British Journal of Anaesthesia 104 (2): 17582 (2010)

doi:10.1093/bja/aep374

Advance Access publication December 26, 2009

Effect of increased body mass index and anaesthetic duration on recovery of protective airway reexes after sevourane vs desurane
R. E. McKay1*, A. Malhotra1, O. S. Cakmakkaya1 2, K. T. Hall1, W. R. McKay1 and C. C. Apfel1
Department of Anaesthesia and Perioperative Care, C-450, University of California San Francisco, San Francisco, CA 94143-0648, USA. 2Cerrahpasa Medical School, University of Istanbul, Istanbul, Turkey
*Corresponding author. E-mail: eshimar@anesthesia.ucsf.edu
Background. Increased BMI may increase the bodys capacity to store potent inhaled anaesthetics, more so with more soluble agents. Accordingly, we asked whether increased BMI and longer anaesthesia prolonged airway reex recovery. Methods. We measured time from anaesthetic discontinuation until rst response to command (T1); from response to command until ability to swallow (T2); and from anaesthetic discontinuation to recovery of ability to swallow (T3) in 120 patients within three BMI ranges (18 24, 25 29, and !30 kg m22). All received sevourane or desurane, delivered via an LMA. Results. T1 and T3 after sevourane exceeded T1 and T3 after desurane: 6.6 (SD 4.2) vs 4.0 (1.9) min (P,0.001), and 14.1 (SD 8.3) vs 6.1 (2.0) min (P,0.0001). T3 correlated more strongly with BMI after sevourane (28 s per kg m22, P0.02) than desurane (7 s per kg m22, P0.03). Regarding T2, patients receiving sevourane with BMI !30 kg m22 were less often able to swallow 2 min after response to command than were those with BMI 18 24 or 25 29 kg m22 (3/20 vs 10/20 or 9/20, P,0.05). Each sevourane MAC-hour delayed T3 by 4.5 min (268 s) (R0.46, P,0.001) whereas each desurane MAC-hour delayed T3 by 0.2 min (16 s) (R0.10, P0.44). Conclusions. Prolonged sevourane administration and greater BMI delay airway reex recovery. The contribution of BMI to this delay is more pronounced after sevourane than desurane. Br J Anaesth 2010; 104: 17582 Keywords: airway, reexes; anaesthetics, desurane; anaesthetics, sevourane; anaesthetics, volatile; pharmacokinetics, obesity; pharmacokinetics, uptake Accepted for publication: November 27, 2009
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Volunteers1 and patients2 4 awaken more rapidly after desurane than sevourane anaesthesia, in part at least because of the lesser solubility of desurane. Does a more rapid awakening translate into greater patient safety, particularly into a faster recovery of protective airway reexes? At 25% of MACawake, sevourane, isourane, and propofol signicantly decrease the coordination of pharyngeal muscles,5 and patients anaesthetized with desurane recover protective airway reexes faster than those anaesthetized with sevourane.6

Interim ndings from this trial were presented as a poster at the 2008 European Society of Anaesthesia in Copenhagen, Denmark. European Journal of Anaesthesiology 2008; 25 (Suppl 44): 2AP2 7. Declaration of interest. R.E.M. has received research support in the past from Baxter Healthcare for other studies, but did not receive support for this study. She has also received honoraria for speaking from Baxter Healthcare. Baxter manufactures sevourane and desurane. R.E.M. is a member of the Speakers Bureau for Baxter Healthcare, manufacturer of sevourane and desurane. In addition, Baxter Healthcare has provided research support to the University of California for some of R.E.M.s investigator-initiated projects in the past.

# The Author [2009]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournal.org

McKay et al.

Might body habitus affect recovery? Large differences in body mass (e.g. 350 g rats vs a 6300 kg whale) correlate with rate of anaesthetic uptake,7 and obesity modestly increases uptake of isouranebut does not appear to concurrently slow rate of recovery.8 The faster awakening from sevourane than isourane, and from desurane than sevourane, reects progressively smaller blood and tissue solubilities. Lean tissues, such as the vessel-rich group (heart, kidney, and viscera), and muscles receive most of the cardiac output, but have much smaller afnities for anaesthetics than does fat; thus anaesthetic equilibration with these tissues, respectively, takes minutes vs hours.9 11 Both high anaesthetic capacity and low blood ow prolong time to equilibration of potent inhaled anaesthetics with the bulk fat compartment, and result in relatively low partial pressures of anaesthetic in that tissue. Anaesthetic partial pressure in bulk fat increases so slowly9 that bulk fat continues to take up anaesthetic after administration has been discontinued, and this process could accelerate recovery. As opposed to bulk fat, fat immediately adjacent to viscera (e.g. omental and perirenal fat) and muscle (dermis and s.c. fat) may take up anaesthetic by intertissue diffusion, possibly accounting for 30% of anaesthetic uptake.12 13 In contrast to bulk fat, anaesthetic content in fat receiving anaesthetic by intertissue diffusion is much greater and may release anaesthetic earlier in recovery. Sevourane fat/gas and muscle/gas partition coefcients are 2.8 and 2.2 times greater than those of desurane, suggesting greater distribution of sevourane vs desurane to fat.14 16 Furthermore, if an increased BMI increased the interface area between fatty tissues, viscera and muscle, an increased BMI might delay awakening and recovery of protective reexes more after anaesthesia with sevourane compared with desurane.6 Accordingly, we hypothesized that overweight (BMI 2529) and obese (BMI !30) patients would (i) respond to command and experience recovery of protective airway reexes more slowly after anaesthesia, and that (ii) this relationship would be more pronounced after sevourane, given its greater fat solubility, than after desurane. We also hypothesized that increasing duration of anaesthesia would delay recovery of protective reexes less after anaesthesia with desurane.

Methods
With approval from the University of California Committee on Human Research, we recruited patients aged 18 75, in BMI ranges 18 24, 25 29, and !30 kg m22, undergoing surgery for which an LMA was the planned method of airway management, and randomly assigned these patients to receive sevourane or desurane. Any patient with a history of neuromuscular disorder, stroke, dysphagia, dysphonia, impaired gastric emptying, or previous pharyngeal or upper gastrointestinal surgery or

radiation was excluded. We determined that all could swallow 20 ml of water in an upright position. We judged swallowing to be adequate if no coughing or drooling occurred after the water passed into the mouth, and no water remained in the oropharynx upon subsequent visual inspection. Anaesthesia consisted of premedication with midazolam 2 mg, induction with lidocaine (0 1.5 mg kg21) and propofol (1 3 mg kg21), fentanyl as necessary, and maintenance of anaesthesia with sevourane or desurane (randomly assigned) at a concentration judged to be appropriate by the clinician in oxygen 50% and nitrous oxide 50%. Neuromuscular blocking agent was avoided in all cases. Standard anti-emetic prophylaxis consisted of dexamethasone 4 mg, administered at induction, and ondansetron 4 mg, administered 15 45 min before the end of surgery. An observer, blinded to anaesthetic assignment, noted the time from discontinuation of anaesthetic administration until the patients rst appropriate response to commands open your eyes and squeeze my hand. At 2, 6, 14, 22, and 30 min after rst response to either command, the patient was placed in a 608 upright position and asked to swallow 20 ml of water. Swallowing was judged successful as described above. Outcomes measured were: (i) time from anaesthetic discontinuation until rst response to command (T1; recovery of consciousness); (ii) time from rst response to command until rst demonstrated ability to swallow (T2); and (iii) time from anaesthetic discontinuation until rst demonstrated ability to swallow (T3). Analysis of T1, T2, and T3 vs BMI and maintenance anaesthetic was conducted both separately and together in a multivariate analysis. Post hoc analyses were performed to distinguish whether lean body mass (calculated from a previously validated formula, noted in the Appendix),17 duration of anaesthesia (MAC-hours), age, or fentanyl administration contributed independently to pharyngeal recovery. Regarding the impact of increasing fat, we also considered two opposing kinetic effects. As bulk fat and BMI increase, the area of interface between lean tissue and bulk fat increases, providing greater surface area for uptake of anaesthetic by intertissue diffusion, an effect that would be expected to delay recovery. On the other hand, the surface to volume ratio of bulk fat decreases with increasing volume, and bulk fat equilibrates very slowly and should continue to absorb anaesthetic well into the recovery period. Thus, the effect of increased interface surface of fat, while important, may asymptotically reach a limit. In contrast to fat served by intertissue diffusion, bulk fat itself might be expected to accelerate recovery, particularly during the time immediately after discontinuation of anaesthetic administration. Thus, beyond some point, further increase in BMI might actually counteract the kinetic effect of intertissue diffusion on recovery. Accordingly, we performed post hoc analysis to assess

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whether a stronger correlation between delayed recovery and BMI exists within a more restricted BMI range.

Table 1 Patient characteristics of populations, by BMI category. *P,0.05, BMI !30 vs 18 24 kg m22; **P,0.01, sevourane vs desurane BMI range (kg m22)

Statistical analysis
On the basis of previous recovery data,2 we calculated that a sample size of 120 (60 receiving sevourane and 60 receiving desurane), with BMI ranging from 21 to 37, would produce an 80% chance of detecting a difference in slope of 13.4 s in awakening time vs BMI (kg m22) for sevourane compared with desurane. Comparison of categorical outcomes was made by x2 analysis with Yates correction where indicated. Comparison of continuous variables was made by t-test, ANOVA, or linear regression. Statistical analysis was performed using STATA version 9.2 (College Station, TX, USA).
Number of subjects Sevourane Desurane Age Sevourane Desurane Female [n (%)] Sevourane Desurane MAC-hours Sevourane Desurane Fentanyl (mg) Sevourane Desurane Anaesthetic discontinuation to response to command (T1, min) Sevourane Desurane Anaesthetic discontinuation to rst ability to swallow (T3, min) Sevourane Desurane Time after rst response to command 2 min Sevourane Desurane 6 min Sevourane Desurane 14 min Sevourane Desurane 22 min Sevourane Desurane 30 min Sevourane Desurane

18 24

25 29

!30

20 20 41 (13) 39 (8) 17 (85) 14 (70) 0.9 (0.6) 0.9 (0.7) 131 (89) 127 (97)

20 20 44 (14) 39 (19) 7 (35) 11 (55) 1.1 (0.6) 0.9 (0.4) 142 (72) 146 (73)

20 20 48 (14) 49 (13) 10 (50) 8 (40) 1.3 (1.2) 1.2 (1.0) 187 (129) 200 (134)

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Results
Patient characteristics
Age, per cent females, MAC-hours, and administered dose of fentanyl in patients anaesthetized with sevourane vs desurane in BMI ranges 1824, 2529, and !30 are shown (Table 1). The average BMI value was 27.4 with a standard deviation of 5.1. Two patients (one receiving sevourane and the other desurane) were excluded from linear regression analysis on the basis of outlying BMI values (52 and 64 kg m22, respectively, both more than 3 SD above the mean), although they were included in the other analyses. The BMI of the 118 subjects in the linear regression analysis ranged from 18.3 to 40.2 kg m22.

5.1 (3.6) 3.2 (1.6)

8.0 (5.5) 3.3 (1.9)

6.7 (2.7) 4.3 (1.9)**

9.8 (5.4) 15.6 (8.7) 17.1 (8.8)* 5.2 (1.6) 6.6 (2.0) 6.5 (2.2)** Number of subjects able to swallow without coughing or drooling 10 20 18 20 20 20 20 20 20 20 9 20 14 20 19 20 19 20 19 20 3* 19** 12 20** 17 20 19 20 19 20

Recovery of consciousness
Time from anaesthetic discontinuation until rst response to command (T1) was shorter among patients receiving desurane than those receiving sevourane [4.0 (SD 1.9) vs 6.6 (4.2) min, P,0.001]. T1 correlated signicantly (linear regression) with lean body mass but not with BMI (Table 2).

Table 2 Linear regression analysis was performed on recovery endpoints [anaesthetic discontinuation until rst response to command (response to command, T1) and time from anaesthetic discontinuation until rst ability to swallow (airway reex recovery, T3)] vs BMI and lean body mass Endpoint Population Body mass index Coefcient (s kg21 m2) Response to command (T1) Airway reex recovery (T3) All Sevourane Desurane All Sevourane Desurane 6.06 5.70 5.23 20.2 28.3 7.0 P-value Lean body mass Coefcient (s kg21) 5.14 7.60 2.51 7.30 11.60 2.36 P-value

Recovery of airway reexes in the overall population and in patients given sevourane vs desurane
Time from discontinuation of anaesthetic until rst ability to swallow (T3) was shorter and more predictable among patients receiving desurane compared with sevourane [6.1 (SD 2.0) vs 14.1 (8.3) min, P,0.001, Table 2]. In the combined (all patients) population, T3 correlated directly with increasing BMI [0.34 min (20 s) per kg m22; R0.24, P0.01, linear regression]. Anaesthetic choice inuenced this correlation. The slope for the correlation between T3 vs BMI was greater after sevourane anaesthesia [0.47 min (28 s) per kg m22; R0.30, P0.02] than

0.114 0.369 0.090 0.010 0.020 0.031

0.001 0.003 0.034 0.021 0.023 0.060

after desurane [0.12 min (7 s) per kg m22; R0.28, P0.03, linear regression, Fig. 1A]. The difference between these slopes did not reach statistical signicance (ANOVA P0.09). A longer time from anaesthetic

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2500

Patients receiving sevoflurane y = 28x + 70, R = 0.30 Patients receiving desflurane y = 7x + 177, R = 0.28

2000 Time (s) from anaesthetic discontinuation until first ability to swallow (T3), 1000 s = 17 min

1500 P =0.02 1000

500 P=0.03 0

15

20

25

30 BMI (kg m2)

35

40

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2500

Patients receiving sevoflurane y = 46x 361, R = 0.38 Patients receiving desflurane y = 6x + 199, R = 0.21

2000

Time (s) from anaesthetic discontinuation until first ability to swallow (T3), 1000 s = 17 min

1500 P<0.01 1000

500

P=0.12

0 15 20 25 30 35 40 BMI (18 35 kg m2)

Fig 1 (A) Longer time from anaesthetic discontinuation to airway reex recovery showed positive correlation with BMI, by 28 s per kg m22 after sevourane and by 7 s per kg m22 after desurane. ANOVA difference in slopes P0.09. (B) Results from post hoc analysis are shown. Among a restricted population (BMI 1835 kg m22), the longer time from sevourane discontinuation to airway reex recovery correlated with greater BMI, by 46 s per kg m22. There was no statistically signicant correlation between rate of airway reex recovery vs BMI after desurane administration. ANOVA difference in slopes P0.01.

discontinuation to rst response to command correlated with lean body mass but not BMI by linear regression (Table 2). Delay in T3 correlated (linear regression) with estimated lean body mass by 1.8 min per 10 kg after sevourane (R0.30, P0.02) and 0.4 min per 10 kg after desurane (R0.20, P0.06). Recovery of airway reexes may be dened as the time from response to command (rather than time from discontinuation of anaesthetic administration) until recovery of ability to swallow (T2). This has the advantage of starting

from the same level of behavioural recovery (awareness) with both inhaled anaesthetics. T2 showed virtually no variability among patients receiving desurane; 59 of 60 subjects swallowed successfully at the earliest test interval (2 min), and all were able to do so at the second interval (6 min). In contrast, only 22 of 60 patients receiving sevourane could swallow without coughing or drooling at the 2 min test interval, 44 of 60 at the 6 min interval, and 56 of 60 at the 14 min interval (Fig. 2). Patients receiving sevourane with BMI .30 kg m22 were less likely to

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BMI 1829

100 *
BMI 30

80
BMI 1824

60 ** Per cent of patients able to 40 BMI 2529 swallow 20 #

BMI 30

Sevoflurane

Desflurane

10

14

10

14

Minutes after response to command

Fig 2 Airway reex recovery was signicantly less predictable after sevourane compared with desurane until 14 min after response to command (**P,0.00001 at 2 min; *P0.0005 at 6 min). After desurane, airway reex recovery was complete in 59 of 60 subjects by 2 min after following commands, and in all subjects at subsequent test periods. After sevourane, patients with BMI !30 kg m22 were less likely able to swallow 2 min after following command compared with those with BMI 1829 kg m22 (#P,0.05).

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swallow 2 min after following command than those subjects with BMI ,30 kg m22; by 6 min, this relationship failed to show statistical signicance (Table 1, Fig. 2). Two subjects receiving sevourane did not swallow adequately at any of the test intervals, still coughing or drooling 30 min after response to command.

Exploratory post hoc analysis of factors inuencing recovery of airway reexes

A multivariate post hoc analysis examined the inuence of other factors on time to recovery of airway reexes. The strongest factor inuencing time from discontinuation of anaesthetic administration until return of ability to swallow water (T3) was the choice of anaesthetic (sevourane vs desurane). Duration of anaesthesia (MAC-hours) was the next important factor but was inuenced, in turn, by anaesthetic choice: for sevourane T3 increased by 4.47 min (268 s) per MAC-hour (R0.46, P,0.001); in contrast, T3 did not correlate signicantly with MAC-hours desurane [0.25 min (16 s) per MAC-hour, R0.10, P0.44, Fig. 3]. A smaller factor was patient age, with an increase of 1.7 min per decade after sevourane (P0.018) and 0.6 min per decade after desurane (P0.001). Opioid administration did not signicantly correlate with T2 or T3, in uni- or multivariate analysis.

some large BMI. Post hoc examination of our data suggested this might occur at BMI exceeding 35 kg m22. Accordingly, we performed post hoc analyses conned to BMI values of 35 or less, nding, as anticipated, signicant differences between sevourane and desurane anesthetized patients that were more clear-cut than the entire data set (i.e. containing BMI values .35) suggested (Fig. 1B). The T3 coefcients in this restricted group (n109) were 0.76 min (46 s) per kg m22 vs 0.47 min (28 s) per kg m22 in the unrestricted group among patients receiving sevourane, and 0.10 min (6 s) vs 0.12 min (7 s) in the unrestricted group after desurane. Therefore, these T3 coefcients among the restricted population were greater among patients receiving sevourane, and the slopes differed signicantly (and to a greater extent than in the unrestricted population) between patients receiving sevourane vs desurane (ANOVA P0.01) (Table 3).

Discussion
Overall times from response to command (T2) or discontinuation of anaesthetic administration until airway reex recovery (T3) both correlated signicantly with increased BMI. Consistent with previous ndings, those time intervals were signicantly longer after sevourane than desurane anaesthesia.1 4 The anaesthetic chosen (sevourane vs desurane) and MAC-hours of sevourane contributed most to delayed airway reex recovery (T3), with lesser contributions of BMI and patient age. Airway reex recovery correlated with BMI more strongly after sevourane compared with desurane anaesthesia, possibly because of sevouranes greater solubility in fat, particularly fat immediately adjacent to

Exploratory post hoc analysis of a restricted BMI group

In consideration of the expected opposing kinetic effects of increased lean surface interface with fat vs increased bulk fat, we assessed whether the delay in airway reex recovery associated with greater BMI reached a ceiling at

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2500

Patients receiving sevoflurane y = 268x + 549, R = 0.46 Patients receiving desflurane y = 16x + 350, R = 0.10

2000 P<0.001 Time (s) from anaesthetic discontinuation to first ability to swallow (T3), 1000 s = 17 min 1500

1000

500

P=0.441

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0 0 1 2 MAC Hours
Fig 3 Longer administration of sevourane signicantly delayed airway reex recovery, by 4.5 min (268 s) per MAC-hour (R0.47, P,0.001). In contrast, duration of desurane administration showed a delay of only 0.2 min (16 s) per MAC-hour (R0.10, P0.44).

Table 3 Multiple linear regression accounting for BMI and MAC-hours vs T3 (anaesthetic discontinuation until rst ability to swallow) among all subjects and those receiving sevourane or desurane. Coefcients represent time (s) vs variable Airway reex recovery time (T3) Coefcient 95% condence interval All subjects Anaesthetic (desurane) MAC-hours BMI (kg m22) After sevourane MAC-hours BMI (kg m22) After desurane MAC-hours BMI (kg m22) P-value

2461.1 150.1 16.7 253.7 24.3 14.4 6.9

2581.8 2340.4 0.000 75.0 225.2 0.000 4.8 28.5 0.006 122.2 3.1 227.0 0.5 385.3 0.000 45.7 0.026 55.7 0.490 13.2 0.035

lean tissue. Our ndings support the hypothesis that both blood ow and intertissue diffusion determine anaesthetic transferred to and from fat, even during anaesthetics lasting less than hours. Recovery of protective airway reexes differs between sevourane and desurane more than their blood/gas and tissue/blood solubilities alone would suggest: the slope for time to airway reex recovery (T3) vs BMI for sevourane is four-fold larger than that of desurane, a ratio more closely approximating their respective fat/gas than lean tissue/gas partition coefcients. Ability to swallow at standard time intervals following response to command (T2) was more variable and delayed after sevourane in patients with increased BMI. In contrast, ability to swallow was consistently successful after desurane, and therefore no relationship between T2 and BMI could be established.

Although our data suggest that increasing BMI delayed recovery of airway reexes, particularly after sevourane (Fig. 1), delayed time from anaesthetic discontinuation until rst response to command (T1) correlated more strongly with lean body mass (Table 2), specically with sevourane but not desurane (multivariate analysis not shown). These results support the nding by Wahrenbrock that the rate of increase (and presumably, the rate of decrease) of alveolar anaesthetic concentration, is inversely related to body size.7 The rationale behind this nding is that metabolism, ventilation, and perfusion per kilogram decrease with increasing body size. If heavier individuals have smaller perfusion per kilogram, their tissues should have longer time constants. Our data suggest that increased BMI prolongs recovery of protective airway reexes after administration of anaesthetic, and that this relationship is more pronounced after sevourane than desurane anaesthesia. That is, small MAC fractions of anaesthetic can impair vital protective functions during early recovery, even in seemingly awake patients, and thus such patients can be vulnerable to airway obstruction or aspiration. Obesity compounds this problem. Patients with BMI .30 kg m22 are at a two- to three-fold greater risk of critical respiratory events (airway obstruction, hypoventilation, and desaturation) during early recovery from anaesthesia compared with non-obese patients.18 19 Small MAC fractions of anaesthetic may add to these respiratory events by blunting hypoxic ventilatory responses,20 and such an effect has greater consequences for overweight and obese patients.

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Our study has several limitations. First, our population was relatively healthy, had short to moderate length surgery, and was managed without tracheal intubation, neuromuscular blocking agent, or high-dose opioid, hindering generalization of our ndings to a more complex surgical population. We would speculate, however, that airway reex recovery and BMI might correlate more strongly in intubated patients undergoing major surgery requiring longer anaesthesia because these factors themselves are associated with untoward respiratory effects.21 22 Secondly, opioid administration failed to correlate with airway reex recovery, contradicting evidence suggesting an association between opioid use and pharyngeal dysfunction.23 Possible explanations for our negative nding are the relatively modest doses given to these patients (all breathed spontaneously during surgery), and the overshadowing contributions of MAC-hours of sevourane, BMI, and age. Thirdly, possibly presence of the LMA may have impaired sensory input needed for initiation of swallowing efforts. It is unclear why that effect would preferentially inuence patients as a function of BMI or chosen anaesthetic.24 Fourthly, possibly a lingering effect of anaesthetics (opioid, inhaled agents) contributed to suppression of cough, thereby making the swallowing test less sensitive than other established tests of pharyngeal function. However, this is an unlikely explanation, since previous investigations indicate that most intubated patients awakening from isourane begin to cough at concentrations of 0.5 MAC or greater, suggesting that inhaled anaesthetics in low concentration do not effectively obtund the cough reex.25 Finally, our water swallowing test provides a yes no result rather than quantitative (graded) data. And, although there is no visual conrmation of the misdirected bolus into the laryngeal inlet, water-swallowing tests correlate strongly with aspiration as conrmed by imaging.26 27 In summary, the overweight patient, with higher risk and poorer tolerance for postoperative physiological insults such as hypoventilation, airway obstruction, and aspiration, is likely to experience slower recovery of protective physiological function after sevourane compared with desurane anaesthesia. And increasing duration of anaesthesia, again especially after sevourane, may further slow such recovery. Finally, patients who require either neuromuscular blocking drugs or tracheal intubation may be at still greater risk, since both of these interventions contribute independently to pharyngeal dysfunction and morbidity.21 22

Funding
All authors are supported by UCSF, and UCSF has received funds from Baxter Healthcare and Abbott Laboratories. Both manufacture sevourane and Baxter manufactures desurane. However, this trial was supported only by departmental funds from the University of California, and did not receive support from Baxter Healthcare or other industry source.

Appendix
Lean body mass calculation17
9:27 103 body weight kg 6:68 103 216 BMI kg m2 9:27 103 body weight kg Female : 8:78 103 244 BMI kg m2 Male :

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Acknowledgement
The authors wish to thank Edmond I. Eger, MD, Emeritus Professor, University of California San Francisco, for his numerous suggestions on preparation of this manuscript.

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