Chapter 5 Inhaled Anesthetics
Physical properties
4. Why are vaporizers required for the inhaled administration of volatile anesthetics?
5. Describe how a vaporizer for volatile anesthetics works.
6. What are the characteristics of desflurane that preclude its delivery in the conventional variable-bypass vaporizer?
7. What considerations must be taken into account when administering inhaled anesthetics at high altitude?
8. What are two potentially toxic compounds that can be produced as a result of the degradation or metabolism of volatile anesthetics?
9. What is a potentially toxic compound that can be produced as a result of the interaction between sevoflurane and the carbon dioxide absorbent? What factors may increase this risk?
10. What is the potential risk of human exposure to compound A? How can this risk be minimized?
11. What is a potentially toxic compound that can be produced as a result of the interaction between desflurane and the carbon dioxide absorbent? What factors may increase this risk?
12. What is the potential risk of carbon monoxide production from the carbon dioxide absorbent?
Relative potency of inhaled anesthetics
13. How are relative inhaled anesthetic potencies compared?
14. What are MAC values for isoflurane, sevoflurane, desflurane, and nitrous oxide in a 30- to 55-year-old?
15. What concentration of anesthetic is sufficient to provide amnesia in volunteers? How does this value relate to surgical patients?
Pharmacokinetics of inhaled anesthetics
18. Describe the process by which induction of anesthesia is achieved by an inhaled anesthetic.
19. What six factors determine the alveolar partial pressure of anesthetic?
20. Describe a strategy that allows maintenance of stable anesthetic partial pressure in the brain after the induction of anesthesia.
21. How does a shunt affect the induction of an inhalation anesthetic?
22. How is anesthetic solubility expressed?
23. How does anesthetic solubility influence speed of induction?
24. What is the “second gas effect”?
25. How does nitrous oxide affect the enzyme methionine synthase? How might this relationship affect patients receiving nitrous oxide?
26. How does nitrous oxide affect closed air-filled spaces in the body? What is the clinical relevance of this?
27. What are some differences between the induction of inhaled anesthesia and recovery from anesthesia?
Circulatory effects
30. Why might an individual patient’s responses vary in the circulatory effects of equipotent doses of a given inhaled volatile anesthetic?
31. How do inhaled volatile anesthetics affect arterial blood pressure? What is the mechanism by which this effect occurs?
32. How does the substitution of nitrous oxide for an equipotent portion of volatile anesthetic affect arterial blood pressure at a given anesthetic dose?
33. How do inhaled volatile anesthetics affect heart rate? What is the mechanism by which this occurs?
34. How do inhaled volatile anesthetics affect cardiac output?
35. How do inhaled volatile anesthetics affect myocardial rhythm?
36. How do inhaled volatile anesthetics affect myocardial conduction?
37. How do inhaled volatile anesthetics affect coronary artery blood flow? What is coronary artery steal syndrome? What is its clinical relevance?
Effects on ventilation
38. How is the rate of breathing affected by inhaled volatile anesthetics?
39. How is the tidal volume affected by inhaled volatile anesthetics?
40. How is the minute ventilation affected by inhaled volatile anesthetics? How is the overall pattern of ventilation affected by inhaled volatile anesthetics?
41. How is the ventilatory drive affected by inhaled volatile anesthetics?
42. How does the addition of nitrous oxide to a volatile anesthetic affect the ventilatory drive and the resultant PaCO2?
43. How do inhaled volatile anesthetics affect hypoxic pulmonary vasoconstriction?
44. How do inhaled volatile anesthetics affect bronchial tone?
45. How do inhaled anesthetics differ in their capacity to cause airway irritation? How do these differences affect their use in various clinical situations?
Other organ system effects
46. How does nitrous oxide affect cerebral blood flow and intracranial pressure?
47. How do inhaled volatile anesthetics affect cerebral blood flow and intracranial pressure?
48. How do inhaled volatile anesthetics affect cerebral metabolic oxygen requirements?
49. How do inhaled volatile anesthetics affect evoked potentials?
50. What electroencephalographic (EEG) changes occur with increasing concentration of inhaled volatile anesthetics?
51. How do inhaled volatile anesthetics affect neuromuscular function?
52. Which inhaled anesthetics have the potential to trigger malignant hyperthermia?
Answers*
Mechanism of action
1. Characteristics of the anesthetic state include immobility, amnesia, analgesia, and skeletal muscle relaxation. (81)
2. Characteristics of the anesthetic state that are achieved by inhaled volatile anesthetics include immobility, amnesia, and skeletal muscle relaxation. Analgesia is difficult to define in an amnestic, immobile patient, but surrogate measures of perception of painful stimuli (i.e., increases in heart rate or blood pressure at the time of incision or intubation) suggest that inhaled anesthetics do not possess analgesic characteristics at concentrations typically used in clinical practice. (81)
3. Nitrous oxide contributes to immobility, but is not reliable in doing so when administered alone. It has amnestic effects at higher concentration (although these are difficult to assure), and in contrast to potent inhaled anesthetics, does not contribute to skeletal muscle relaxation. (81)
Physical properties
4. Volatile anesthetics exist as liquids at room temperature and at atmospheric pressure. The inhaled delivery of these anesthetics requires that the anesthetics be vaporized. Vaporizers allow not only the vaporization of liquid anesthetics, but they also reliably and accurately deliver the specified concentration of anesthetic to the common gas outlet and ultimately to the patient. Nitrous oxide exists as a gas at room temperature and therefore does not require a vaporizer for inhaled delivery to a patient. (81)
5. Conventional volatile anesthetic vaporizers are classified as agent-specific, variable-bypass, flow-over, temperature-compensated, out-of-circuit vaporizers. After passing through the flowmeters, gases mix in the common manifold, then enter the vaporizers. Once in the vaporizer there are different streams of flow that the gases can take. The gases may be diverted by a temperature-compensating bypass valve to the bypass chamber, or they may enter the vaporizing chamber.
6. The two characteristics of desflurane that preclude its delivery in a conventional variable-bypass vaporizer are its volatility and its potency. At 20 °C, the vapor pressure of desflurane is 669 mm Hg, whereas those of isoflurane and sevoflurane are 238 mm Hg and 157 mm Hg, respectively. In addition, the boiling point of desflurane is near room temperature. Because of its volatility, erratic and dangerously high concentrations of desflurane would be delivered if a conventional variable-bypass vaporizer were to be used. The Tec-6 heated vaporizer was developed to address this problem. Desflurane’s potency is substantially lower than that of other volatile anesthetics—roughly three times less than that of sevoflurane and almost five times less than that of isoflurane. Thus, the large number of molecules converted from liquid to gas phase would create a large cooling effect (from the heat of vaporization) and it would not be possible to compensate without externally heating the anesthetic. Thus, desflurane vaporization requires a vaporizer that is electrically heated and pressurized for these reasons. (83 and Table 8-1)
7. Although vaporizer output is conventionally expressed in volumes percent, the pharmacologically relevant measure is anesthetic partial pressure. Administration of anesthesia at high altitude will result in higher volumes percent vaporizer output when a variable bypass vaporizer is used. However, the increase in anesthetic partial pressure will be minimized by the overall decrease in ambient pressure, and the clinical effect will be very small. On the other hand, the Tec 6 vaporizer behaves differently, since it is a blender of two gases and maintains constant volumes percent output. Therefore, at high altitude, although the volumes percent output will be unaffected, the delivered partial pressure will be substantially smaller and an adjustment must be made to avoid unintentional delivery of partial pressures below those clinically needed. The anesthesiologist should select the desired anesthetic vaporizer setting that would be appropriate at sea level, and multiply by this value by the ratio of sea level divided by the local barometric pressures. (82-83)
8. Two potentially toxic compounds that can be produced as a result of the degradation or metabolism of volatile anesthetics include compound A and carbon monoxide. (83)
9. A potentially toxic compound that can be produced as a result of the interaction between sevoflurane and the carbon dioxide absorbent is compound A. This can occur with either soda lime or baralyme, but the risk appears to be higher with baralyme. Other factors that may increase the risk of compound A production include the low inflow of fresh gases, high concentrations of sevoflurane, higher absorbent temperatures, and fresh absorbent. (83, Table 8-1)
10. The concern with exposure to compound A is for nephrotoxicity. Compound A has been shown to be nephrotoxic in animals. Indeed, in humans prolonged exposure to sevoflurane at low fresh gas flows (1 L/min) has been shown to result in transient proteinuria, enzymuria, and glycosuria. There has been no evidence for increased serum creatinine levels or prolonged deleterious effects, however. This is evidenced by the millions of anesthetics that have been administered with sevoflurane without harm. Regardless, the recommendation is that when sevoflurane is administered fresh gas flows should be greater than 1 L/min for the first 2 hours, then 2 L/min thereafter. (83)
11. A potentially toxic compound that can be produced as a result of the interaction between desflurane and the carbon dioxide absorbent is carbon monoxide. Carboxyhemoglobin concentrations can reach as high as 30%. This can occur with either soda lime or baralyme, but the production of carbon monoxide appears to be greater with baralyme. Other factors that appear to increase the production of carbon monoxide include the higher anesthetic concentrations, an increased temperature, and greater dryness of the absorbent. The majority of cases of carbon monoxide toxicity occurred after 2 days of disuse of the absorbent, particularly with continued airflow through the circle system. (83, Table 8-1)
12. The production of carbon monoxide from the interaction between desflurane and carbon dioxide absorbent can result in the inhaled delivery of carbon monoxide to the patient. The diagnosis of carbon monoxide poisoning under these conditions can be difficult because the toxicity may be masked by the anesthesia itself and the pulse oximetry readings are likely to be unchanged. (83)
Relative potency of inhaled anesthetics
13. Relative potency between inhaled anesthetics is most commonly described by the dose required to suppress movement in 50% of patients in response to surgical incision, known as MAC (minimum alveolar concentration). Since this dose has a standard deviation of approximately 10%, 95% of patients should not move in response to incision at 1.2 MAC, and 99% should not move at 1.3 MAC. (83-84 and Table 8-1)
14. In a 30- to 55-year-old, MAC of isoflurane is 1.15%, sevoflurane 1.85%, desflurane 6%, and nitrous oxide 104%. MAC values are additive. For example, 0.5 MAC of nitrous oxide administered with 0.5 MAC isoflurane has the same effect as 1 MAC of any inhaled anesthetic in preventing movement in response to incision. (83-84, Table 8-1)
15. The expired concentration of isoflurane that prevented recall of events in 50% of volunteers was 0.20 MAC, and the concentration preventing recall in 95% of volunteers was 0.40 MAC. Assuming a standard normal distribution in dose-response, and a standard deviation of 0.10 MAC, the calculated highest anesthetic concentration required by 1 in 100,000 subjects with the highest requirement would be 4.27 standard deviations above the mean, or 0.627 MAC or more. Extrapolation of this value to the context of surgery must be made with caution, however, because (1) the dose required to prevent recall of painful as opposed to verbal stimulation may be considerably larger; and (2) the ratio of concentration necessary to prevent recall versus MAC differs substantially between potent inhaled anesthetics and nitrous oxide (recall occurs with as much as 0.6 MAC of nitrous oxide). (84)
16. Age has a large influence on MAC, being highest at 6 months of age. After 6 months of age, MAC declines, increases again during adolescence, and thereafter declines until the end of life. Other factors that increase MAC include acute amphetamine use, cocaine, ephedrine, and chronic alcohol use. Hyperthermia, hypernatremia, and red hair color also increase MAC. (Table 8-2)
17. Older age decreases MAC. Hyponatremia, anemia, hypothermia, hypoxia, and pregnancy all decrease MAC, as does acute alcohol ingestion and chronic amphetamine use. The concomitant administration of certain drugs such as propofol, etomidate, barbiturates, ketamine, opioids, local anesthetics, benzodiazepines, α2-agonists, lithium, and verapamil all decrease MAC. (Table 8-2)
Pharmacokinetics of inhaled anesthetics
18. The induction of anesthesia relies on delivery of inhaled anesthetic from the alveoli to the brain via the arterial blood. By controlling the inspired partial pressure, a gradient is created between the machine, the alveoli, the arterial blood, and the brain. Higher inspired anesthetic partial pressure is needed during inhaled induction to offset the impact of anesthetic uptake into the blood and tissues. This is termed the concentration effect. The delivery of higher fresh gas flow allows the avoidance of rebreathing anesthetic-depleted gases. Anesthetic present in the alveoli is taken up by the blood and carried to the tissues, including the brain; initially the uptake of anesthetic in the blood limits the rate at which the partial pressure in the brain can rise. As the gradient diminishes, alveolar partial pressure approaches equilibrium with blood and vessel rich tissue and the partial pressure in the alveoli begins to reflect partial pressure in the brain. The primary objective of inhalation anesthesia is to establish equilibrium between the alveoli and the brain, such that there is a constant, optimal partial pressure of anesthetic in the brain. This can be reflected in the partial pressure of anesthetic in the alveoli, or end-tidal anesthetic value. (84)
19. The alveolar partial pressure is determined by input of anesthetic into the alveoli minus the uptake of anesthetic into the pulmonary arterial blood. The input of anesthetic into the alveoli is determined by the inspired partial pressure of anesthetic, alveolar ventilation, and the characteristics of the breathing circuit. The uptake of anesthetic from the alveoli is determined by the anesthetic solubility in blood and tissues, cardiac output, and the alveolar to venous partial pressure difference. For a high partial pressure in the alveoli, and thus a rapid induction of anesthesia, the following should occur: a high inspired partial pressure of anesthetic, a high minute ventilation, a low volume breathing circuit, high fresh gas flows, a low solubility of anesthetic in the tissues, a low cardiac output, and a small alveolar to venous partial pressure difference. (84-85 and Table 8-3)
20. A higher inspired anesthetic partial pressure is needed during an inhaled induction to offset the impact of anesthetic uptake into the blood and tissues and higher fresh gas flow allows for the avoidance of rebreathing. Uptake diminishes as the anesthetic partial pressure in blood and tissues approaches that in the alveoli. The speed at which this equilibration takes place is expressed as a time constant. The time constant related to a tissue group is correlated to the amount of anesthetic that can be dissolved in that tissue divided by the blood flow received by the tissues. The vessel-rich tissue group (i.e., brain, heart, kidneys, and liver) accounts for less than 10% of the body mass but it receives 75% of cardiac output. One time constant reflects about 67% equilibration between blood and tissue, and complete equilibration is achieved in three time constants. After three time constants (6 to 12 minutes), 75% of returning venous blood has the same anesthetic partial pressure as the alveolus, resulting in narrowing of the alveolar-venous difference, reduced uptake, and if inspired anesthetic concentration is maintained, a rapid increase in brain concentration. The brain time constant for isoflurane is 3 to 4 minutes, whereas those of sevoflurane and desflurane are about 2 minutes. Therefore, complete equilibration between alveoli and the brain may be achieved as quickly as 6 to 10 minutes. Delivered anesthetic concentration must therefore be decreased after 5 to 10 minutes to avoid a subsequent rapid rise in brain concentration after equilibration with the vessel-rich tissues has taken place. The decrease in delivered anesthetic may be achieved by decreasing vaporizer concentration, fresh gas flows, or both. (84-85, Table 8-4 and Figure 8-4)
21. A right-to-left shunt slows the rate of the induction of an inhalation anesthetic through the dilutional effect of shunted blood without the mixing of anesthetic with blood that is being delivered to the tissues from ventilated alveoli. The clinical impact of this is probably negligible, however. (87)
22. Anesthetic solubility in blood and tissues is denoted by partition coefficients. A partition coefficient can be viewed as the affinity of anesthetic for one particular tissue, and indicates the quantitative ratio of anesthetic distributed between two phases when partial pressures are equal. For example, a blood gas partition coefficient of 0.65 means that the concentration of sevoflurane in the alveolus is 1 and 0.65 in blood at equilibrium. Partition coefficients are dependent upon temperature and, unless otherwise stated, are given for 37° C. (85-86 and Table 8-1)
23. When an anesthetic has a high solubility in blood, it means that a large amount of inhaled anesthetic must be dissolved in the blood before equilibration with the gas phase is reached. The blood can be considered a pharmacologically inactive reservoir, and the size of this reservoir is directly related to the solubility of the anesthetic in blood. Therefore greater inhaled anesthetic solubility slows induction. (86 and Figure 8-5)
24. The second gas effect describes the influence of one gas, administered at high volume, on the uptake of a companion gas. The process occurs when a large volume of “first” gas (e.g., nitrous oxide) is taken up during induction, and this uptake effectively concentrates the “second” gas (oxygen or potent inhaled anesthetic) into a smaller alveolar volume. Pharmacokinetic models have proven the second gas effect, but its clinical importance is doubtful. (85)
25. Nitrous oxide inactivates methionine synthase, the enzyme that regulates vitamin B12 and folate metabolism. While this inactivation may not usually produce clinically evident change, patients with an underlying critical illness, exposure to chemotherapy, or preexisting vitamin B12 deficiency may suffer neurologic or hematologic sequelae. Another consequence of methionine synthase inactivation is increased serum homocysteine concentration since the enzyme is needed to convert cysteine to methionine. Elevated homocysteine levels and increased frequency of ischemic episodes have been concurrently demonstrated in patients undergoing carotid endarterectomy while receiving nitrous oxide. (86-87)
26. Nitrous oxide is 34 times more soluble than nitrogen in blood, as reflected by their respective blood gas partition coefficients of 0.46 versus 0.014. As a result, nitrous oxide can more readily diffuse out of the circulation and occupy an air-filled compartment than the air in the compartment can diffuse from the compartment into the circulation. The result of this imbalance is an increase in the gas contents of a closed air-filled space. The space and volume of gas will expand if the walls of the space are compliant (e.g., intestinal gas, pneumothorax, air embolism), or the pressure in the space will increase if the walls of the space are noncompliant (e.g., middle ear, eye, cerebral ventricles, supratentorial subdural space). The magnitude of volume or pressure increase in the air-filled space will be influenced by the alveolar partial pressure of nitrous oxide, blood flow to the compartment, and the duration of nitrous oxide administration. Presence of a closed pneumothorax is a contraindication to nitrous oxide administration. Difficulty with ventilation encountered in the setting of chest trauma may reflect nitrous oxide expansion of a previously unrecognized pneumothorax. Air bubbles associated with venous air embolism expand rapidly when exposed to nitrous oxide. (87)
27. The recovery from anesthesia differs from the induction of anesthesia in several ways. First, there cannot be a concentration effect to accelerate recovery. For example, the inhaled pressure of anesthetic cannot be less than zero to augment the partial pressure of anesthetic gradient from the brain to the alveoli. Second, there are variable concentrations of anesthetic in the tissues at the start of recovery, and there are thus multiple reservoirs of anesthetic throughout the body. These reservoirs are of variable influence, and their significance is dependent on the duration of the anesthetic as well as the solubility characteristic of the anesthetic itself. And finally, the metabolism of anesthetic may impact the rate of recovery. The clinical significance of the metabolism of anesthetics on the rate of recovery of anesthetics is minimal for the less lipid-soluble anesthetics such as isoflurane, desflurane, and sevoflurane. The metabolism of halothane may play a role in the rate of recovery of anesthesia. (88, Figures 8-6, 8-7)
28. All volatile anesthetics are biotransformed to a variable extent in the liver. Halothane, isoflurane, and desflurane all undergo oxidative metabolism (15% to 40%, 0.2%, and 0.02%, respectively) by cytochrome P-450 enzymes to produce trifluoroacetate. Sevoflurane is metabolized (5% to 8%) to hexafluoroisopropanol. (Table 8-1, 89, 96)
29. Diffusion hypoxia is a term used to describe the dilution of oxygen in the alveoli due to the presence of another gas. This can occur at the conclusion of a nitrous oxide anesthetic when there is an initial high volume output of nitrous oxide diffusing from the blood to the alveoli and filling the alveoli. If the patient is breathing room air at the time, the partial pressure of oxygen in the alveoli can be diluted to the extent that hypoxia results. Diffusion hypoxia at the conclusion of a nitrous oxide anesthetic can be avoided through the inhaled delivery of 100% oxygen. (90)
Circulatory effects
30. The circulatory effect of an inhaled anesthetic for a given patient is influenced by multiple factors. These can include the effects of age, surgical stimulation, coexisting diseases such as myocardial dysfunction and stenotic valve lesions, intravascular fluid volume status, and concurrent drug administration. (90)
31. The volatile anesthetics all produce a dose-dependent decrease in mean arterial blood pressure, although the mechanism by which they exert their effects varies. Halothane primarily acts to decrease blood pressure by decreasing myocardial contractility and cardiac output. Isoflurane, desflurane, and sevoflurane primarily decrease blood pressure through their effects of peripheral vasodilation and an associated decrease in systemic vascular resistance. Nitrous oxide, when administered alone, causes minimal if any alteration in blood pressure. (90 and Figures 8-8 and 8-9, Table 8-6)
32. Nitrous oxide, when administered alone, causes little if any alteration of blood pressure. The substitution of nitrous oxide for an equipotent dose of a volatile anesthetic therefore results in a smaller decrease in arterial blood pressure than would have otherwise occurred if the volatile anesthetic were administered alone. This is in part the basis for the administration of nitrous oxide in combination with a volatile anesthetic. The combination of nitrous oxide with a volatile anesthetic allows for an increase in the MAC of anesthesia delivered with less circulatory depression than would occur if an equivalent dose of anesthetic composed of a volatile agent alone were to be used. (92-93 and Figure 8-11)
33. Halothane has minimal effect on heart rate. Isoflurane, sevoflurane, and desflurane all tend to increase heart rate, but each behaves in a somewhat different manner. At concentrations as low as 0.25 MAC, isoflurane induces a linear, dose-dependent heart rate increase. Heart rate shows minimal increase with desflurane below 1 MAC, but above 1 MAC a steep dose-dependent increase in heart rate and blood pressure may be observed. In contrast to desflurane and isoflurane, heart rate in the presence of sevoflurane does not increase until the concentration exceeds 1.5 MAC. The tendency for desflurane to stimulate the circulation (i.e., increase MAP and heart rate) is attenuated with the administration of β-adrenergic blocker (esmolol), opioid (fentanyl), and the passage of time (10 to 15 minutes). The transient increase in heart rate that occurs above 1 MAC of desflurane results from sympathetic nervous system stimulation, rather than baroreceptor reflex response to decreased MAP. (90-91 and Figure 8-12)
34. Halothane produces a dose-dependent decrease in the cardiac index that parallels the decrease in blood pressure that is seen with its administration. In contrast, cardiac index is minimally influenced by administration of isoflurane, sevoflurane, and desflurane over a wide range of concentrations in young healthy adults. (92 and Figure 8-10)
35. The only inhaled volatile anesthetic that has any effect on myocardial rhythm is halothane. The administration of halothane may be accompanied by a junctional rhythm, and halothane sensitizes the myocardium to premature ventricular extrasystoles, especially in the presence of catecholamines. Sensitization of the myocardium to ventricular extrasystoles is exaggerated in the presence of hypercarbia. In contrast, isoflurane, sevoflurane, and desflurane do not affect myocardial rhythm. (93)
36. Inhaled volatile anesthetics all prolong the QT interval on the electrocardiogram, particularly halothane and sevoflurane. Although malignant arrhythmias have been reported in patients receiving halothane who were subsequently found to have congenital long QT syndrome, the clinical significance of sevoflurane’s QT interval prolongation is unclear. Regardless, sevoflurane should be avoided in patients with known congenital long QT syndrome. (93)
37. Isoflurane has been shown to selectively dilate small coronary arterioles in animal models. If coronary arterioles undergo vasodilation and blood flow is diverted from narrowed arterioles that are already maximally dilated to healthy arterioles with less resistance, this theoretically could result in ischemia in the areas supplied by the narrowed arterioles, and this process is known as “coronary steal.” However these concerns turned out not to be valid. Isoflurane, sevoflurane, and desflurane all appear to exert a protective effect on the heart, limiting the area of myocardial injury and preserving function after exposure to ischemic insult. (93)
Effects on ventilation
38. Inhaled volatile anesthetics produced a dose-dependent increase in the rate of breathing. Although the exact mechanism for this is unclear, it is believed to result from central nervous system stimulation by the anesthetic. (93)
39. Inhaled volatile anesthetics decrease the tidal volume of patients breathing the anesthetic, leading to an increase in dead space ventilation in a dose-dependent manner. (93)
40. Inhaled anesthetics increase breathing frequency and decrease tidal volume in a dose-dependent manner. The pattern of breathing is regular, rapid, and shallow. The decrease in tidal volume is not sufficiently compensated by the increase in respiratory rate, however. This results in a decrease in the minute ventilation of individuals breathing an inhaled anesthetic. The resting PaCO2 of these patients is increased as a result. The resting PaCO2 is used as an index to evaluate the degree of respiratory depression that is produced by inhaled anesthetics. (93)
41. Inhaled anesthetics produce a dose-dependent depression of the ventilatory drive. The mechanism by which this occurs is thought to be due to direct depression of the medullary ventilatory centers along with a lesser contribution from depressant effects on chest wall mechanics. Normally, minute ventilation should increase by 1 to 3 L/m for every 1 mm Hg increase in carbon dioxide, but in anesthetized patients there is a blunting of carbon dioxide responsiveness. This effect of inhaled anesthetics results in a progressive increase in carbon dioxide as anesthetic concentration rises. Indeed, at 1 MAC, carbon dioxide responsiveness is two to four times less than baseline values. At 1.7 MAC of desflurane in 100% oxygen, volunteer subjects become apneic. Volatile anesthetics all blunt or abolish the ventilatory stimulation evoked by arterial hypoxemia, even at a partial pressure below that where patients are awake. This is of great clinical importance during early recovery, when the concomitant effects of opioid and unresolved neuromuscular weakness may interact to compound ventilatory depression. (93-94 and Figures 8-14, 8-15, and 8-16)
42. The administration of nitrous oxide to patients does not change their PaCO2 levels from awake levels. Although there is an increase in the anesthetic depth when nitrous oxide is added to a volatile anesthetic, the patient’s PaCO2 does not change with the addition of nitrous oxide to the volatile anesthetic. Similarly, the substitution of nitrous oxide for an equivalent dose of volatile anesthetic results in less of an increase in the PaCO2 than that which would have otherwise occurred with the volatile anesthetic alone. (94, Figures 8-14 and 9-15)
43. Hypoxic pulmonary vasoconstriction is a reflex response of pulmonary arterioles to vasoconstrict in areas of low alveolar PaO2 in an attempt to decrease perfusion to underventilated alveoli, as in atelectasis. Although inhaled volatile anesthetics alter pulmonary blood flow, inhibition of hypoxic pulmonary vasoconstriction is minimal. (94-95)
44. All volatile inhaled anesthetics have been shown to be bronchodilators and exert some attenuation of bronchospasm with their administration. The bronchodilating effects of inhaled volatile anesthetics may be due to decreased efferent vagal tone from the central nervous system and through direct relaxation of bronchial smooth muscle. In the absence of bronchoconstriction, the bronchodilating effects of the inhaled volatile anesthetics are small. (95)
45. Sevoflurane, halothane, and nitrous oxide are all nonpungent, causing minimal or no irritation over a broad range of concentrations. For this reason, sevoflurane and halothane, usually with nitrous oxide, are selected most frequently for inhaled induction of anesthesia, since very high concentrations can be introduced to overcome the initial uptake of anesthesia into the blood. Both desflurane and isoflurane are pungent, and can irritate the airway at concentrations above 1 MAC when given without opioids or propofol. However, isoflurane and desflurane may be administered via laryngeal mask airway (LMA) after propofol induction without greater incidence of coughing, breath holding, laryngospasm, or desaturation compared with sevoflurane or propofol, probably because anesthetic maintenance usually does not require concentrations in excess of 1 MAC, and small doses of opiate (1 μg/kg of fentanyl) attenuate or abolish the irritating effects. Because of their pungency, isoflurane and desflurane are not practical for inhaled induction of anesthesia. (95)
Other organ system effects
46. Nitrous oxide increases cerebral blood flow through cerebral vasodilation. The effect of nitrous oxide appears to be blunted in the presence of intravenous anesthetics. Nitrous oxide has less of an effect on cerebral blood flow than volatile anesthetics. Limitation of the inspired concentration of nitrous oxide to less than 0.7 MAC minimizes its effect of cerebral vasodilation. (95)
47. Inhaled volatile anesthetics at concentrations above 0.6 MAC increase cerebral blood flow in a dose-dependent manner, most likely through the direct relaxation of vascular smooth muscle leading to vasodilation. Cerebral blood flow increase is greater with equipotent doses of halothane compared with isoflurane, sevoflurane, or desflurane. Intracranial pressure increases with all inhaled anesthetics above 1 MAC. Inhaled anesthetics do not abolish the cerebral vascular responsiveness to changes in PaCO2. (95-96)
48. Inhaled volatile anesthetics decrease the cerebral metabolic oxygen requirement. Volatile anesthetics also increase cerebral blood flow. Normally, cerebral blood flow parallels the cerebral metabolic oxygen requirement, such that as the cerebral metabolic oxygen requirement increases, so does cerebral blood flow. Given that volatile anesthetics increase cerebral blood flow and decrease cerebral metabolic oxygen requirements, it has been said the volatile anesthetics uncouple these two physiologic characteristics. (95-96)
49. All volatile anesthetics and nitrous oxide depress the amplitude and increase the latency of somatosensory evoked potentials in a dose-dependent manner, and the somatosensory evoked potentials may be abolished at 1 MAC. Motor evoked potentials become unreliable at concentrations as low as 0.2 to 0.3 MAC. (96)
50. Increasing depth of anesthesia with inhaled volatile anesthetics is characterized by increased amplitude and synchrony of electroencephalogram (EEG) waveforms. Periods of electrical silence begin to occupy a greater proportion of time as depth increases (i.e., burst suppression), predominantly at 1.5 to 2.0 MAC. Sevoflurane and enflurane have been associated with appearance of epileptiform EEG activity at high concentrations, although the clinical implications of these observations are not clear. (96)
51. All the inhaled volatile anesthetics produce mild, dose-related skeletal muscle relaxation (desflurane > sevoflurane and isoflurane), and their administration may be helpful in achieving optimum surgical conditions. Use of inhaled volatile anesthetic will likewise potentiate the effect of neuromuscular blocking drugs. The clinician may minimize or avoid the use of neuromuscular blocking drugs by virtue of the inhaled anesthetic’s effects on skeletal muscle tone. At the conclusion of surgery, the presence of inhaled volatile anesthetic will delay the recovery of neuromuscular function when the effects of muscle relaxants are no longer desired. Nitrous oxide does not provide skeletal muscle relaxation. (96)
52. All of the inhaled volatile anesthetics have the potential to trigger malignant hyperthermia in susceptible patients. Studies in animals suggest that this risk may be greater with the use of halothane than with the use of isoflurane, sevoflurane, or desflurane. Nitrous oxide is not a trigger for malignant hyperthermia. (96)
53. All inhaled volatile anesthetics have the potential to cause severe hepatic injury, leading to death or the requirement for liver transplantation. The mechanism for this injury is immunologic, requiring previous exposure to a volatile anesthetic. Trifluoroacetate, produced by metabolism of halothane, isoflurane, and desflurane, binds covalently to hepatocyte proteins and acts as a hapten. Hexafluoroisopropanol, produced by sevoflurane metabolism, does not appear to have the same antigenic behavior as trifluoroacetate. Exposure to halothane may result in a clinically milder form of liver injury characterized by elevation of transaminases, and may be mediated by reductive metabolism and related to conditions where hepatic blood flow is compromised. (96)
