to communicate clearly, sometimes associated with hallucinations, hyperactivity, or hypoactivity. It is most frequently seen in the elderly and very young patients, two groups also at risk of long-term neurotoxicity following general anesthesia (see the next section). Postoperative delirium in patients following thoracic and cardiac surgery is associated with increased morbidity and mortality, and further studies are needed to establish if modifiable factors such as depth of anesthesia influence this outcome.124
In preschool children, emergence delirium or agitation (ED/EA) typically occurs after volatile-based general anesthesia. Its incidence varies wildly, ranging from 2% to 80% depending on gender, age, type of surgery, and level of preoperative anxiety.125 The incidence of ED/EA in children is the same after sevoflurane, desflurane, or isoflurane, suggesting that speed of emergence is not an important factor.126 The incidence of ED/EA in children can be reduced by treating preoperative anxiety and administering sedatives and analgesics, including midazolam, dexmedetomidine, ketamine, or propofol during or near the end of an anesthetic.
While the well-established therapeutic and toxicological actions of inhaled anesthetics are dose dependent and reversed with washout of these drugs from the body, accumulating evidence in animal models suggests that long-lasting sequelae may result from exposure to general anesthetics during both brain development early in life and in the elderly. Effects of volatile anesthetics on the aging brain and postoperative cognitive dysfunction are thoroughly discussed in Chapter 79 (Cognitive Dysfunction After Anesthesia and Surgery). Here, we briefly discuss early neurodevelopmental toxicity, supplementing the information in Chapter 59 (Anesthesia for Children).
Concerns about neurodevelopmental toxicity first emerged from studies demonstrating widespread neuroapoptosis (programmed cell death) in the brains of young rats exposed to various anesthetic drugs for several hours.127,128 Further research in young rodents and nonhuman primates revealed that neuronal and glial apoptosis is produced by all clinically used general anesthetics, is dependent on dose and duration of drug exposure, and is absent in older animals beyond the age of brain and neural circuit development.129,130 Recent evidence also showed that anesthesia in young animals induced aberrant development of synapses and neural circuits.131,132 Moreover, these histopathological changes in animals were associated with behavior deficits in tests of learning and cognition later in life. Mechanistic studies in animals have identified molecular signaling pathways that could represent targets for therapeutic interventions.
Whether these findings in animals translate to human children is a critical question that is not yet settled. To date, clinical cohort studies have focused on neurocognitive outcomes, including performance on standardized academic tests and diagnoses of behavioral and learning abnormalities in children exposed to general anesthesia at less than 3 years of age. Results have been both positive133 and negative,134 and conclusions are limited by retrospective design, variable outcome measurements, and lack of adjustment for duration and type of surgery, as well as confounders such as underlying clinical conditions. Several large long-term studies are currently under way that aim to test if neurocognitive deficits are associated with early childhood anesthetic exposure and to evaluate risk factors and potential strategies to improve outcomes. Until the risks are better defined, there is no basis for altering the care of children who urgently need procedures under general anesthesia.135 A prudent approach may also include, when feasible, postponement of elective surgery until the age 3 years, use of regional instead of general anesthesia, and minimizing both number and duration of anesthetic exposures.
The effects of volatile anesthetics on the cardiovascular system are of paramount clinical importance intraoperatively, particularly in patients at risk for end-organ ischemia. The effects are summarized in Table 34-6.
Table 34-6Effects of Inhaled Anesthetics on Cardiovascular Physiology ||Download (.pdf) Table 34-6 Effects of Inhaled Anesthetics on Cardiovascular Physiology
|Effect ||Nitrous Oxide ||Desflurane ||Sevoflurane ||Isoflurane ||Halothane |
|MAP ||⇔/⇑ ||⇓ ||⇓ ||⇓ ||⇓ |
|SVR ||⇔/⇑ ||⇓ ||⇔ ||⇓ ||⇔ |
|Heart rate ||⇔/⇑ ||⇑ ||⇑ ||⇑ ||⇔ |
|Myocardial function ||⇓ ||⇓ ||⇓ ||⇓ ||⇓ |
|Epinephrine-induced arrhythmia ||⇑ ||⇔ ||⇔ ||⇔ ||⇑ |
Volatile anesthetics decrease MAP in a dose-dependent manner93 by direct vascular and autonomic nervous effects. Volatile anesthetics reduce MAP by decreasing systemic vascular resistance, increasing vascular compliance (the change in circulatory system volume with changes in pressure), and inhibiting myocardial contractility. Halothane depresses myocardial contractility more than other volatile anesthetics. Whereas isoflurane and desflurane decrease systemic vascular resistance, halothane and sevoflurane increase arterial compliance136 (Table 34-7). Desflurane stimulates sympathetic nervous system activity, which may account for its small effect on vascular compliance.137 N2O mildly increases sympathetic activity and systolic blood pressure138 and thus counters the vasodilatory and hypotensive effects of coadministered volatile agents.139
Table 34-7Inhaled Anesthetic Effects on Vascular Resistance and Compliance: Comparison With Sodium Nitroprusside
Volatile anesthetics increase heart rate, both by a baroreceptor reflex in response to decreased arterial pressure and by a direct vagolytic effect. In dogs, desflurane increases heart rate the most, followed by sevoflurane, isoflurane, and halothane.140 Rapid increases in desflurane concentration are associated with both increased heart rate and increased blood pressure,141,142 which are attributed to stimulation of sympathetic activity. The minimal effect of halothane on heart rate is associated with its inhibition of the baroreceptor reflex.143 N2O is associated with only modest transient increases in heart rate,144 which reflect its sympathetic effects and preservation of MAP.
Volatile anesthetics cause myocardial depression, partly by inhibiting calcium ion influx in the myocardium.145 Halothane causes a marked dose-dependent inhibition of myocardial contractility and reduces cardiac output.146,147 Isoflurane, sevoflurane, and desflurane have lesser effects on myocardial contractility. In dogs, all of these anesthetics depress myocardial contractility, delay cardiac chamber relaxation, reduce chamber stiffness, and impair left atrial–left ventricular coupling.148,149 N2O administration also decreases intracellular calcium levels and depresses myocardial contractility.150 Thus, although N2O minimally affects blood pressure and heart rate, it has negative inotropic effects similar to those of potent volatile agents.
Cardiac Rhythm and Conduction
Volatile anesthetics affect the function of cardiac ion channels, increasing the risk of arrhythmias.151 Whereas halothane sensitizes the heart to the arrhythmogenic effects of epinephrine,152 isoflurane, desflurane, and sevoflurane do not.153,154 Halothane, isoflurane, desflurane, and sevoflurane all prolong the QT interval.155,156 In dental outpatients, halothane produced more ventricular arrhythmias than isoflurane.157 In pediatric dental outpatients receiving halothane anesthesia, 48% had ventricular dysrhythmias compared with 8% to 16% of those who received sevoflurane.158 Furthermore, sevoflurane produced mostly single supraventricular ectopic beats, but ventricular tachycardia was observed in 12% of patients receiving halothane. N2O may induce atrioventricular junctional rhythms159 and can lower the threshold for epinephrine-induced arrhythmias in conjunction with halothane.160
Coronary Artery Perfusion
Isoflurane is a coronary vasodilator and can thus potentially induce “coronary steal,” a diversion of blood flow away from fixed stenotic lesions.161 The clinical significance of this phenomenon appears to be mostly theoretical. Isoflurane has been found safe in patients with coronary artery disease as long as adequate perfusion pressure is maintained. Isoflurane also provides beneficial effects via ischemic preconditioning (discussed in a separate section that follows).162 Desflurane and sevoflurane do not cause coronary steal.163,164
Volatile anesthetics depress respiration through both central medullary and peripheral muscular effects. In general, inhaled anesthetics decrease tidal volume and increase respiratory rate. Halothane, isoflurane, desflurane, and sevoflurane dose-dependently reduce tidal volume. The concomitant increase in respiratory rate is more pronounced with halothane, desflurane, and sevoflurane than with isoflurane.164-167 Desflurane maintains minute ventilation with compensatory tachypnea up to alveolar concentrations of 1.6 × MAC. Nonetheless, alveolar ventilation is reduced by all volatile anesthetics, resulting in an increased Paco2. N2O also causes tachypnea and decreased tidal volume but alone causes minimal changes in Paco2. Ventilatory depression is additive when N2O is administered in combination with other inhalational agents.168
Factors that contribute to hypoxia and hypercarbia during inhalational anesthesia include hypoventilation, atelectasis, airway closure, decreased functional residual capacity, and ventilation/perfusion (V/Q) mismatch.169 Volatile anesthetics blunt hypoxic and hypercarbic respiratory drive, increasing the risk of severe hypoxia and hypercarbia in spontaneously breathing patients.170-172 Depression of hypoxic and hypercarbic ventilatory drives occurs even at subanesthetic concentrations. N2O blunts the respiratory drive to hypoxia and hypoventilation, but its clinical effects are minimal because of its low potency.173 Rapid elimination of N2O from blood after discontinuation dilutes alveolar oxygen and without supplemental oxygen can produce diffusion hypoxia (see Elimination of Inhaled Anesthetics via Ventilation).174,175
Hypoxic Pulmonary Vasoconstriction
Hypoxic pulmonary vasoconstriction (HPV) or the Euler-Liljestrand mechanism is a pulmonary vascular phenomenon that diverts blood flow away from poorly ventilated areas of the lung, minimizing V/Q mismatch. The mechanisms underlying HPV are not yet fully understood, but cyclooxygenase, calcium channels, and potassium channels appear to be involved.176 N2O has been shown in vivo to inhibit HPV.177 In isolated lung models, halothane, isoflurane, sevoflurane, desflurane, and N2O all inhibit HPV dose dependently.178-180 In many animal studies, however, clinical concentrations of halothane, isoflurane, sevoflurane, and desflurane have not been shown to inhibit HPV.181,182 In a few studies of chronically instrumented dogs, isoflurane was found to attenuate HPV.183 The conflicting data regarding isoflurane effects on HPV may be attributable to different flow conditions in the pulmonary vasculature during different experiments.
Most volatile anesthetics, including halothane, enflurane, isoflurane, and sevoflurane, are bronchodilators that decrease respiratory resistance and increase dynamic compliance (Table 34-8).184 At equi-MAC concentrations, respiratory resistance is reduced by sevoflurane > halothane > isoflurane.185 In contrast to the other volatile anesthetics, desflurane is associated with either no bronchodilatory effects or bronchoconstrictor effects at higher concentrations.186 Inhalational induction with desflurane should be avoided because its pungency frequently causes coughing and increases risk of laryngospasm. Sevoflurane causes the least amount of subjective airway irritation and is well tolerated during inhalational induction.187 N2O has no effect on respiratory resistance.185
Table 34-8Effects of Inhaled Anesthetics on Respiratory Physiology ||Download (.pdf) Table 34-8 Effects of Inhaled Anesthetics on Respiratory Physiology
|Effect ||Nitrous Oxide ||Desflurane ||Sevoflurane ||Isoflurane ||Halothane |
|Tidal volume ||⇓ ||⇓ ||⇓ ||⇓ ||⇓ |
|Respiratory rate ||⇑ ||⇑ ||⇑ ||⇑ ||⇑ |
|Hypoxic or hypercarbic responses ||⇓ ||⇓ ||⇓ ||⇓ ||⇓ |
|HPV (in vitro) ||⇓ ||⇓ ||⇓ ||⇓ ||⇓ |
|Airway resistance ||⇔ ||⇑ ||⇓ ||⇓ ||⇓ |
HEPATIC AND RENAL SYSTEMS
Volatile anesthetics reduce overall hepatic perfusion by altering portal venous or hepatic arterial inflows. Most agents decrease portal venous flow. Isoflurane has the least overall effect on hepatic perfusion because of compensatory increases in hepatic artery flow.188 In contrast, halothane causes hepatic artery vasoconstriction and decreases overall hepatic blood flow, hepatic oxygen delivery, and hepatic vein blood oxygen saturation.189,190 N2O causes minimal circulatory effects on the liver.
Transient modest increases in liver enzymes are common after exposure to volatile anesthetics (halothane, desflurane, sevoflurane, and isoflurane). This effect is independent of surgical intervention and is almost always clinically insignificant.191,192 The increase in liver enzymes after halothane may be caused by anaerobic reductive metabolism that generates free radicals.193 More severe hepatic injury (halothane hepatitis) is described in the section Breakdown of Inhaled Anesthetics and Toxicity of By-Products.
Volatile anesthetic agents cause dose-dependent decreases in renal blood flow, glomerular filtration rate, and urine output, which can be minimized with preoperative hydration.194-196 Autoregulation of renal blood flow is preserved during halothane anesthesia.195 Decreases in renal blood flow during inhalational anesthesia reflect a reduction in effective circulating volume secondary to increased vascular capacitance. Anesthetics do not directly stimulate antidiuretic hormone (ADH) release, but diminished urine production is associated with an increase in ADH in response to surgical stress.197 N2O causes minimal effects on renal blood flow and function. Nephrotoxicity can be associated with metabolic breakdown of volatile anesthetics (see Breakdown of Inhaled Anesthetics and Toxicity of By-products).
OTHER SYSTEMIC AND ADVERSE EFFECTS
Volatile anesthetics potentiate neuromuscular blockade via direct effects on the neuromuscular junction.198 The muscle relaxant effect of volatile agents is stronger than that of intravenous anesthetics; N2O has no relaxant action. In isolated diaphragmatic muscle, enflurane and sevoflurane enhance fatigability at high concentrations.199,200 This may be mediated in part by cyclic adenosine monophosphate because administration of the phosphodiesterase inhibitor olprinone attenuates the effects of volatile anesthetics.
Malignant hyperthermia (MH) is a life-threatening clinical myopathy triggered by all potent volatile anesthetics and succinylcholine. It is a genetic disorder associated with autosomal dominant transmission of genes encoding mutant forms of the skeletal muscle calcium release channel (the ryanodine receptor protein or RyR1).201,202 On exposure to the triggering drugs, MH-susceptible patients may develop an exaggerated increase in intracellular calcium, resulting in sustained skeletal muscular contracture, which is not inhibited by neuromuscular blocking agents. Sustained contracture produces a hypermetabolic state, leading to increased CO2 production and eventually hyperthermia. This condition is fatal unless treated aggressively and rapidly with intravenous dantrolene and supportive care.
Methionine Synthase Inhibition by Nitrous Oxide
Nitrous oxide irreversibly oxidizes the cobalt atom of vitamin B12, which inhibits the cobalamin-dependent enzyme methionine synthase. This pathway is essential for homocysteine breakdown, nerve myelination, methyl substitutions of neurotransmitters, and DNA synthesis. Most patients are unaffected by temporary inactivation of vitamin B12 after N2O administration. Nonetheless, this reaction can be clinically significant in patients with poor nutrition, preexisting vitamin B12 deficiency, or other metabolic diseases that converge on the same metabolic pathways. N2O exposure may lead to “anesthesia paresthetica,” which is characterized by paresthesias, ataxias, and poor manual dexterity.203 Widespread neuronal damage, status epilepticus, and death were reported in one infant with a preexisting deficiency of 5,10-methylenetetrahydrofolate reductase, an enzyme in the methionine synthetic pathway, after exposure to N2O.204
Inhibition of the methionine synthase by N2O results in an increase in homocysteine.205 Because chronic hyperhomocysteinemia is associated with cardiovascular disease, it has been hypothesized that N2O increases the perioperative risk of myocardial infarction and stroke. However, a large prospective trial (ENIGMA-II) found no increase in cardiovascular morbidity or mortality associated with N2O.206
Halothane and enflurane impair glucose tolerance in animal models by reducing both insulin secretion and receptor sensitivity. Isoflurane has been shown to increase endogenous glucose production and decrease glucose utilization.107,207 The choice of anesthetic drug may also play a role in modulating the stress responses to surgery. In a study of 20 women requiring laparoscopic surgery for ovarian cystectomy, sevoflurane was associated with less increase in cortisol and corticotropin levels than isoflurane.208
Potent inhalational anesthetics can alter immune cell functions in various ways, which in turn may affect recovery from surgery and tumor viability. Halothane depresses the neutrophil oxidative response to inflammatory mediators of infection; this effect is smaller with desflurane, sevoflurane, and isoflurane.209 Sevoflurane impairs transcription factors in human lymphocytes, which may reduce the inflammatory response.210 Volatile anesthetics can also induce apoptosis in human T cells in vitro211 and may affect cytokine function.212 There is suggestive evidence that general anesthesia may result in more tumor recurrence than regional anesthesia for breast and prostate cancer.213 However, other clinical studies suggested that the impact of anesthesia on immune function is transient and of little clinical significance.214
Volatile anesthetics induce cellular responses that protect against ischemia and biochemical stress mediators in multiple organs, including brain, heart, kidney and gut. For example, sevoflurane decreases markers of myocardial and renal damage after coronary artery bypass grafting.215,216 Animal models of renal ischemic injury demonstrate differential preconditioning, with desflurane demonstrating less-protective effects against tubular necrosis than sevoflurane, isoflurane, or halothane.217 Volatile anesthetics can protect against neural ischemia in animal models through pathways involving both nitric oxide metabolism and potassium channels.218,219
Genotoxicity and Teratogenicity
Halogenated hydrocarbons and ethers can cause DNA damage. Halothane and isoflurane produce genotoxicity in proliferating blood lymphocytes in vitro; sevoflurane does not appear to be cytotoxic in an animal model.220 The potential for anesthetic-induced teratogenicity has been studied. Prolonged N2O exposure is teratogenic in a number of embryonic animal models.221 N2O inhibition of vitamin B12–dependent DNA synthesis is the likely cause. Because of potential genetic damage after chronic exposure to inhaled anesthetics, it is currently recommended that operating room air contain less than 25 parts per million (ppm) of N2O and less than 2 ppm of halogenated anesthetics. While workplace exposure to inhaled anesthetics affects certain laboratory tests,222 no significant morbidity has been demonstrated.223 Furthermore, approximately 75,000 pregnant women undergo nonobstetric surgery each year. Although there was once controversy over the effects of surgery and anesthesia in this population, volatile anesthesia appears to be safe for both women and fetuses.224
BREAKDOWN OF INHALED ANESTHETICS AND TOXICITY OF BY-PRODUCTS
Inhaled anesthetics represent a class of drugs eliminated largely via nonmetabolic pathways—for the most part, they leave the body as they entered, unaltered and via ventilatory gas exchange. Undesirable effects directly associated with anesthetics were summarized previously, but others are caused indirectly by chemical decomposition of inhaled anesthetics into toxic by-products. The breakdown of volatile anesthetics into potentially harmful chemicals can occur in the presence of CO2 adsorbents or via enzymatic biotransformation in the body. In general, greater breakdown of inhaled anesthetics leads to greater toxicity.
NONMETABOLIC DECOMPOSITION OF INHALED ANESTHETICS
Although inhaled anesthetics are chemically stable under normal storage conditions (including within vaporizers), decomposition can occur under certain environmental conditions.
Sevoflurane Breakdown and Compound A
When sevoflurane contacts CO2 adsorbents containing a strong base (Baralyme or soda lime), chemical decomposition occurs, releasing volatile breakdown products.225 Compound A generation does not take place with “Amsorb,” a CO2 absorbent without strong alkali metal hydroxides. The major degradation product, compound A (fluoromethyl-2-2-difluoro-1-[trifluoromethyl] vinyl ether), was shown to cause renal injury and death in rats when inhaled at high levels.226 Renal injury is both dose and time dependent, with a threshold of 150 to 300 ppm hours for detectable injury in laboratory animals. Nonetheless, in human volunteer and clinical studies, serum urea nitrogen (BUN) and creatinine levels remain unchanged after exposures that sometimes exceed 300 ppm hours. It is thought that humans sustain less renal injury than rats after compound A exposure because of lower levels of renal cysteine conjugated β-lyase enzyme activity.227,228 Special laboratory markers for subtle renal tubular damage in humans are elevated after 300 ppm hours of compound A exposure, and these normalize within a few days.229
In clinical settings, the inhaled concentration of compound A is proportional to the sevoflurane concentration and inversely related to FGFs. Whereas low gas flows allow compound A to accumulate in the breathing circuit, high gas flows wash out compound A with waste gases. At FGFs of 2 L/min or higher, concentrations of compound A are low enough that the conservative exposure threshold of 150 ppm hours is unlikely to be reached. Sevoflurane package labeling guidelines should be heeded. Clinical studies using standard renal function tests demonstrated that sevoflurane is no more harmful than isoflurane when administered with low FGFs to patients with preexisting renal disease.230
Volatile Anesthetic Breakdown and Desiccated Carbon Dioxide Adsorbents
All of the halogenated volatile anesthetics degrade in the presence of dry alkaline CO2 adsorbents in rebreathing circuits. Decomposition in the presence of dry CO2 adsorbents releases carbon monoxide (CO), formaldehyde, methanol, and heat. These exothermic reactions have resulted in the ignition of breathing circuit components231 and acute respiratory distress syndrome in patients232 and can raise carboxyhemoglobin levels in patients.233 Prevention of these problems is achieved by avoiding desiccation and the strong base CO2 absorbents that accelerate anesthetic breakdown. The base strength of adsorbents depends on their chemical composition: In descending order of reactivity, these bases are KOH > NaOH >> Ba[OH]2. Sevoflurane releases more heat than desflurane or isoflurane,234 and carbon monoxide production is highest with desflurane > enflurane > isoflurane > sevoflurane > halothane.235,236
Photochemical Breakdown of Anesthetic Waste Gases
Waste gases scavenged from anesthesia machines enter the atmosphere, where they are exposed to solar radiation and other gases.237,238 Ultraviolet light catalyzes the reaction between N2O and O2, producing the free radical nitric oxide, which in turn destroys atmospheric ozone.239 Waste N2O from medical uses is about 3% of the total emissions (the majority results from agriculture and combustion of fossil fuels). Halogenated volatile anesthetics act as greenhouse gases.240,241 Halogenated anesthetics also break down when exposed to ultraviolet light to form halogen free radicals, which deplete atmospheric ozone. Volatile anesthetic waste gases represent only a small portion of total atmospheric chlorofluorocarbons, and their ozone-depleting effects are considered to be minimal.
BIOTRANSFORMATION OF INHALED ANESTHETICS
In the liver, enzymes can transform volatile anesthetics by oxidation, reduction, and conjugation.242 These reactions convert hydrophobic substrates into more hydrophilic metabolites that are excreted via the kidneys. Of these, the most important pathways for volatile anesthetics are oxidative, and the enzymes responsible are various members of the large cytochrome P450 (CYP) family. Neonates lack some enzymes that are present in older humans, and diverse other factors, such as drug use and genetic variation, can alter individual metabolic activities. Intrinsic liver disease or hepatic congestion caused by heart failure may result in diminished enzymatic capacity, and intrahepatic blood flow shunting may reduce the efficiency of drug metabolism. CYP enzyme activities may also be inhibited by drugs such as cimetidine and amiodarone or enhanced by prolonged exposure to “inducers” such as phenobarbital, phenytoin, and a wide range of other compounds, including inhaled anesthetics.
Hepatitis Associated With Volatile Anesthetics
Among the currently available agents, halothane undergoes the most hepatic metabolism (20%–25%) and is associated most frequently with significant toxicity. Usually, less than 1% of halothane metabolism is reductive. Halothane’s oxidative metabolism by CYP enzymes generates trifluoroacetic acid, bromide, and an intermediate metabolite, trifluoroacetic chloride, which can covalently modify proteins. Protein acetylation by these compounds primarily occurs within the liver, and modified proteins can act as neoantigens that stimulate the immune system to attack hepatocytes, resulting in fulminant hepatic necrosis. “Halothane hepatitis” occurs in 1 in 6000 to 1 in 35,000 adults after halothane anesthesia and is fatal in 50% to 75% of these cases.243 Genetic factors are likely involved, and females are affected about twice as frequently as males. Hepatic necrosis has been reported in many cases after multiple exposures to halothane, consistent with an amplified secondary immune response. Halothane hepatitis has also been reported in pediatric patients, but its incidence in children is 10 to 20 times lower than in adults.
Other inhaled anesthetics are metabolized by CYP enzymes to reactive acetyl intermediates that can also modify hepatic proteins. Rare cases of fulminant hepatic injury after administration of enflurane, isoflurane, and desflurane have been reported, and the incidence for each anesthetic is related to the degree of their metabolism (2.5%, 0.2%, and 0.02%, respectively).244
Metabolism of some inhaled anesthetics releases inorganic fluoride ions (F–), which can cause polyuric renal failure and increased mortality (for reviews, see Anders245 and Kharasch242). Clinical findings include hypernatremia, hyperosmolarity, and increased BUN and creatinine. This problem is primarily associated with methoxyflurane, a very blood- and tissue-soluble anesthetic that is no longer in use. Metabolic release of fluoride is linked to methoxyflurane nephrotoxicity in a dose-related manner, and its causal relationship was shown in animal experiments. Renal injury after methoxyflurane is rare at fluoride blood levels below 50 μM; moderate injury is seen at 50 to 80 μM and severe injury at higher levels. In rats, clinical and pathologic changes similar to those in human fluoride nephrotoxicity can be produced by intravenous administration of fluoride at similar levels.
Other fluorinated anesthetics, particularly enflurane and sevoflurane, release detectable amounts of fluoride when metabolized in the liver. Nephrotoxicity, however, is rarely associated with these drugs. Serum fluoride levels during and after enflurane anesthesia are usually below 50 μM, but those during and after sevoflurane anesthesia often peak above 50 μM. However, sevoflurane is much less soluble in blood and tissue than methoxyflurane. Sevoflurane is eliminated rapidly at the end of anesthesia, which halts fluoride production. In contrast, methoxyflurane is retained in tissues, and fluoride concentrations continue to increase after delivery is halted, reaching peak levels 2 to 3 days after anesthesia. Moreover, methoxyflurane is decomposed to fluoride within the kidneys more than sevoflurane, so intrarenal fluoride levels are higher than those detected in blood samples.246
INERT GASES: FUTURE ANESTHETICS?
Although the safety of inhaled anesthetics has improved greatly since the nineteenth century, all of the currently used agents are far from ideal because of their toxic effects on various physiologic systems (Table 34-9). The inert gas xenon was shown to produce anesthesia in 1951, and further study has revealed a pharmacokinetic and pharmacodynamic profile that approaches the ideal for an inhalational anesthetic.247 Xenon is an odorless, tasteless, nonflammable, and nonexplosive gas. Similar to other noble gases (helium, neon, argon, krypton, and radon), it is extremely chemically inert, undergoes no metabolic transformation, and has no direct negative environmental effects. Xenon does not cause airway irritation, and its blood-gas partition coefficient is 0.14, which makes inhalation induction significantly faster than with N2O or desflurane. Xenon, similar to N2O, produces minimal cardiovascular or respiratory depression. It produces no direct systemic organ toxicity, and there is evidence that xenon has neuroprotective effects,248,249 including the attenuation of cognitive dysfunction after cardiopulmonary bypass in an animal model.250 However, clinical studies have not demonstrated this benefit in patients.251,252
Table 34-9Advantages and Disadvantages of Inhaled Anesthetics ||Download (.pdf) Table 34-9 Advantages and Disadvantages of Inhaled Anesthetics
|Anesthetic ||Advantages ||Disadvantages |
|Nitrous oxide || |
No odor, taste, or pungency
Rapid uptake and elimination
Minimal cardiovascular depression
|Halothane || || |
|Enflurane || |
Good muscle relaxation
Stable heart rate
|Isoflurane || |
Good muscle relaxation
Maintains cardiac output
|Desflurane || || |
|Sevoflurane || || |
|Xenon || |
No odor, taste, or pungency
Very rapid uptake and elimination
Minimal cardiovascular depression
No toxic metabolites
Limited worldwide supply
Because MAC for xenon is about 0.7 atm for patients near age 40 years and ED95 ≈ 1.3 × MAC ≈ 0.9 atm, its use as a sole anesthetic agent is likely limited to older patients who require lower concentrations. One of its few negative physiological effects, similar to N2O, is airspace expansion. Xenon has analgesic effects, which are likely attributable to inhibition of N-methyl-d-aspartate (NMDA)–sensitive glutamate receptors. Unlike ketamine, an intravenous anesthetic that also acts on NMDA receptors, xenon is not associated with emergence delirium.
The main barrier to routine use of xenon is the high cost of its fractional distillation from air, where its concentration is about 1 part per 12 million. Xenon cannot be synthesized, so these factors are unlikely to change unless new sources are discovered. Energy expended in collecting xenon also creates secondary negative environmental impacts. Methods for conserving (closed-circuit delivery) and recycling xenon may make its clinical use economically possible in the future.
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