Characteristics of Anesthetic Agents Used for Induction and Maintenance of General Anesthesia

Edmond I. Eger, II, MD


Am J Health Syst Pharm. 2004;61(20) 

In This Article

Inhaled Anesthetics

Inhaled anesthetic agents include nitrous oxide (the oldest of all anesthetics) and various halogenated agents: desflurane (halogenated solely with fluorine—halogenation increases potency and is essential to ensure nonflammability), halothane (halogenated with fluorine, chlorine, and bromine), isoflurane (halogenated with fluorine and chlorine), and sevoflurane (halogenated solely with fluorine). Halothane was the first fluorinated inhaled anesthetic that was wildly successful, rapidly displacing all other potent inhaled anesthetics. Efforts to develop other halogenated anesthetics with more of the characteristics of the ideal inhaled anesthetic agent than halothane led to the introduction of isoflurane, desflurane, and sevoflurane.

The inhaled anesthetics affect many receptors (e.g., GABAA, glycine, acetylcholine, serotonin, NMDA) in manners that plausibly could explain anesthesia. Which receptors mediate anesthesia remains unclear.

Characteristics of the ideal inhaled anesthetic agent include ample potency, low solubility in blood and tissues, resistance to physical and metabolic degradation, and a protective effect in and lack of injury to vital tissues. Physical and metabolic degradation can yield compounds that cause injury. Other ideal characteristics include the lack of a propensity to cause seizures, respiratory irritation, and circulatory stimulation; little or no effect on the ozone layer; and a low acquisition cost. Cost considerations will be addressed in detail in the article by Chernin in this supplement.

The ideal anesthetic agent produces anesthesia while allowing the use of a high concentration of oxygen. The minimum alveolar concentration (MAC) of an anesthetic agent at one atmosphere that abolishes movement in response to a noxious stimulus in 50% of subjects provides the standard definition of inhaled anesthetic potency. In 30– 60 year-old patients, MAC values for halothane, isoflurane, sevoflurane, and desflurane are 0.75%, 1.15%, 1.85%, and 6.0% at one atmosphere, respectively, which indicates that they all are potent and can be given with a high concentration of oxygen.[4,5] By contrast, the MAC for nitrous oxide is 104% at one atmosphere, and it must be given in a pressurized chamber due to safety considerations.

Solubility of an anesthetic agent in blood is quantified as the blood:gas partition coefficient, which is the ratio of the concentration of an anesthetic in the blood phase to the concentration of the anesthetic in the gas phase when the anesthetic is in equilibrium between the two phases. For example, the partition coefficient is 0.5 if the concentration of an anesthetic in arterial blood is 3% and the concentration in the lungs is 6%. A low blood:gas partition coefficient reflects a low affinity of blood for the anesthetic, a desirable property because it predicts a more precise control over the anesthetic state and a more rapid recovery from anesthesia. The blood:gas partition coefficients for inhaled anesthetics vary from a low of about 0.45 for nitrous oxide and desflurane and 0.65 for sevoflurane to 1.4 for isoflurane and 2.4 for halothane ( Table 1 ).

Similarly, the tissue:gas partition coefficient is the ratio of the concentration of an anesthetic in a tissue to the concentration of the anesthetic in the gas phase when the anesthetic is in equilibrium between the two phases. A low tissue:gas partition coefficient reflects low tissue solubility. The tissue:gas partition coefficients for nitrous oxide in brain and fat are lower than values for the potent inhaled anesthetics ( Table 1 ), indicating that its tissue solubility is low. Desflurane and nitrous oxide solubilities in lean tissues are similar, but the solubility of desflurane in fat is ten times greater. Desflurane tissue solubility is approximately half that of sevoflurane; sevoflurane is half as soluble as isoflurane; and isoflurane is half as soluble as halothane.

Differences in the solubility of inhaled anesthetic agents in blood and tissues have important implications for patient recovery from anesthesia. We predict that recovery from anesthesia with desflurane would be more rapid than recovery after sevoflurane anesthesia, and recovery after sevoflurane anesthesia would be more rapid than recovery after anesthesia with isoflurane. Several reports support that prediction.[36,37,38,39] In a randomized, multicenter study of 246 adults undergoing short ambulatory procedures, patients receiving sevoflurane were oriented and able to sit up without nausea or dizziness significantly earlier than patients receiving the more soluble isoflurane.[36] However, there was no significant difference between the two treatment groups in the time to discharge from the post anesthesia care unit (PACU).

In a randomized study of 50 adults undergoing short elective oro-facial procedures, on average, patients receiving desflurane were oriented 6 minutes earlier and were discharged from the PACU 19 minutes sooner than patients receiving the more soluble isoflurane.[37] The differences were significant.

Recovery after minor gynecologic surgery was compared in 60 women receiving either desflurane or sevoflurane.[28] The time to orientation was 5 minutes shorter and the time to discharge home was 0.5 hour sooner in the desflurane group than in the sevoflurane group. The differences between treatment groups were significant. Differences among inhaled anesthetic agents in time to orientation and time to discharge may result in savings if the shorter times are acted upon by PACU personnel. However, they may not impact settings where policies and procedures require a long duration of stay in the PACU.

Differences between inhaled anesthetic agents may be still more important after prolonged anesthesia because of greater tissue accumulation of the anesthetic. Recovery after prolonged anesthesia (approximately five hours) using desflurane or isoflurane was compared in 30 patients.[39] As predicted from solubility differences, the time until the patient opened his or her eyes was significantly shorter with desflurane than isoflurane (12 minutes versus 24 minutes). The time until the patient was ready for discharge from the PACU also was significantly shorter with desflurane (46 minutes) than isoflurane (81 minutes). These differences exceed those observed in the study comparing the two anesthetics in patients undergoing short elective orofacial procedures described above.

To minimize waste and decrease cost, potent inhaled anesthetic agents are delivered in a circle absorption system containing absorbents that remove carbon dioxide and allow re-breathing of the inhaled anesthetic. The absorbents consist of divalent (calcium hydroxide, barium hydroxide) and monovalent (sodium hydroxide, potassium hydroxide) bases plus 15% water. Calcium hydroxide makes up the bulk of absorbents such as soda lime (Sodasorb®) or Baralyme®. Bases can degrade potent inhaled anesthetics. The degradation products may depend on whether the absorbent is moist or desiccated (desiccation may occur with prolonged exposure of the absorbent to high fresh gas inflow rates) and the type of inhaled anesthetic. Some degradation products cause concern. For example, both moist and dry absorbents degrade sevoflurane to compound A, a nephrotoxin in animals and possibly in humans. Desiccated absorbents can degrade all inhaled anesthetics to carbon monoxide (most with desflu-rane)[40]; this problem does not occur with moist absorbents. These dangers are noted in the package insert.

In a bench model, sevoflurane degradation by desiccated absorbent produced high temperatures (an exothermic reaction), carbon monoxide, and an explosion and fire.[41] Several clinical cases of fires have been reported. Therefore, the product labeling for sevoflurane carries a warning that extremely rare cases of spontaneous fire in the respiratory circuit of the anesthesia machine have been reported during sevoflurane use in conjunction with a desiccated carbon dioxide absorbent.[42] The problem has not been reported with other potent inhaled anesthetics. Halothane does not degrade to compound A, yet it does degrade to a parallel unsaturated nephrotoxic compound. However, it is not produced in the amounts that compound A is produced; therefore, the danger of nephrotoxicity is less.[43]

Nephrotoxicity from compound A has been demonstrated in animals exposed to high concentrations of compound A, although it is rare in humans.[44] Nevertheless, the product labeling for sevoflurane includes a warning that the administration of sevoflurane for more than two MAC hours (e.g., one MAC for two hours or two MAC for one hour) and at fresh gas flow rates less than 2 L/min may be associated with proteinuria and glucosuria.[42] Therefore, exposure to sevoflurane that exceeds two MAC hours at flow rates of 1–2 L/min should be avoided to minimize exposure to compound A, and the use of fresh gas flow rates less than 1 L/min is not recommended.[42] These flow rate limitations make the delivery of sevoflurane less economical than it could otherwise be because low fresh gas flow rates conserve anesthetic.

Metabolic degradation products of inhaled anesthetics can injure tissues. The type of injury depends on the extent of metabolism and the nature of the metabolites. In the past, metabolic degradation of anesthetics was a major concern (e.g., chloroform degradation results in hepatic injury), but it is a relatively rare concern for the potent inhaled anesthetics used today.[44]

Desflurane, halothane, and isoflurane all are metabolized to trifluoroacetate, which can cause hepatotoxicity through an immunologic mechanism involving trifluoroacetyl hapten formation and an autoimmune response.[44] The incidence of hepatic injury depends on the extent of metabolism, with the highest rates associated with halothane and much lower rates with isoflurane and desflurane ( Table 2 ). Indeed, only one case of injury attributed to desflurane has been reported, although desflurane has been given to tens of millions of patients.[45]

Approximately 5% of an inhaled sevoflurane dose is metabolized to inorganic fluoride and hexafluor-oisopropanol.[44] Sevoflurane is not associated with hepatotoxicity.

Nitrous oxide is not subject to metabolism. However, it inactivates methionine synthase, a vitamin B12dependent enzyme essential for DNA production.[47] Nitrous oxide can cause tissue injury by inactivating methionine synthase, but this problem is rare and probably occurs only in patients with vitamin B deficiency or with prolonged exposure to nitrous oxide. Injury is to blood-forming elements or to the central nervous system.[48,49]

Hypoxic preconditioning is a phenomenon whereby a short period of hypoxia protects vital tissues from a longer subsequent period of hypoxia. Similarly, a brief administration of inhaled anesthetics before, during, or after experimentally-induced myocardial hypoxia decreases the amount of tissue injury (i.e., infarct size) caused by hypoxia in animals.[50] The protective effect of the potent inhaled anesthetics varies; the infarct size can be significantly smaller with desflurane, halothane, or isoflurane than in the control group, with less of a difference in infarct size between the sevoflurane group and the control group.[50] The infarct size is smallest with desflurane.

Whether the differences in protective effect observed in animals translate into differences in humans was evaluated in a controlled study of 45 high-risk patients (i.e., more than 70 years old with three-vessel coronary disease and an ejection fraction less than 50%) undergoing coronary artery bypass surgery and randomized to receive propofol, desflurane, or sevoflurane.[51] The percentage of patients with abnormal postoperative levels of troponin I, proteins that reflect myocardial cell injury, was significantly higher in the propofol group than in the desflurane or sevoflurane group, but the percentages in the desflurane and sevoflurane groups did not differ.

Thus, potent inhaled anesthetic agents protect vital tissues. Differences in protective effect among the various agents in animals have not been observed in humans.

Seizures and agitation have been reported in patients (primarily children and young adults) receiving sevoflurane.[42,52] Desflurane, halothane, isoflurane, and nitrous oxide are not associated with seizures. Intraoperative epileptiform discharges on the electroencephalogram and postoperative agitation were evaluated in a study of 41 adult women undergoing gynecologic surgery using either i.v. propofol or inhaled sevoflurane for maintenance of anesthesia.[53] Intraoperative epileptiform activity occurred in 31% of patients receiving sevoflurane and none receiving propofol. Agitation one hour after surgery was reported by 31% of the sevoflurane group and 12% of the propofol group, a significant difference. Sevoflurane may be more likely to cause seizures in patients who have a baseline risk for seizures.

Inhaled anesthetics differ in their pungency (a pungent agent is characterized by a sharp or acrid taste or odor) and tendency to irritate the airways. In a double-blind study, 81 patients who were not premedicated were randomized to inhale two MAC of desflurane (12%), isoflurane (2.3%), or sevoflurane (4%) for 60 seconds from an anesthetic breathing circuit by mask.[54] Twenty (74%) of 27 patients receiving desflurane and 11 (41%) of 27 patients receiving isoflurane complained of respiratory irritation (they coughed and objected verbally or removed the mask forcefully). One patient receiving sevoflurane coughed, but completed the study. The differences between treatment groups were significant.

Because of its low pungency and low risk of respiratory irritation, sevoflurane is currently the most popular anesthetic agent in North America for anesthesia induction by inhalation. Conversely, desflurane is avoided for induction because of its high pungency and high risk of respiratory irritation. The product labeling for desflurane warns that it should not be used for induction of anesthesia via mask in pediatric patients because of the high incidence of moderate to severe laryngospasm, coughing, breath holding, increase in secretions, and oxyhemoglobin de-saturation.[46] The observed episodes of desaturation in children (especially preschool children) have not been observed in adults. Probably the pediatric airway is more sensitive than an adult airway.[55]

Respiratory irritation is absent when one MAC of desflurane, isoflurane, or sevoflurane is used instead of two MAC.[56] A threshold for respiratory irritation can be identified experimentally by increasing the concentration of inhaled anesthetic until a concentration is reached that produces respiratory irritation. This threshold is one MAC (6%) for desflurane and one and one-half MAC (1.8%) for isoflurane.[56] There is no threshold for halothane or sevoflurane because they do not cause respiratory irritation at any concentration.

Opioids markedly decrease the potential for respiratory irritation from inhaled anesthetic agents. In a randomized study of 180 adults receiving inhaled desflurane for induction of anesthesia, the incidence of coughing was 75–80% less in patients pretreated with small i.v. doses of the opioid agonist fentanyl 1 µg/kg (5%) or morphine 0.1 mg/kg (8%) than in a control group pretreated with i.v. saline (25%).[57]

The absence of respiratory irritation by any anesthetic at concentrations less than one MAC has important clinical implications. Many anesthetics are delivered via a laryngeal mask airway (LMA), and irritation of the airway can compromise the use of this technique. However, studies demonstrate that during maintenance of anesthesia via an LMA, the incidence of coughing or other manifestations of irritation does not differ among anesthetics.[58,59,60]

Potent inhaled anesthetics differ minimally in their effects on the circulation during steady state of anesthesia. In 12 healthy, male volunteers receiving one and one-quarter MAC of desflurane or sevoflurane for eight hours in an experimental (i.e., non-surgical) setting, heart rate and mean arterial blood pressure differed from control with both anesthetics, but they did not differ between the two anesthetics.[61]

The heart rate response to induction using inhaled desflurane or sevoflurane was compared in 21 healthy, young volunteers who received progressively larger dial (vaporizer) concentration steps (onehalf MAC, one MAC, and one and one-half MAC) of desflurane (3%, 6%, and 9%, respectively) or sevoflurane (1%, 2%, and 3%, respectively).[62] The rapid transition from one MAC to one and one-half MAC transiently increased heart rate and blood pressure in the desflurane group and slightly decreased heart rate and blood pressure in the sevoflurane group.

The effect of rapid increases in concentrations of desflurane and isoflurane on heart rate and blood pressure was compared in 12 healthy, male volunteers who were randomized to receive both anesthetic agents for induction on separate occasions.[63] Both desflurane and isoflurane caused transient increases in heart rate and blood pressure at concentrations approximating MAC or greater, and the increase was greater with desflurane than with isoflurane. Thus, inhaled anesthetics differ in their circulatory stimulatory effects during induction of anesthesia, but only limited differences are usually seen during maintenance of anesthesia.

Weiskopf and colleagues[64] also observed transient increases in heart rate and blood pressure when the end-tidal desflurane concentration was increased rapidly (e.g., over one minute) from 4% to 8% in healthy volunteers. The heart rate-blood pressure response was greater when the increase in end-tidal concentration was more rapid. The researchers also evaluated the impact of two different fentanyl doses (1.5 µg/kg and 4.5 µg/kg), and found a dose-related attenuation of the heart rate response to desflurane.[64] Thus, if desflurane is used for induction of anesthesia, circulatory stimulation can be minimized by increasing the concentration gradually, limiting the increase in concentration (i.e., not exceeding the threshold for circulatory stimulation), and using fentanyl for premedication. The product labeling for desflurane advises against the use of desflurane as the sole agent for anesthetic induction in patients with coronary artery disease or any patient where increases in heart rate or blood pressure are undesirable.[46]

Compounds with a chlorine or bromine moiety (e.g., halothane, isoflurane, chlorofluorocarbons) can deplete the atmospheric ozone layer, resulting in increased ultraviolet radiation reaching the earth. This is of potential but limited concern with halothane and isoflurane, and essentially without concern with desflurane and sevoflurane (both of which lack chlorine and bromine moieties).[65] A greenhouse effect (prevention of loss of infrared energy) is only an issue (and a trivial one, at that, relative to other sources such as fertilizer) with nitrous oxide.

Its high MAC (i.e., low potency) limits the usefulness of nitrous oxide relative to the more potent halogenated inhaled anesthetics. Although halothane has some characteristics of the ideal inhaled anesthetic agent (e.g., ample potency and lack of respiratory irritation, circulatory stimulation, and seizures), the greater solubility and risk of hepatotoxicity limit its present application. Choosing among sevoflurane, isoflurane, and desflurane involves weighing the advantages and disadvantages of each agent. All three agents have ample potency and a protective effect in vital tissues, and they can degrade to carbon monoxide in the presence of a desiccated carbon dioxide absorbent.

Sevoflurane has an intermediate solubility in blood and tissues and it does not cause respiratory irritation, circulatory stimulation, or hepatotoxicity. It is particularly useful for the induction of anesthesia, and it is environmentally friendly (i.e., it does not deplete the ozone layer). However, sevoflurane may be associated with nephrotoxicity from physical degradation to compound A, seizures, and postoperative agitation. There is a risk of explosion and fire in the respiratory circuit of the anesthesia machine if sevoflurane is used with a desiccated carbon dioxide absorbent. Sevoflurane has a high acquisition cost, and flow rate limitations required to minimize exposure to compound A add to the cost of using sevoflurane.

Isoflurane has a relatively high solubility in blood and tissues and it is associated with an intermediate risk for respiratory irritation (between that of sevoflurane and desflurane), circulatory stimulation, and hepatotoxicity. It does not cause seizures. Isoflurane has a minimal effect on the ozone layer and has a far lower acquisition cost than sevoflurane and desflurane.

Compared with sevoflurane and isoflurane, desflurane has a lower solubility in blood and tissues (i.e., it allows the most rapid recovery). It is associated with essentially no risk for hepatotoxicity. It also may protect vital tissues to a greater extent, although research in humans is needed to determine whether there are differences in protection among the anesthetic agents. Desflurane is not associated with seizures, and it is environmentally friendly. However, desflurane is associated with a higher risk of respiratory irritation and circulatory stimulation than the other agents. It has a cost similar to that of sevoflurane.