Although the mechanism of action of inhalation anesthetics is complex, likely involving numerous membrane proteins and ion channels, it is clear that producing their ultimate effect depends on attainment of a therapeutic tissue concentration in the central nervous system (CNS). There are many steps in between the anesthetic vaporizer and the anesthetic’s deposition in the brain (Figure 8-1).
Factors Affecting Inspiratory Concentration (FI)
The fresh gas leaving the anesthesia machine mixes with gases in the breathing circuit before being inspired by the patient. Therefore, the patient is not necessarily receiving the concentration set on the vaporizer. The actual composition of the inspired gas mixture depends mainly on the fresh gas flow rate, the volume of the breathing system, and any absorption by the machine or breathing circuit. The higher the fresh gas flow rate, the smaller the breathing system volume, and the lower the circuit absorption, the closer the inspired gas concentration will be to the fresh gas concentration. Clinically, these attributes translate into faster induction and recovery times.
Factors Affecting Alveolar Concentration (FA)
If there were no uptake of anesthetic agent by the body, the alveolar gas concentration (FA) would rapidly approach the inspired gas concentration (FI). Because anesthetic agents are taken up by the pulmonary circulation during induction, alveolar concentrations lag behind inspired concentrations (FA/FI <1.0). The greater the uptake, the slower the rate of rise of the alveolar concentration and the lower the FA:FI ratio.
Because the concentration of a gas is directly proportional to its partial pressure, the alveolar partial pressure will also be slow to rise. The alveolar partial pressure is important because it determines the partial pressure of anesthetic in the blood and, ultimately, in the brain. Similarly, the partial pressure of the anesthetic in the brain is directly proportional to its brain tissue concentration, which determines clinical effect.
Therefore, the greater the uptake of anesthetic agent, the greater the difference between inspired and alveolar concentrations, and the slower the rate of induction.
Three factors affect anesthetic uptake: solubility in the blood, alveolar blood flow, and the difference in partial pressure between alveolar gas and venous blood.
Relatively soluble agents, such as nitrous oxide, are taken up by the blood less avidly than more soluble agents, such as halothane. As a consequence, the alveolar concentration of nitrous oxide rises faster than that of halothane, and induction is faster. The relative solubilities of an anesthetic in air, blood, and tissues are expressed as partition coefficients (Table 8-1). Each coefficient is the ratio of the concentrations of the anesthetic gas in each of two phases at steady state. Steady state is defined as equal partial pressures in the two phases. For instance, the blood/gas partition coefficient (λb/g) of nitrous oxide at 37°C is 0.47. In other words, at steady state, 1 mL of blood contains 0.47 as much nitrous oxide as does 1 mL of alveolar gas, even though the partial pressures are the same. Stated another way, blood has 47% of the capacity for nitrous oxide as alveolar gas. Nitrous oxide is much less soluble in blood than is halothane, which has a blood/gas partition coefficient at 37°C of 2.4. Thus, almost five times more halothane than nitrous oxide must be dissolved to raise the partial pressure of blood. The higher the blood/gas coefficient, the greater the anesthetic’s solubility and the greater its uptake by the pulmonary circulation. As a consequence of this increased solubility, alveolar partial pressure rises more slowly, and induction is prolonged. Because fat/blood partition coefficients are greater than 1, blood/gas solubility is increased by postprandial lipidemia and is decreased by anemia.
Table 8-1 Partition Coefficients of Volatile Anesthetics at 37°C.1 ||Download (.pdf)
Table 8-1 Partition Coefficients of Volatile Anesthetics at 37°C.1
The second factor that affects uptake is alveolar blood flow, which—in the absence of pulmonary shunting—is essentially equal to cardiac output. If the cardiac output drops to zero, so will anesthetic uptake. As cardiac output increases, anesthetic uptake increases, the rise in alveolar partial pressure slows, and induction is delayed. The effect of changing cardiac output is less pronounced for insoluble anesthetics, as so little is taken up regardless of alveolar blood flow.
Low-output states predispose patients to overdosage with soluble agents, as the rate of rise in alveolar concentrations will be markedly increased.
The final factor affecting uptake of anesthetic by the pulmonary circulation is the partial pressure difference between alveolar gas and venous blood. This gradient depends on tissue uptake. If anesthetics did not pass into organs such as the brain, venous and alveolar partial pressures would become identical, and there would be no pulmonary uptake. The transfer of anesthetic from blood to tissues is determined by three factors analogous to systemic uptake: tissue solubility of the agent (tissue/blood partition coefficient), tissue blood flow, and the difference in partial pressure between arterial blood and the tissue.
To better understand inhaled anesthetic uptake and distribution, tissues have been classified into four groups based on their solubility and blood flow (Table 8-2). The highly perfused vessel-rich group (brain, heart, liver, kidney, and endocrine organs) is the first to encounter appreciable amounts of anesthetic. Moderate solubility and small volume limit the capacity of this group, so it is also the first to reach steady state (ie, arterial and tissue partial pressures are equal). The muscle group (skin and muscle) is not as well perfused, so uptake is slower. In addition, it has a greater capacity due to a larger volume, and uptake will be sustained for hours. Perfusion of the fat group nearly equals that of the muscle group, but the tremendous solubility of anesthetic in fat leads to a total capacity (tissue/blood solubility × tissue volume) that would take days to approach steady state. The minimal perfusion of the vessel-poor group (bones, ligaments, teeth, hair, and cartilage) results in insignificant uptake.
Table 8-2 Tissue Groups Based on Perfusion and Solubilities. ||Download (.pdf)
Table 8-2 Tissue Groups Based on Perfusion and Solubilities.
|Characteristic||Vessel Rich||Muscle||Fat||Vessel Poor|
|Percentage of body weight||10||50||20||20|
|Percentage of cardiac output||75||19||6||0|
|Perfusion (mL/min/100 g)||75||3||3||0|
Anesthetic uptake produces a characteristic curve that relates the rise in alveolar concentration to time (Figure 8-2). The shape of this graph is determined by the uptakes of individual tissue groups (Figure 8-3). The initial steep rate of uptake is due to unopposed filling of the alveoli by ventilation. The rate of rise slows as the vessel-rich group—and eventually the muscle group—approach steady state levels of saturation.
FA rises toward FI faster with nitrous oxide (an insoluble agent) than with halothane (a soluble agent). See Figure 8-1 for an explanation of FA and FI.
The rise and fall in alveolar partial pressure precedes that of other tissues. (Modified and reproduced, with permission, from Cowles AL et al: Uptake and distribution of inhalation anesthetic agents in clinical practice. Anesth Analg 1968;4:404.)
The lowering of alveolar partial pressure by uptake can be countered by increasing alveolar ventilation. In other words, constantly replacing anesthetic taken up by the pulmonary bloodstream results in better maintenance of alveolar concentration. The effect of increasing ventilation will be most obvious in raising the FA/FI for soluble anesthetics, as they are more subject to uptake. Because the FA/FI very rapidly approaches 1.0 for insoluble agents, increasing ventilation has minimal effect. In contrast to the effect of anesthetics on cardiac output, anesthetics that depress spontaneous ventilation (eg, ether or halothane) will decrease the rate of rise in alveolar concentration and create a negative feedback loop.
The slowing of induction due to uptake from alveolar gas can be reduced by increasing the inspired concentration. Interestingly, increasing the inspired concentration not only increases the alveolar concentration, but also increases its rate of rise (ie, increases FA/FI), because of two phenomena (see Figure 8-1) that produce a so-called “concentrating effect.” First, if 50% of an anesthetic is taken up by the pulmonary circulation, an inspired concentration of 20% (20 parts of anesthetic per 100 parts of gas) will result in an alveolar concentration of 11% (10 parts of anesthetic remaining in a total volume of 90 parts of gas). On the other hand, if the inspired concentration is raised to 80% (80 parts of anesthetic per 100 parts of gas), the alveolar concentration will be 67% (40 parts of anesthetic remaining in a total volume of 60 parts of gas). Thus, even though 50% of the anesthetic is taken up in both examples, a higher inspired concentration results in a disproportionately higher alveolar concentration. In this example, increasing the inspired concentration 4-fold results in a 6-fold increase in alveolar concentration. The extreme case is an inspired concentration of 100% (100 parts of 100), which, despite a 50% uptake, will result in an alveolar concentration of 100% (50 parts of anesthetic remaining in a total volume of 50 parts of gas).
The second phenomenon responsible for the concentration effect is the augmented inflow effect. Using the example above, the 10 parts of absorbed gas must be replaced by an equal volume of the 20% mixture to prevent alveolar collapse. Thus, the alveolar concentration becomes 12% (10 plus 2 parts of anesthetic in a total of 100 parts of gas). In contrast, after absorption of 50% of the anesthetic in the 80% gas mixture, 40 parts of 80% gas must be inspired. This further increases the alveolar concentration from 67% to 72% (40 plus 32 parts of anesthetic in a volume of 100 parts of gas).
The concentration effect is more significant with nitrous oxide, than with the volatile anesthetics, as the former can be used in much higher concentrations. Nonetheless, a high concentration of nitrous oxide will augment (by the same mechanism) not only its own uptake, but theoretically that of a concurrently administered volatile anesthetic. The concentration effect of one gas upon another is called the second gas effect, which is probably insignificant in the clinical practice of anesthesiology.
Factors Affecting Arterial Concentration (Fa)
Normally, alveolar and arterial anesthetic partial pressures are assumed to be equal, but in fact, the arterial partial pressure is consistently less than end-expiratory gas would predict. Reasons for this may include venous admixture, alveolar dead space, and nonuniform alveolar gas distribution. Furthermore, the existence of ventilation/perfusion mismatching will increase the alveolar-arterial difference. Mismatch acts as a restriction to flow: It raises the pressure in front of the restriction, lowers the pressure beyond the restriction, and reduces the flow through the restriction. The overall effect is an increase in the alveolar partial pressure (particularly for highly soluble agents) and a decrease in the arterial partial pressure (particularly for poorly soluble agents). Thus, a bronchial intubation or a right-to-left intracardiac shunt will slow the rate of induction with nitrous oxide more than with halothane.
Factors Affecting Elimination
Recovery from anesthesia depends on lowering the concentration of anesthetic in brain tissue. Anesthetics can be eliminated by biotransformation, transcutaneous loss, or exhalation. Biotransformation usually accounts for a minimal increase in the rate of decline of alveolar partial pressure. Its greatest impact is on the elimination of soluble anesthetics that undergo extensive metabolism (eg, methoxyflurane). The greater biotransformation of halothane compared with isoflurane accounts for halothane’s faster elimination, even though it is more soluble. The CYP group of isozymes (specifically CYP 2EI) seems to be important in the metabolism of some volatile anesthetics. Diffusion of anesthetic through the skin is insignificant.
The most important route for elimination of inhalation anesthetics is the alveolus.
Many of the factors that speed induction also speed recovery: elimination of rebreathing, high fresh gas flows, low anesthetic-circuit volume, low absorption by the anesthetic circuit, decreased solubility, high cerebral blood flow (CBF), and increased ventilation. Elimination of nitrous oxide is so rapid that alveolar oxygen
are diluted. The resulting diffusion hypoxia
is prevented by administering 100% oxygen
for 5-10 min after discontinuing nitrous oxide. The rate of recovery is usually faster than induction because tissues that have not reached equilibrium will continue to take up anesthetic until the alveolar partial pressure falls below the tissue partial pressure. For instance, fat will continue to take up anesthetic and hasten recovery until the partial pressure exceeds the alveolar partial pressure. This redistribution is not as useful after prolonged anesthesia (fat partial pressures of anesthetic will have come “closer” to arterial partial pressures at the time the anesthetic was removed from fresh gas)—thus, the speed of recovery also depends on the length of time the anesthetic has been administered.