Handbook of Clinical Anesthesia

Chapter 17

Inhaled Anesthetics

The popularity of inhaled anesthetics for establishing general anesthesia is based on their ease of administration (via inhalation) and the ability to monitor their effects (clinical signs and end-tidal concentrations) (Fig. 17-1) (Ebert TJ, Schmid PG: Inhaled anesthetics. In Clinical Anesthesia. Edited by Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC. Philadelphia: Lippincott Williams & Wilkins, 2009, pp 411–443). The most popular potent inhaled anesthetics used in adult surgical procedures are sevoflurane, desflurane, and isoflurane (Fig. 17-1). Sevoflurane is the most commonly used inhaled anesthetic for pediatric patients.

1. Pharmacokinetic Principles
2. Drug pharmacologyis classically divided into pharmacodynamics (what the body does to a drug) and pharmacokinetics (what the drug does to the body). Drug pharmacokinetics has four phases: absorption (uptake), distribution, metabolism, and excretion (elimination).
3. Unique Features of Inhaled Anesthetics
4. Speed, Gas State, and Route of Administration.The inhaled anesthetics are among the most rapidly acting drugs in existence, and when administering a general anesthetic, this speed provides a margin of safety and also means efficiency.
5. Technically, nitrous oxide and xenon are the only true gases; the other inhaled anesthetics are vapors of volatile liquids (for simplicity, all of them are referred to as gases).
6. A unique advantage of anesthetic gases is the ability to deliver them to the bloodstream via the patient's lungs.

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Figure 17-1. Chemical structure of inhaled anesthetics. Whereas halothane (no longer commercially available) is an alkane, all the other volatile anesthetics are ether derivatives. Isoflurane, enflurane, and desflurane are methyl ethyl ether derivatives, and sevoflurane is a methyl isopropyl ether. Isoflurane and enflurane are isomers, and desflurane differs from isoflurane in the substitution of a fluorine for a chlorine atom.

1. Physical Characteristics of Inhaled Anesthetics(Tables 17-1 and 17-2)
2. The goal of delivering inhaled anesthetics is to produce the anesthetic state by establishing a specific concentration (partial pressure) in the central nervous system (CNS). This is achieved by establishing the desired partial pressure in the lungs that ultimately equilibrates with the brain and spinal cord.
3. At equilibrium, the CNS partial pressure equals the blood partial pressure, which equals alveolar partial pressure.

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Table 17-1 Physiochemical Properties of Volatile Anesthetics

Sevoflurane Desflurane Isoflurane Enflurane Halothane Nitrous Oxide Boiling point (°C) 59 24 49 57 50 -88 Vapor pressure at 20°C (mm Hg) 157 669 238 172 243 38,770 Molecular weight (g) 200 168 184 184 197 44 Oil:gas partition coefficient 47 19 91 97 224 1.4 Blood:gas partition coefficient 0.65 0.42 1.46 1.9 2.50 0.46 Brain:blood solubility 1.7 1.3 1.6 1.4 1.9 1.1 Fat:blood solubility 47.5 27.2 44.9 36 51.1 2.3 Muscle:blood solubility 3.1 2.0 2.9 1.7 3.4 1.2 MAC in oxygen, 30–60 yr at 37°C, PB760 (%) 1.8 6.6 1.17 1.63 0.75 104 MAC in 60% to 70% nitrous oxide 0.66 2.38 0.56 0.57 0.29   MAC, >65 yr (%) 1.45 5.17 1.0 1.55 0.64   Preservative No Yes No No Thymol No Stable in moist carbon dioxide absorbents No Yes Yes Yes No Yes Flammability (%) (in and 30% oxygen) 10 17 7 5.8 4.8   Recovered as metabolites (%) 2–5 0.02 0.2 2.4 20   MAC = minimum alveolar concentration.

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Table 17-2 Tissue Groups and Pharmacokinetics

Group % Body Mass % Cardiac Output Perfusion (mL/min/100 g) Vessel rich 10 75 75 Muscle 50 19 3 Fat 20 6 3

1. Anesthetic Transfer: Machine to Central Nervous System(Table 17-3)
2. Uptake and Distribution
3. F_A/F_I. A common way to assess anesthetic uptake is to follow the ratio of the alveolar anesthetic concentration (F_A) to the inspired anesthetic concentration (F_I) over time (F_A/F_I) (Fig. 17-2).

Figure 17-2. The increase in the alveolar anesthetic concentration (FA) toward the inspired anesthetic concentration (FI) is most rapid with the least-soluble anesthetics (nitrous oxide, desflurane, and sevoflurane) and intermediate with the more soluble anesthetics (isoflurane and halothane). After 10 to 15 minutes of administration (about three time constants), the slope of the curve decreases reflecting saturation of vessel-rich group tissues and subsequent decreased uptake of the inhaled anesthetic.

Table 17-3 Factors That Increase or Decrease the Rate of Increase of Alveolar Anesthetic Concentration (FA)/Inspired Anesthetic Concentration (FI)

Increase Decrease   Low blood solubility High blood solubility The lower the blood:gas solubility, the faster the increase in FA/FI Low cardiac output High cardiac output The lower the cardiac output, the faster the increase in the FA/FI High minute ventilation Low minute ventilation The higher the minute ventilation, the faster the increase in FA/FI High pulmonary arterial to venous partial venous partial Low pulmonary arterial to venous partial venous partial At the beginning of induction, the pulmonary to venous blood partial pressure gradient is zero, but it increases rapidly, and FA/FI increases rapidly. Later during induction and maintenance, the pulmonary venous blood partial pressure increases more slowly, so FA/FI increases more slowly

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2. Distribution (Tissue Uptake).Factors that increase or decrease the rate of increase of F_A/F_I determine the speed of induction of anesthesia (Fig. 17-2 and Table 17-3).
3. Metabolismplays little role in opposing induction but may have some significance in determining the rate of recovery.
4. Overpressurization and Concentration Effect
5. Overpressurization (delivering a higher F_Ithan the F_A actually desired for the patient) is analogous to an intravenous bolus and thus speeds the induction of anesthesia.
6. Concentration effect (the greater the F_Iof an inhaled anesthetic, the more rapid the rate of increase of the F_A/F_I) is a method used to speed the induction of anesthesia (Fig. 17-3).

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Figure 17-3. The concentration effect is demonstrated in the top half of the graph in which 70% nitrous oxide produces a more rapid increase in the alveolar anesthetic concentration (FA)/inspired anesthetic concentration (FI) ratio of nitrous oxide than does administration of 10% nitrous oxide. The second gas effect is demonstrated in the lower graphs in which the FA/FI ratio for halothane increases more rapidly when administered with 70% nitrous oxide than with 10% nitrous oxide.

1. Second Gas Effect
2. A special case of the concentration effect is administration of two gases simultaneously (nitrous oxide and a potent volatile anesthetic) in which the high volume uptake of nitrous oxide increases the F_A(concentrates) of the volatile anesthetic.
3. Ventilation Effects
4. Inhaled anesthetics with a low blood solubility have a rapid rate of increase in the F_A/F_Iwith induction of anesthesia such that there is little room to improve this rate of increase by increasing or decreasing ventilation (Fig. 17-3).
5. To the extent that inhaled anesthetics depress ventilation with an increasing F_I, alveolar ventilation

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decreases, as does the rate of increase of F_A/F_I (negative feedback that results in apnea and may prevent an overdose).

Figure 17-4. Elimination of anesthetic gases is defined as the ratio of end-tidal anesthetic concentration (FA) to the last FA during administration and immediately before beginning elimination (FAO). During the 120-minute period after ending anesthetic delivery, the elimination of sevoflurane and desflurane is 2 to 2.5 times faster than the elimination of isoflurane or halothane.

1. Perfusion Effects
2. As with ventilation, cardiac output does not greatly affect the rate of increase of the F_A/F_Ifor poorly soluble anesthetics.
3. Cardiovascular depression caused by a high F_Iresults in depression of anesthetic uptake from the lungs and increases the rate of increase of F_A/F_I (positive feedback that may result in profound cardiovascular depression).
4. Exhalation and Recovery
5. Recovery from anesthesia, similar to induction of anesthesia, depends on the drug's solubility (primary determinant of the rate of decrease in F_A), ventilation, and cardiac output (Fig. 17-4).

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2. The “reservoir” of anesthetic in the body at the conclusion of anesthesia is determined by the solubility of the inhaled anesthetic and the dose and duration of the drug's administration (can slow the rate of decrease in the F_A).
3. Pharmacokinetic differences between recovery and induction of anesthesia include the absence of overpressurization (cannot give less than zero) during recovery and the presence of tissue anesthetic concentrations present at the start of recovery (tissue concentration of zero at the start of anesthesia induction).
4. Clinical Overview of Current Inhaled Anesthetics (Table 17-1 and Fig. 17-1)
5. Isoflurane
6. Isoflurane is a halogenated methyl ethyl ether that has a high degree of stability and has become the “gold standard” anesthetic since its introduction in the 1970s.
7. Coronary vasodilation is a characteristic of isoflurane, and in patients with coronary artery disease, there has been concern that coronary steal could occur (rare occurrence).
8. Desflurane
9. Desflurane is a completely fluorinated methyl ethyl ether that differs from isoflurane only by replacement of a chlorine with a fluorine atom.
10. Compared with isoflurane, fluorination of desflurane results in low tissue and blood solubility (similar to nitrous oxide), greater stability (near-absent metabolism to trifluoroacetate), loss of potency, and a high vapor pressure (decreased intermolecular attraction). A heated and pressurized vaporizer requiring electrical power is necessary to deliver desflurane.
11. Disadvantages of desflurane include its pungency (it cannot be administered by face mask to an awake patient), transient sympathetic nervous system stimulation when F_Iis abruptly increased, and degradation to carbon monoxide when exposed to dry carbon dioxide absorbents (more so than isoflurane).
12. Sevoflurane
13. Sevoflurane is completely fluorinated methyl isopropyl ether with a vapor pressure similar to that of isoflurane. It can be used in a conventional vaporizer.

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2. Compared with isoflurane, sevoflurane is less soluble in blood and tissues (it resembles desflurane), is less potent, and lacks coronary artery vasodilating properties.
3. Sevoflurane has minimal odor and pungency (it is useful for mask induction of anesthesia) and is a potent bronchodilator.
4. Similar to enflurane, the metabolism of sevoflurane results in fluoride, but unlike enflurane, this has not been associated with renal concentrating defects.
5. Unlike other volatile anesthetics, sevoflurane is not metabolized to trifluroacetate but rather to hexafluoroisopropanol, which does not stimulate formation of antibodies and immune-mediated hepatitis.
6. Sevoflurane does not decompose to carbon monoxide or to dry carbon dioxide absorbents but rather is degraded to a vinyl halide (compound A), which is a dose-dependent nephrotoxin in rats. Renal injury has not been shown to occur in patients, even when fresh gas flows are 1 L/min or less.
7. Xenon
8. This inert gas has many characteristics of an “ideal” inhaled anesthetic (blood gas partition coefficient of 0.14, provides some analgesia, nonpungent, does not produce myocardial depression).
9. The principal disadvantages of xenon are its expense (difficult to obtain) and high minimum alveolar concentration (MAC) (71%).
10. Nitrous Oxide
11. Nitrous oxide is a sweet-smelling, nonflammable gas of low potency and limited blood and tissue solubility that is most often administered as an adjuvant in combination with other volatile anesthetics or opioids.
12. Controversy surrounding the use of nitrous oxide is related to its unclear role in postoperative nausea and vomiting, potential toxicity related to inactivation of vitamin B₁₂, effects on embryonic development, and adverse effects related to its absorption into air-filled cavities and bubbles. (Compliant spaces such as a pneumothorax expand, and noncompliant spaces such as the middle ear experience increased pressure.)

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1. Inhalation of 75% nitrous oxide may expand a pneumothorax to double its size in 10 minutes.
2. Accumulation of nitrous oxide in the middle ear may diminish hearing after surgery.

III. Neuropharmacology of Inhaled Anesthetics

1. Minimum Alveolar Concentration
2. MAC is the F_Aof an anesthetic at 1 atm and 37°C that prevents movement in response to a surgical stimulus in 50% of patients (analogous to an ED50 for injected drugs; Table 17-1). Clinical experience is that 1.2 to 1.3 MAC consistently prevents patient movement during surgical stimulation. Although these MAC levels do not absolutely ensure the defining criteria for brain anesthesia (i.e., the absence of self-awareness and recall), it is unlikely for a patient to be aware of or to recall the surgical incision at these anesthetic concentrations unless other conditions exist so that MAC is increased (Table 17-4). Self-awareness and recall are prevented by 0.4 to 0.5 MAC.
3. Standard MAC values are roughly additive (0.5 MAC of a volatile anesthetic and 0.5 MAC of nitrous oxide is equivalent to 1 MAC of the volatile anesthetic).
4. A variety of factors may increase or decrease MAC (Table 17-4).
5. Other Alterations in Neurophysiology.The currently used volatile anesthetics have qualitatively similar effects on cerebral metabolic rate, the electroencephalogram (EEG), cerebral blood flow (CBF), and flow–metabolism coupling. There are differences in effects on intracerebral pressure, cerebrospinal fluid (CSF) production and resorption, CO₂reactivity, CBF autoregulation, and cerebral protection. Nitrous oxide departs from the more potent agents in several respects.
6. Cerebral Metabolic Rate and Electroencephalogram.All of the potent agents depress cerebral metabolic rate (CMR) to varying degrees in a nonlinear fashion. As soon as spontaneous cortical neuronal activity is absent (isoelectric EEG), no further decreases in CMR are generated.
7. Desflurane and sevoflurane decrease CMR similar to isoflurane.

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Table 17-4 Factors That Influence (Increase or Decrease) Minimum Alveolar Concentration

Increase Increased central neurotransmitter levels (monoamine oxidase inhibitors, acute dextroamphetamine administration, cocaine, ephedrine, levodopa) Hyperthermia Chronic ethanol abuse Hypernatremia Decrease Increasing age Metabolic acidosis Hypoxia (PaO2 38 mm Hg) Induced hypotension (MAP <50 mm Hg) Decreased central neurotransmitter levels (alpha-methyldopa, reserpine) α-2 Agonists Hypothermia Hyponatremia Lithium Hypo-osmolality Pregnancy Acute ethanol administration Ketamine Lidocaine Opioids Opioid agonist–antagonist analgesics Barbiturates Diazepam Hydroxyzine Delta-9-Tetrahydrocannabinol Verapamil Anemia (<4.3 mL oxygen/dL blood)

1. Conflicting data are available concerning whether sevoflurane has proconvulsant effects. (This questions the appropriateness of administering it to patients with epilepsy.)
2. Cerebral Blood Flow, Flow–Metabolism Coupling, and Autoregulation.All of the potent agents increase CBF in a dose-dependent manner (Fig. 17-5). The dose-dependent increase in CBF caused by volatile anesthetics occurs despite concomitant decreases in cerebral metabolic rate (uncoupling).

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Figure 17-5. Cerebral blood flow measured in the presence of normocapnia and in the absence of surgical stimulation in volunteers. At light levels of anesthesia, halothane (but not isoflurane, sevoflurane, or desflurane) increases cerebral blood flow. Isoflurane increases cerebral blood flow at 1.6 minimum alveolar concentration (MAC).

3. Intracerebral pressure (ICP)parallels CBF, and mild increases in ICP accompany isoflurane, sevoflurane, and desflurane concentrations above 1 MAC.
4. Cerebrospinal Fluid Production and Resorption.Anesthetic effects on ICP via changes in CSF dynamics are less important than anesthetic effects on CBF.
5. Cerebral Blood Flow Response to Hyper- and Hypocarbia.Significant hypercapnia is associated with dramatic increases in CBF with or without the administration of volatile anesthetics.
6. Cerebral Protection.Cerebral hypoperfusion secondary to hypotension may be associated with better tissue oxygenation than during hypotension by other means. Human neuroprotection outcome studies for sevoflurane and desflurane have not been published.
7. Processed Electroencephalograms and Neuromonitoring.All volatile anesthetics produce dose-dependent effects on the EEG, sensory evoked potentials, and motor evoked potentials. Visual evoked potentials are more sensitive to the effects of volatile anesthetics than are somatosensory evoked potentials.

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1. Nitrous Oxide.The effects of nitrous oxide on cerebral physiology are not clear (these effects vary widely with species). However, nitrous oxide appears to have an antineuroprotective effect.
2. The Circulatory System
3. Hemodynamics
4. Volatile anesthetics produced dose-dependent and similar decreases in systemic blood pressure (Fig. 17-6). The primary mechanism to decrease blood pressure with increasing dose is related to their potent effects to lower regional and systemic vascular resistance (Fig. 17-7).
5. In volunteers, sevoflurane to about 1 MAC results in minimal changes in heart rate; isoflurane and desflurane are associated with an increase of 5% to 10% from baseline 10 to 15 (Fig. 17-6).
6. Rapid increases in the delivered concentration of desflurane (and to a lesser extent, isoflurane) may transiently increase heart rate and systemic blood pressure.
7. Administration of an opioid or clonidine blunts the heart rate responses evoked by volatile anesthetics, including responses associated with abrupt increases in the delivered concentration of volatile drug.
8. Myocardial Contractility.Human studies with isoflurane, sevoflurane, and desflurane have not demonstrated significant changes in echocardiographic-determined indices of myocardial function.
9. Other Circulatory Effects
10. Nitrous oxide is associated with increased sympathetic nervous system activity when administered alone or in combination with other volatile anesthetics.
11. Isoflurane, sevoflurane, and desflurane do not predispose patients to ventricular arrhythmias or sensitize the heart to the arrhythmogenic effects of epinephrine.
12. Coronary stealhas not been confirmed to occur with isoflurane, desflurane, or sevoflurane concentrations up to 1.5 MAC.
13. Myocardial ischemia and cardiac outcomeseem more related to events that alter myocardial oxygen delivery

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and demand rather than the specific anesthetic drug selected.

Figure 17-6. Heart rate and systemic blood pressure changes (from awake baseline) in volunteers receiving general anesthesia with a volatile anesthetic. Halothane and sevoflurane produced little change in heart rate at less than 1.5 minimum alveolar concentration. All anesthetics caused similar decreases in blood pressure. MAP = mean arterial pressure.

1. Cardioprotection from Volatile Anesthetics
2. Volatile anesthetics mimic ischemia preconditioning and initiate a cascade of intracellular events resulting in myocardial protection against ischemia and reperfusion

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injury that last beyond elimination of the anesthetic.

Figure 17-7. Cardiac index, systemic vascular resistance, and central venous pressure (CVP) changes from awake baseline in volunteers receiving general anesthesia with a volatile anesthetic. Whereas increases in CVP in the presence of halothane may reflect myocardial depression, increases in the presence of desflurane are more likely caused by venoconstriction.

2. It is likely that anesthetic cardioprotection lessens myocardial damage (based on troponin levels) during cardiac surgery with or without cardiopulmonary bypass.
3. Sulfonylurea oral hyperglycemic drugs close K_ATPchannels and abolish anesthetic preconditioning. Hyperglycemia also prevents preconditioning, so insulin therapy should be started when oral agents are discontinued before surgery.
4. Autonomic Nervous System
5. Isoflurane, desflurane, and sevoflurane produce similar dose-dependent depression of reflex control of sympathetic nervous system outflow.
6. Desflurane is unique in evoking increased sympathetic nervous system outflow (paralleled by increased plasma concentrations of catecholamine) when the delivered concentration of this drug is abruptly increased (Fig. 17-8).
7. The Pulmonary System
8. General Ventilatory Effects.All volatile anesthetics decrease tidal volume but have lesser effects on decreasing minute ventilation because of an offsetting response to increase breathing frequency (Fig. 17-9). The increase in resting PaCO₂ as an index of depression of ventilation is somewhat offset by surgical stimulation (Fig. 17-10). The degree of respiratory depression from inhaled anesthetics is reduced when anesthesia administration exceeds 5 hours.
9. Ventilatory mechanics.Functional residual capacity is decreased during general anesthesia (decreased intercostal muscle tone, alterations in diaphragm position, changes in thoracic blood volume).
10. Response to Carbon Dioxide and Hypoxemia
11. All of the inhaled anesthetics produce a dose-dependent depression in the ventilatory response to hypercarbia (Fig. 17-11).
12. Even subanesthetic concentrations of volatile anesthetics (0.1 MAC) produce depression of chemoreceptors responsible for the ventilatory response to hypoxia.

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Figure 17-8. Stress hormone responses to a rapid increase in anesthetic concentration from 4% to 12% inspired. Data are mean ± SE. A = awake; B = value after 32 minutes of 0.55 minimum alveolar concentration (MAC). Time represents minutes after initiation of increased anesthetic concentration.

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Figure 17-9. Comparison of mean changes in resting PaCO2, tidal volume, respiratory rate, and minute ventilation in patients receiving an inhaled anesthetic.

1. Bronchiolar Smooth Muscle Tone
2. Bronchoconstriction during anesthesia is most likely caused by mechanical stimulation of the airway in the presence of minimal concentrations of inhaled anesthetics. This response is enhanced in patients with reactive airway disease.
3. Volatile anesthetics relax airway smooth muscle by directly depressing smooth muscle contractility and indirectly by inhibiting the reflex neural pathways. Airway resistance increases more with desflurane than sevoflurane (Fig. 17-12).
4. Pulmonary Vascular Resistance
5. The pulmonary vasodilator action of volatile anesthetics is minimal. The effect of nitrous oxide on

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pulmonary vascular resistance may be exaggerated in patients with resting pulmonary hypertension.

Figure 17-10. The effect of surgical stimulation on the ventilatory depression produced by isoflurane with or without nitrous oxide.

2. All inhaled anesthetics inhibit hypoxic pulmonary vasoconstriction in animals. Nevertheless, in patients undergoing one-lung ventilation during thoracic surgery, minimal effects on PaO₂and intrapulmonary shunt fraction occur regardless of the volatile anesthetic being administered (Fig. 17-13).
3. Hepatic Effects
4. Postoperative liver dysfunction has been associated to varying degrees with all of the volatile anesthetics in common use. Anesthetics may cause hepatitis that is mild and does not require a previous exposure. Another mechanism requires repeat exposure and probably represents an immune reaction to oxidatively derived metabolites of anesthetics.
5. Ether-based anesthetics (isoflurane, desflurane, sevoflurane) maintain or increase hepatic artery blood flow while decreasing or not changing portal vein blood flow (Fig. 17-14).

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Figure 17-11. All inhaled anesthetics produce similar dose-dependent decreases in the ventilatory response to carbon dioxide.

Figure 17-12. Changes in airway resistance before (baseline) and after tracheal intubation were significantly different in the presence of sevoflurane compared with desflurane.

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Figure 17-13. Shunt fraction (top panel) and alveolar–arterial oxygen gradient (bottom panel) before, during, and after one-lung ventilation (OLV) in patients anesthetized with desflurane or isoflurane.

VII. Neuromuscular System and Malignant Hyperthermia

1. Volatile anesthetics (not nitrous oxide) directly relax skeletal muscle (most prominent >1 MAC) and potentiate the action of neuromuscular blocking drugs. (The infusion rate of rocuronium required to maintain neuromuscular blockade is 30% to 40% less with isoflurane, desflurane, and sevoflurane than with propofol.)
2. Although the mechanism of this potentiation is not entirely clear, it appears to be largely caused by a postsynaptic effect at the nicotinic acetylcholine receptors located at the neuromuscular junction. (Volatile anesthetics act synergistically with neuromuscular blocking drugs to enhance their action.)

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Figure 17-14. Changes (%, mean ≠ SE) in hepatic blood flow during administration of isoflurane or halothane.

1. All volatile anesthetics serve as triggers for malignant hyperthermia (halothane greatest and desflurane less), but nitrous oxide is only a weak trigger.

VIII. Genetic Effects, Obstetric Use, and Effects on Fetal Development

1. The Ames test, which identifies chemicals that act as mutagens and carcinogens, is negative for isoflurane, desflurane, sevoflurane, and nitrous oxide.
2. Volatile anesthetics can be teratogenic in animals but none of them has been shown to be teratogenic in humans.
3. Nitrous oxide decreases the activity of vitamin B₁₂-dependent enzymes (methionine synthetase, thymidylate synthetase) by irreversible oxidation of the cobalt atom of vitamin B₁₂by nitrous oxide.
4. Administration of 70% nitrous oxide results in 50% inactivation of methionine synthetase in 46 minutes.

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2. There is concern these changes might have an effect on a rapidly developing embryo or fetus because methionine synthetase and thymidylate synthetase are involved in the formation of myelin and DNA, respectively.
3. A sensory neuropathy that is often combined with signs of posterior lateral spinal cord degenerations has been described in humans who chronically inhaled nitrous oxide for recreational use.
4. Uterine smooth muscle tone is diminished by volatile anesthetics in similar fashion (dose dependent) to the effects of volatile anesthetics on vascular smooth muscle.
5. Uterine relaxation can be troubling at concentrations of volatile anesthetics above 1 MAC and may delay the onset time of newborn respiration. Consequently, for an urgent cesarean section, a common technique is general anesthesia with low concentrations of the volatile anesthetic (0.5–0.75 MAC) combined with nitrous oxide.
6. Uterine relaxation may be desirable when it is necessary to remove a retained placenta.
7. No causal relationship has been shown between exposure to waste anesthetic gases, regardless of the presence or absence of scavenging systems, and adverse health effects. Despite the unproven influence of trace concentrations of volatile anesthetics on fetal development and spontaneous abortions, the use of scavengering systems is common. The National Institute for Occupational Safety and Health recommends exposure levels of 25 parts per million for nitrous oxide and 2 parts per million for halogenated anesthetics.
8. Anesthetic Degradation by Carbon Dioxide Absorbers
9. Compound A
10. Sevoflurane undergoes base catalyzed degradation in carbon dioxide absorbents to form a vinyl ether designated as compound A (Fig. 17-15). The production of compound A is enhanced in low-flow and closed-circuit breathing systems and by warm or very dry carbon dioxide absorbents.

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Figure 17-15. Compound A levels produced from three carbon dioxide absorbents during 1 minimum alveolar concentration (MAC) sevoflurane anesthesia delivered at a fresh gas flow of 1 L/min (mean ≠ SE). *P < 0.05 versus soda lime and barium hydroxide lime.

2. Species differences are present in the threshold for compound A–induced nephrotoxicity. (The β-lyase– dependent metabolism pathway for compound A breakdown to cysteine-S conjugates is less in humans than rats.) There is a high probability that renal injury in patients receiving sevoflurane does not occur regardless of the fresh gas flow rate.
3. Carbon Monoxide and Heat
4. Carbon dioxide absorbents degrade sevoflurane, desflurane, isoflurane, and isoflurane to carbon monoxide (patients at risk for carbon monoxide intoxication) when carbon dioxide absorbent has become desiccated (water content <5%).
5. The degradation is the result of an exothermic reaction of the anesthetics with the absorbent.
6. Instances of carbon monoxide poisoning have occurred when the carbon dioxide absorbent has been presumably desiccated because an anesthetic machine has been left on with a high fresh gas flow passing through the carbon dioxide absorbent over an extended period.
7. Although desflurane produces the most carbon monoxide with anhydrous carbon dioxide absorbents the reaction with sevoflurane produces the most heat. This is an exothermic reaction with the potential for fires and patient injuries.

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3. Although sevoflurane is not flammable at less than 11%, formaldehyde, methanol, and formate may result from degradation at high temperatures and when combined with oxygen may be flammable.
4. Generic Sevoflurane Formulations.Although the generic formulations of sevoflurane are chemically equivalent, the water content of the formulations differs, resulting in different resistance to degradation to hydrogen fluoride when exposed to Lewis acids (metal halides and metal oxides that are present in modern vaporizers).
5. Anesthetic Metabolism
6. Fluoride-Induced Nephrotoxicity
7. The safety of sevoflurane with regard to fluoride concentrations may be caused by a rapid decline in plasma fluoride concentrations because of less availability of the anesthetic for metabolism from a faster washout compared with enflurane.
8. Furthermore, a minimal amount of renal defluorination may contribute to the relative absence of renal concentrating defects.
9. Clinical Utility of Volatile Anesthetics
10. For Induction of Anesthesia.There is renewed interest in mask induction of anesthesia (especially pediatric patients) using sevoflurane (which is poorly soluble and nonpungent).
11. For Maintenance of Anesthesia.Because of their ease of administration and ability to adjust (titrate) the dose, volatile anesthetics remain the most popular drugs for maintenance of anesthesia.

XII. Pharmacoeconomics and Value-Based Decisions

1. In the current environment of cost containment, clinicians are constantly pressured to use less expensive anesthetic agents, including antiemetics, neuromuscular blocking drugs, and volatile anesthetics.

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1. Factors involved in value-based decisions include drug efficacy (all volatile anesthetics are similar in efficacy) and side effects (hepatic toxicity and cardiac sensitization cause by halothane offset its low cost).
2. The need for rescue medications to treat nausea and vomiting after volatile anesthesia should be weighed in any cost analysis.
3. Reducing the fresh gas flow of sevoflurane and desflurane can decrease by half the cost per MAC hour of these more expensive anesthetics without compromising their speed and effectiveness.

Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine

Title: Handbook of Clinical Anesthesia, 6th Edition

Copyright ©2009 Lippincott Williams & Wilkins

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