Context-Sensitive Decrement Times for Inhaled Anesthetics Eger, Shafer 2005

Tutorial: Context-Sensitive Decrement Times for Inhaled AnestheticsEdmond I Eger II, MD, and Steven L. Shafer, MD Department of Anesthesia and Perioperative Care, University of California, Department of Biopharmaceutical Science, UCSF, San Francisco, California, and Department of Anesthesia, Stanford University, Stanford, California, Context-sensitive decrement times for inhaled anesthetics connect two values: a) the duration of anesthesia (nominally at a constant alveolar concentration)—the “context” and b) the time to decrease the alveolar or vital tissue (e.g., brain, heart, kidney, and liver, collectively called the vessel-rich group of tissues) concentration by some fractional “decrement” of the starting concentration. Increasing duration of anesthesia increases the time to a given decrement in a nonlinear manner that may considerably delay recovery. In the present report we use a commercially available simulation program (Gas Man®) to confirm and enlarge on these concepts. In this simulation, increasing duration of anesthesia can markedly delay complete awakening for isoflurane. Increasing anesthesia duration imposes considerably less delay in awakening from sevoflurane compared with isoflurane. For desflurane, only prolonged anesthesia or decrements of 95% and more should delay awakening from anesthesia. These changes are shown to be the result of the relative solubility of each anesthetic in blood and tissue. An increase in cardiac output is also shown to delay awakening. (Anesth Analg 2005;101:688 –96) C ontext-sensitive decrement times can help us understand why one anesthetic may differ greatly from another in time to recovery from anesthesia (1,2). Duration of anesthesia can play a large distinguishing effect, and this effect is the focus of the present essay. For inhaled anesthetics, context-sensitive decrement times connect two values: a) anesthetic duration (nominally at a constant alveolar concentration)—the “context” and b) the time needed to decrease the alveolar or vital tissue (e.g., brain, heart, kidney and liver, collectively called the vessel rich group of tissues or VRG) (3) concentration by some fractional “decrement” of the starting concentration (e.g., an 80% decrement time would be the time needed to reach 20% of the starting concentration. After only a few minutes of anesthesia, the VRG is thought to be in equilibrium with the alveolar concentration. Both alveolar (or plasma) and effect-site decrement times might be of interest (4). The present report focuses on VRG decrement times while noting the difference from alveolar Supported, in part, by National Institutes of Health Grant 1PO1GM47818, Bethesda, MD. Dr. Eger is a paid consultant to Baxter Healthcare Corp. Accepted for publication January 18, 2005. Address correspondence and reprint requests to Edmond I Eger II, MD, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143– 0464. Address e-mail to egere@ anesthesia.ucsf.edu. DOI: 10.1213/01.ANE.0000158611.15820.3D decrement times. Times to achieve a particular decrement in the VRG are a more appropriate focus than the alveolar concentrations because the central nervous system contains the effect-site for depressant drugs such as opioids, hypnotics, and inhaled anesthetics (5). However, as we will show, the times for a given decrement in the alveoli closely approximate those for the VRG. Some things intuitively follow from the above description. An anesthetic of short duration produces a shorter time to a specific decrement (say, 95%) because a longer anesthetic duration increases anesthetic accumulation in tissue depots. This accumulation limits the decrease in drug concentration at the conclusion of anesthesia. Similarly, a greater anesthetic solubility in tissues promotes a greater accumulation of anesthetic in tissues, an accumulation that will linger during recovery from anesthesia. More soluble drugs also equilibrate slower and this can affect recovery in a complex manner. The greater accumulation over time and the slower equilibration are two views of the same fact: the body stores more molecules of a highly soluble drug in tissue than a poorly soluble drug at the same partial pressure of drug (e.g., the same “free” drug) in the brain. Anesthetic solubility is a prime determinant of recovery from anesthesia. The blood/gas partition coef0.45 for desflurane and 0.65 for ficient or (e.g., sevoflurane) (6) defines the solubility in blood and ©2005 by the International Anesthesia Research Society 0003-2999/05 688 Anesth Analg 2005;101:688–96 Methods We tested these concepts using simulations performed by Gas Man® (Version 3. then the concentration could only decrease very slowly from this level. the decrease in the alveolar anesthetic concentration will be greater at a specific time of recovery (e. some slower (muscle and skin). (8. and some slower still (fat). with anesthetic Y. Using overpressure. 80%. have solubility characteristics between the extremes of anesthetics X or Y. anesthetics will differ minimally in the time to reach that decrement. we have intermediate effects on decrement times. Subsequently. For anesthetic Y with enormous solubility. It is a commercially available computer program used for education (11. and. Gas Man® is a physiologically based model of inhaled anesthetic uptake and distribution. A longer anesthesia will cause more anesthetic to accumulate in muscle and fat.42 and 0. As a result. Thus.ANESTH ANALG 2005. heart. moderately soluble anesthetics like isoflurane will show a considerable increase in decrement times with increasing duration of anesthesia (2). That is.101:688 –96 ANESTHETIC PHARMACOLOGY EGER AND SHAFER CONTEXT-SENSITIVE DECREMENT TIMES 689 describes the affinity or capacity of blood to hold anesthetic (note that determinations of solubility differ slightly from laboratory to laboratory. it does not take much time to eliminate anesthetic from the rapidly equilibrating tissues. and desflurane. At a 90% decrement. 90%. this does not take much time. equilibration becomes a vital determinant of decrement time because the decrement will be to whatever degree of equilibration has occurred. for a nearly insoluble anesthetic the increase must be trivial. liver. That is. 95%) will also influence the separation among anesthetics. when anesthetic administration ceases. In fact.g. Furthermore. for example. sevoflurane. the affinity or capacity of desflurane for blood is 0. Inhaled anesthetic . increasing the time for recovery from anesthesia.12) and can accurately predict expired anesthetic concentrations during induction and emergence from anesthesia (13). initially the washout from the rapidly equilibrating VRG dictates blood and alveolar concentration during recovery. The extremes of solubility illustrate its importance to context-sensitive decrement times (see the Appendix for details). at a 95% decrement. whereas for an extremely soluble anesthetic the increase must be considerable.45 times (45% of) the affinity for the gas phase. If we chose a smaller decrement (say 50%). the final part of the elimination curve moves higher and higher. the concentration decreases very rapidly at first. Context-sensitive decrement times vary as a function of the duration of anesthesia (a “context”) as well as the solubility of the anesthetic. the elimination of anesthetic vapor from fat. then slower. We have been simplistic in the previous explanations. the time to reach a 50% decrement is small for isoflurane.g. isoflurane. The most commonly used potent anesthetic vapors.1. although it does take more time to get drug out of the VRG than into the VRG because there is no equivalent of overpressure during washout of drug. the alveolar anesthetic concentration decreases in a multiexponential manner. For the same duration of anesthesia.49). Not so. and desflurane regardless of anesthesia duration (2). We assumed that we could treat the body as a single bag of gloop wherein all tissues equilibrate equally. Note that when is zero. kidney). However. some tissues equilibrate quickly (the brain.8) (10). Gas Man® assumes several things. then still slower until at last it decreases at a rate dictated by the slowest component.. 50%. F may be calculated from equation B (7): F 100%* 1/ 1 * Q/VA (B) where Q is cardiac output and VA is alveolar ventilation. F 100%. Because these tissues equilibrate quickly. if the blood returning to the lungs were half equilibrated with the inspired partial pressure of Y. only a trivial fraction is cleared at the lungs (test this by putting in a very large number for in equation B). The particular decrement selected (e. nearly all of X is cleared at the lungs (test this by inserting a very small value for in equation B). the anesthesiologist may force anesthetic into quickly equilibrating tissues (especially the brain) to rapidly reach anesthetizing concentrations. Thus.9) estimated time constants of 3– 6 minutes for the VRG. For anesthetic X with minimal solubility. This follows from the fraction of anesthetic (F) cleared from the blood as it passes through the lungs. sevoflurane would also show an increase after a brief anesthetic. separations among anesthetics arise. Yasuda et al. the value for desflurane is given as anything between 0. and this increase occurs after relatively brief anesthetics. Thus. Similarly. as the duration of anesthesia increases. elimination from muscles and fat also determines the alveolar concentration during recovery from anesthesia. By definition: Concentration in Blood/Concentration in Gas (A) It is assumed that equilibrium (the same partial pressure of anesthetic) exists between the two phases— blood and gas. As we will show. So the time to almost any decrement must be short regardless of the extent of equilibration. as indicated in the previous discussion. sevoflurane. Sevoflurane also shows an increase but only after longer anesthetics.. 10 min after discontinuation of anesthetic administration) with a less soluble anesthetic. But at smaller decrements. ventilation. Results As predicted. 1C).g. and 240 min after the start of anesthesia.5 70 Halothane 2. At a 90% decrement (Fig. the graph for sevoflurane draws away from that for desflurane after a 120-min anesthesia. VRG. By using the largest anesthetic concentrations that could be delivered and an open system. muscle group [MG]. anesthetic metabolism. and. or ventilation/perfusion abnormalities. particularly for anesthesia in the usual clinical range of up to 120 min duration. On average. VRG vessel rich group. The model allows the user to fix the essential elements: anesthetic solubility in blood and tissues.. the solubility of desflurane is roughly half that of sevoflurane. the time to an 80% decrement is relatively short for desflurane. 92%. 90. and 5% sevoflurane. Blood/Gas and Tissue/Gas Settings Used by Gas Man Version 3. from 4% isoflurane). gas and blood flows. the solubility of sevoflurane is half that of isoflurane. It does not correct for intertissue diffusion of anesthetics.97 13 Sevoflurane 0.9 150 The default values for solubility in Gas Man . The particular (Euler) integration used stabilizes the behavior of the model under extreme conditions of fresh gas flow.. These trends progress with increasing decrements. Finally.1. fat group [FG]) attached to another compartment. A nonrebreathing system continued to be used. the equilibration follows first-order kinetics. We manipulated the vaporizer settings to rapidly achieve and maintain the target concentrations.8 Desflurane Blood VRG Muscle Fat 0. we rapidly (4 –7 min of simulated time) achieved alveolar target concentrations of 10% desflurane. For isoflurane anesthesia exceeding 90 min in duration. the rise occurs at a still earlier time. and 95%. The time to an 88% decrement shows the delay in recovery produced by accumulation of sufficient anesthetic in muscle and fat to make the slow terminal washout from these tissues rate limiting (Fig. and the solubility of isoflurane is half that of halothane. For anesthesia shorter than 90 min. At 30. Each compartment equilibrates instantly with the anesthetic brought to it. We also simulated the effect of different cardiac outputs on decrement times for sevoflurane.3 2.1 2.8 9. gas and blood flows. and compartment volumes determine the rate of equilibration. In . the rapid washout from the VRG cannot produce an 88% decrease in concentration because the slower washout of drug from the muscle and fat increasingly prolongs the time to an 88% decrement compared with sevoflurane and desflurane. 210. accumulation of drug in tissue does not appreciably influence 80% decrement times for anesthesia of less than 240 min duration. and tissue volumes. We noted the minutes of washout needed to decrease the alveolar and VRG concentrations by 50%. 80%. then at 2% for the last 30 min (before discontinuing anesthetic administration). isoflurane might be maintained at 4% for 60 min.54 0. we now see an increase with desflurane. 1B). Decrements examined were from the primary concentration used (e.5 4. 90%. 60. 4% isoflurane. It is these differences that underlie the differences in context-sensitive decrement times illustrated in the figures. At a 95% decrement (Fig.690 ANESTHETIC PHARMACOLOGY EGER AND SHAFER CONTEXT-SENSITIVE DECREMENT TIMES ANESTH ANALG 2005. 120. In addition. Each cardiac output was applied throughout the simulation.4 34 Isoflurane 1. except for the concentration effect. accumulation of isoflurane in tissue increasingly delays the time to an 80% decrement. anesthetic administration was abruptly discontinued (the vaporizer setting decreased to zero) and the circuit was flushed. we simulated the effect of decreasing the alveolar concentration by half during the last 30 min of anesthesia (e. The actual concentrations are not relevant to this exercise except that they allowed accurate determinations of the time to various decrements. we used 4 L/min and 8 L/min. 60%. For anesthesia longer than 90 min.101:688 –96 Table 1. with the effect more pronounced for sevoflurane than for desflurane. Solubility settings were those available in Gas Man® (Table 1). 1D). the breathing circuit.65 1. to mimic the effect of “tapering” at the end of anesthesia. For sevoflurane and desflurane. the difference between times for sevoflurane and desflurane to achieve a particular decrement increases.g. and the rise in the sevoflurane curve occurs at an earlier time. 150. the times to an 80% decrement would likely be clinically indistinguishable among the three drugs. kinetics may be described with a flow-limited 4 compartment mammillary model (lungs.42 0. isoflurane and sevoflurane. 180. For comparisons among desflurane. 1A).1 4. These delays might be clinically appreciable. and sevoflurane (Fig. The times for sevoflurane and desflurane also show the influence of drug accumulation on recovery. 88%. and cardiac output. 1E). isoflurane. we used an alveolar ventilation of 4 L/min and a cardiac output of 6 L/min. Solubility in blood and tissues. although the effect is much greater and earlier with sevoflurane. At a 92% decrement (Fig. 70%. In addition to the 6 L/min used in a comparison of the anesthetics. B. At a 92% decrement. and increasing the duration of anesthesia produces an earlier increase with sevoflurane.101:688 –96 ANESTHETIC PHARMACOLOGY EGER AND SHAFER CONTEXT-SENSITIVE DECREMENT TIMES 691 Figure 1. Although the time to an 80% decrement in the concentration in the vessel rich group (VRG) of tissues differs among desflurane. The effect of increasing duration of anesthesia on decrement times can be illustrated for individual anesthetics. 2. particularly after 90 min. The graph for sevoflurane now appears similar to the graph for isoflurane in A. The trend seen in B proceeds further for a 90% decrement (C).g.. The graph for isoflurane deviates immediately after 30 min whereas the graph for sevoflurane deviates after 90 min. 2. after which the three curves diverge. an increasing duration lengthens the time to a given decrement and shortens the time to an appreciable increase in time to reach that decrement. E. At a 95% decrement. but the qualitative relationship between anesthetics (e. the primary cause of the increase in time with larger decrements and longer anesthesia is that the rapid washout from the VRG by itself cannot produce the required decrement and recovery increasingly depends on washout from more slowly equilibrating tissues. A.ANESTH ANALG 2005. it is short for anesthesia lasting 120 min. the graph for desflurane rises steeply after a 60-min anesthesia. Solubility influences both effects: the lengthening is greater with the more soluble sevoflurane. after which time the time to an 80% decrement appreciably lengthens with isoflurane. each case. sevoflurane. As indicated in Figure 2A (desflurane) and B (sevoflurane). The time to achieve a 95% decrement appreciably separate sevoflurane and isoflurane from desflurane at 30 min of anesthesia. and compare Figs. C. This approach to tapering anesthesia during the last 30 min of anesthesia does not cause anesthesia with isoflurane to allow the rapid attainment . desflurane versus sevoflurane) remains the same. and isoflurane as a function of their different solubilities. B and D). The difference for isoflurane seen in A is exaggerated for an 88% decrement (B). A and C. and the graph for sevoflurane deviates after 120 min. the three pictured anesthetics are similar only after a 30-min anesthetic. The graph for desflurane is distinctly lower at all time points. D. Now the graph for isoflurane deviates from the other 2 anesthetics when anesthesia exceeds 60 min. particularly after a 90-min anesthesia. Decreasing the anesthetic concentration by half for the last 30 min of anesthesia shortens the times to a specific decrement (compare Figs. The progression seen for desflurane in Figure 1. D. An increase in cardiac output (presuming the VRG shares in the increase in blood flow) narrowed the difference between alveolar and VRG decrement times whereas a decrease in cardiac output did the reverse (data not shown). half of MAC). of course. MAC. C. Thus.692 ANESTHETIC PHARMACOLOGY EGER AND SHAFER CONTEXT-SENSITIVE DECREMENT TIMES ANESTH ANALG 2005. to be expected from equation B. A decrease in cardiac output does the reverse. The simulations showed little difference (approximately 2 to 3 min) between the average values for the decrement times for the VRG versus the alveolar concentrations regardless of duration of anesthesia (data not shown). 3). We can rewrite our definition of F. B. E.g. not half MAC). The figure is intended to demonstrate the effect of tapering during the last 30 min of anesthesia. the fraction of anesthetic cleared from the blood as it passes through the lungs. demonstrating that only for a 95% decrement is there a marked increase in the time to the decrement and that this prolongation occurs after 60 min of anesthesia. B. Administration of the smaller concentration during the last 30 min of anesthesia does decrease the time to a given decrement (compare Figure 2. An increase in cardiac output increases time to reach a given decrement and causes an earlier increase in the time to reach a given decrement... The simulation from which these graphs were drawn imposed a primary (e. Even with tapering. of longer decrement times (compare Fig. The remarks made for Figure 2. 2E with any of the remaining graphs in Fig. The graphs present the time to reach the indicated decrement as a percentage of the primary concentration (i. With all other factors held constant. C apply here for “tapering” with sevoflurane. A and C). the times to reach decrements of 88% or greater are prolonged with isoflurane. showing that for a 90% or greater decrement is there a marked increase in the time to the decrement after 30 to 90 min of anesthesia. each enters the equation for F in an identical form. The difference was slightly smaller with desflurane than with sevoflurane because of the greater tissue/ blood partition coefficients of sevoflurane. 2). .e. A. as F 100%* 1/[1 ( *Q)/VA]. Note that Q and are multiplied. The concentration imposed during the last 30 min of anesthetic delivery equaled half the primary concentration (e. This is. and an increase in Q has the same effect as a proportional increase in . Compare with Figure 2. The progression seen for sevoflurane in Figure 1..101:688 –96 Figure 2. one MAC) concentration of desflurane for anesthesia until the last 30 min of anesthetic delivery. our simulations show that cardiac output can considerably influence the times to a given decrement (Fig.g. whereas other drugs (e. we would wish to get below 0. If we chose 90%.15). Second. neuromuscular blocking drugs) do not pass through the blood-brain barrier at all.g. we demonstrate the importance of cardiac output as a determinant of decrement times. under 120 minutes (Fig. inhaled anesthetics enter and leave the body via the lungs whereas injected compounds usually enter via a vein and require the liver and kidneys for their removal (and thus. by increasing blood flow to the liver. an increase in cardiac output may accelerate rather than retard recovery from anesthesia with injected drugs). whereas the curve for 6 L/min deviates after 90 min of anesthesia. but if we had chosen 1 MAC. Thus.05 MAC or less. 1. the patient given typical doses of fentanyl may receive 0.. As in the present essay. noting the importance (as do we) of blood and tissue solubility.” They use a readily available tool (Gas Man®) to determine decrement times.g.A). we must ask “90% of what?” If we had chosen 2 MAC. in contrast to inhaled anesthetics. Our simulations describe a larger range of decrement times and apply a test of “tapering. particularly after more than 1 hour of anesthesia. Further. we note that the pharmacokinetics of all anesthetic adjuvants (e. the curve for 8 L/min deviates from both curves after 30 min of anesthesia. The threshold for measurable impairment of cognitive function equals 0.101:688 –96 ANESTHETIC PHARMACOLOGY EGER AND SHAFER CONTEXT-SENSITIVE DECREMENT TIMES 693 Figure 3. except that the gas transfer must deal with the concentration and second gas effects. By definition. note the role of p-glycoprotein in morphine plasma-brain equilibration). thereby accelerating the clearance of an IV drug but minimally affecting recovery from an inhaled anesthetic. Finally..2 MAC. Third. But some injected anesthetics are actively transported (e. The different routes of administration and elimination also may produce opposite effects.ANESTH ANALG 2005. inhaled anesthetics passively and easily traverse all membranes. Parenthetically. midazolam or opioids). then a 90% decrement would mean a decrease to 0. In addition. Thus. Discussion These results confirm and enlarge upon the predictions concerning context-sensitive decrements for inhaled anesthetics made by Bailey (2). 2E). that would require a 95% decrement. Neither of these examples considers the impact of drugs given concurrently (e. The patient who gets isoflurane might be “awake” after a prolonged anesthetic.0 MAC. An increase in cardiac output (ventilation held constant) can appreciably increase the time to a 92% decrement for sevoflurane. That is a major reason to use adjuvant drugs in combination with inhaled anesthetics. Administration of fentanyl may markedly decrease the alveolar concentration required to prevent movement (14. Thus. although there will be a difference among anesthetics because of solubility. a constant inspired concentration of inhaled anesthetic closely (but not exactly) mimics a constant rate IV infusion.5).1 MAC during recovery— further if other depressant drugs (midazolam) have been given. Desflurane would allow the earliest return to a sense of “normally awake” (20). . For example.1 MAC. In both cases. particularly for the most common durations of anesthesia.. If we began with 1. The concepts underlying context-sensitive decrement times were first developed for IV anesthetics (1. with several modifications.19). but a prolonged period of time would be required to reach a 90% or more decrement. to IV anesthetics and anesthetic adjuvants. if we were at 1 MAC during anesthesia. What we have outlined in the present essay applies. But which decrement time is important to recovery from anesthesia? In part there is no simple answer to this question because the concentration reached is not indicated by the decrement time. The same is true to a lesser extent with sevoflurane.5 MAC during surgery. we must ask.g. drug transfer follows first-order principles. an 80% decrement might be reached reasonably quickly (Fig. fentanyl) determine their deposition and thereby add to the complexity of interpretation of the present article’s simulations. lipid and aqueous. such a level must be attained to have 50% of patients respond appropriately to command. First. But recovery means more than simply responding to command.g.17). This is seen for the increase from 4 to 6 L/min and from 6 to 8 L/min. “what MAC-fraction is important regarding recovery?” MACawake for desflurane or isoflurane is a third of MAC (16. Such administration will decrease the separation of awakening times among anesthetics because a smaller decrement allows emergence from anesthesia. then a 90% decrement would mean a decrease to 0.. increasing cardiac output will increase hepatic blood flow.1 MAC (18. detailing the effect of the choice of decrement on decrement times. the differences cannot be great because all will allow an 80% decrement to be reached in a short period of time. these reports made use of multicompartmental uptake and elimination.” That is. but would not feel “awake. An approach to complete recovery probably demands that the patient be at 0. e.07 mL per 100 mL of blood. The use of volunteers also avoids the confounding effects of surgery and other medications. decreasing the alveolar concentration would have only a modest effect on anesthetic stored in muscles or fat. The clinician may taper the delivery towards the end of anesthesia. For example. that we instantaneously clear all of anesthetic Y from the alveoli. 2E). Appendix Imagine what happens at the extremes of solubility. James H. The blood can hold an enormous amount of anesthetic vapor Y.. 2. or 0. Now if we transfer enough of Y from blood to the fresh alveolar gas to bring the concentration to 1% (actually 0.101:688 –96 Numerous studies indicate the importance of solubility to various end-points of recovery. 95%). A faster recovery would occur because of the unloading of part of the anesthetic contained by the VRG. 2.999%) in the .07%. 4 L/min.. Because Q VA. That is a 99. Assume also a bit of magic: that we instantaneously eliminate all residual anesthetic from the lungs.694 ANESTHETIC PHARMACOLOGY EGER AND SHAFER CONTEXT-SENSITIVE DECREMENT TIMES ANESTH ANALG 2005. Now imagine that all (well. The blood can hold very little anesthetic X. nearly all because F 99. (37) that recovery of pharyngeal function requires that the patient reach effect-site concentrations well below MACawake and that this differentiates the effects of desflurane from sevoflurane (pharyngeal dysfunction persists longer after anesthesia with sevoflurane. on discontinuing anesthetic administration and instantaneously washing out the residual anesthetic from the lungs. the concentration in the gas phase would be 0. Solubility and anesthetic kinetics remain key to the time to recovery. Specifically.9% if 0. and recovery is quicker with desflurane than with either sevoflurane (20.26 –29) or isoflurane (30 –36). but the exact numbers do not matter).07%. 2. the concentration in the blood (as defined by equation A) equals 70*0. In summary. and thus the acceleration of recovery would be limited. suppose that we stop the delivery of anesthetic Y. every 100 mL of alveolar gas would only contain 1 mL of anesthetic vapor. Context-sensitive decrements provide a powerful approach to understanding the importance of solubility and kinetics to recovery. Consistent with the present analysis. even at an alveolar concentration of 70%. the alveolar concentration would immediately decrease from 70% to 0. C and D with Fig.07 mL per 100 mL of gas.e. That is. the effect was limited. ending with a smaller concentration that allows a faster recovery from anesthesia. A and B with Fig. many factors determine recovery from anesthesia. and the most accurate estimates of differences may be found in studies of volunteers where anesthetic duration and concentration can be precisely controlled. at the same partial pressure of anesthetic) with the 70% alveolar concentration. although 100 mL of blood would contain 1000 mL of anesthetic vapor. the effect of increasing anesthetic duration has a greater effect on the more soluble sevoflurane (i. equation A indicates that the concentration in blood equals 1%*1000 or 1000% (i. Suppose we stop the delivery of anesthetic X and that the alveolar ventilation and cardiac output are equal (say.001) anesthetic X in the blood traversing the lungs is transferred into the fresh alveolar ventilation gas. Suppose that the blood/gas partition coefficient of anesthetic X is 0. Suppose the blood/gas partition coefficient of anesthetic Y is 1000. Philip in the construction of the manuscript and his advice concerning the use of Gas Man . Thus. We appreciate the several suggestions made by Dr. Volunteers given desflurane awaken sooner than those given sevoflurane (27).. with the blood at equilibrium (i. a lesser solubility produces an earlier recovery to a given end-point. This possibility was simulated by decreasing the alveolar concentration by half for the last 30 minutes of anesthesia (compare Fig. The clinician may rightly argue that we cannot assume a constant alveolar or VRG delivery of anesthetic to the end of anesthesia.9% decrement.. As with anesthetic X. and that the alveolar ventilation and cardiac output are equal. a partition coefficient seen with alcohols (38).e. But a very different change occurs at the other extreme. at an alveolar concentration of 1%. particularly at larger decrements (e. that is not how clinical anesthesia is delivered. Note that with isoflurane.001 mL anesthetic vapor per 100 mL of blood. Recovery is quicker with sevoflurane than with isoflurane (21–25).g. However. Although this maneuver shortened times to particular decrements. times to reach specific decrements still are prolonged relative to desflurane and sevoflurane without such a “tapering” (compare Figs.) It may underlie the demonstration by McKay et al. or 0. increasing duration of anesthesia results in a longer time to a given end-point than is the case with desflurane. and we have extended the analysis of contextsensitive decrement times to greater decrements.001 and that the alveolar concentration is 70% (70 mL of anesthetic vapor per 100 mL of alveolar gas). C and D). even with a terminal 30 minutes at half the maintenance concentration. Variability in patient responses and the use of adjuvant drugs may obscure these differences. 1000 mL of anesthetic vapor per 100 mL of blood). Moreover.) Such observations are part of what distinguishes the present from previous reports: we have new data such as those presented by McKay et al.) This appears to be true for both shortterm end-points (response to command) and longterm end-points (recovery of normal judgment and cognition as assessed by recovery of normal digit symbol substitution results. Ebert TJ. Severinghaus JW. 23. Yasuda N.83:314 –9. Weiskopf RB. Garfield JM. 11. Anesth Analg 1992. Role of lung factors. Effects of isoflurane and nitrous oxide in subanesthetic concentrations on memory and responsiveness in volunteers.5 mL of vapor must move from blood into each 100 mL of alveolar gas.5/ 0. 8. Pharmacokinetic parameters relevant to recovery from opioids. Kinetics of desflurane. Med Educ 1989. 26. Anesthesiology 1992. Campbell C. Philip JH. Crankshaw DP. Mahmoud NA. essentially a 0% decrement. Laurence AS. Fletcher JE. Assume that the concentration of X and Y in the blood phase is only half (50%) of the concentration that would be produced at equilibrium. Starkweather JA. and halothane in humans. Effect of subanesthetic concentrations of enflurane and halothane on human behavior. Yasuda N. 0. Chestnut Hill. These observations indicate that the lack of equilibration had a big effect on Y and virtually no effect on X. Eger EI II. 18.74:241–5. Similarly. 10. and permitting the remaining molecules in the blood phase to re-establish equilibrium.85:681– 6.84:429 –31. Lockhart SH. et al.999%. Cook TL. a decrement of 50%. Anesthetic uptake and action. Uhrich TD. the situation differs for anesthetic Y. isoflurane. 21. Ding Y. Eger EI II. Pharmacokinetics. Smith I. Thus. 1974:77–96. the alveolar concentration decreases from 1% to 0. Philip JH. et al. 72:316 –24. This is somewhat closer to reality. For anesthetic X. Philip BK. 20. the far larger number of molecules in the blood will establish a new equilibration that will reflect the concentration of Y that was in the blood before the Y molecules were removed from the air: half (50%) of the initial alveolar concentration of 1%. Bogetz MS. et al. Uptake and distribution of anesthetic agents. Anesth Analg 1995. 1963:59 –71. Smith M. Winter PM. Context-sensitive half-times and other decrement times of inhaled anesthetics. Can J Anaesth 1995. Paskin S. Eger EI II. . et al. In the previous examples. Shafer SL. When we remove all the molecules of Y from alveolar air.74: 489 –98. and those molecules were removed. Desflurane or sevoflurane for gynaecological day-case anaesthesia with spontaneous respiration? Anaesthesia 2001. Recovery from sevoflurane anesthesia: a comparison to isoflurane and propofol anesthesia. 4. Anesth Analg 1991. 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