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ANESTHETIC PHARMACOLOGY

The Influence of Gender on Loss of Consciousness with Sevoflurane or Propofol

Department of Anesthesiology, Emory University School of Medicine, Grady Memorial Hospital, Atlanta, Georgia

Address correspondence and reprint requests to Jay W. Johansen, MD, PhD, Department of Anesthesiology, Emory University School of Medicine, Grady Memorial Hospital, Atlanta, GA 30303. Address e-mail to jay_johansen{at}emoryhealthcare.org.

	Abstract

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Studies have suggested that hypnotic requirements for general anesthesia and emergence may be influenced by gender. In this study, we examined the effect of gender on the hypnotic requirement for loss of consciousness (LOC) using either a volatile (sevoflurane) or an IV (propofol) anesthetic. One-hundred-fifteen unpremedicated, ASA physical status I–II patients, aged 18–40 yr old, received either sevoflurane by mask to a predetermined end-tidal concentration (%ET_sevo) or propofol by target-controlled infusion (effect site) while breathing spontaneously. After sufficient time for equilibration, LOC was assessed by lack of response to mild prodding. The up-down method of Dixon was used to determine the hypnotic target concentration at 50% response (LOC₅₀). No statistically significant difference in LOC₅₀ was noted between men and women for sevoflurane (0.83% ± 0.1% and 0.92% ± 0.09% ET, respectively). Men required significantly more propofol than women (2.9 ± 0.2 versus 2.7 ± 0.1 µg/mL, respectively). However, there was no difference in the bispectral index (BIS) at LOC for men or women with either hypnotic anesthetic. This investigation identified a small, statistically significant difference in hypnotic requirement at LOC₅₀ between men and women with propofol but not with sevoflurane. As defined by BIS, men and women had equivalent hypnotic states at LOC₅₀, indicating that gender had no clinically significant effect on hypnotic requirements. However, BIS at a defined clinical end-point (LOC₅₀) was significantly different between the sevoflurane and propofol groups, suggesting that neurophysiological effects of these anesthetics may be different.

	Introduction

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The effect of gender on anesthetic drug pharmacokinetic and pharmacodynamic variables has not been routinely investigated (1,2). It remains controversial whether gender affects anesthetic requirements. Pregnancy decreases the minimum alveolar anesthetic concentration (MAC) required to eliminate movement in 50% of patients to surgical incision (3–5). However, in a retrospective data analysis by Eger et al. (6), nonpregnant women had a similar MAC for a number of volatile anesthetics compared with men. In addition, Tanifuji et al. (7) found that women’s menstrual cycle did not affect MAC despite large differences in plasma progesterone concentrations.

Gan et al. (8) found, in a multicenter trial, that gender was a highly significant, independent predictor for recovery time using a propofol/alfentanil/nitrous oxide anesthetic. Women required more propofol to maintain equivalent bispectral index (BIS) levels than men under general anesthesia. No significant difference was noted in total propofol/alfentanil doses or in maintenance or preemergent BIS values. Women awoke significantly faster, as measured by eye opening and by response to verbal command (MAC_awake) after discontinuation of the propofol infusion. Gan et al. (8) suggested that a combination of pharmacokinetic and pharmacodynamic factors were responsible for the gender difference.

Gan et al. (8) reported reanalysis of an earlier study (9), finding that women had significantly larger propofol plasma concentrations at the point of loss of consciousness (LOC; loss of response to voice command) and that women had consistently higher BIS values at similar propofol plasma concentrations than men. Because BIS measures the pharmacodynamic response of hypnotic medications, they suggested that women may have a different sensitivity to propofol. Ward et al. (10) found that women had a smaller volume of distribution for propofol and a larger clearance resulting in a larger initial peak and smaller final concentration during similar continuous infusions. They confirmed faster emergence times for women compared with men at equivalent BIS values using propofol anesthesia. They concluded that pharmacokinetic differences were predominately responsible for this effect.

Emergence from anesthesia is a complex, nonsteady-state process that can be influenced by the multiple drugs given during anesthesia, stimuli from airway instrumentation, and type and length of surgery (11). Plasma drug levels and end-tidal gas measurements are not in equilibrium with, and lag behind, brain concentrations, making it difficult to control intra- and interindividual variables. Steady-state conditions can be approximated by maintaining drug delivery for 3 distribution half-lives (t_1/2) for a given medication and delivery route. Exogenous stimuli can be minimized by studying patients before surgery and by maintaining spontaneous ventilation without airway instrumentation.

The goal of this study was to examine the role of gender on anesthetic requirements for loss of arousal response to light touch or mild shaking using either an IV (propofol) or volatile (sevoflurane) anesthetic under conditions approximating steady-state.

	Methods

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After IRB approval, 115 consenting patients scheduled for elective surgery under general anesthesia were enrolled between November 2002 and June 2003. All patients were ASA physical status I or II and between the ages of 18 and 40 yr old. Exclusion criteria were hearing impairment, active daily or weekly substance abuse, and nonfluency in English. In addition, patients with significant heart, lung, liver, renal, neurological disease, seizure disorder, those currently prescribed major psychoactive medication, or those whose weight was >150% of ideal body weight were also excluded.

Patients were recruited during preoperative preparation before surgery. Men and women were separately randomized to either propofol or sevoflurane anesthesia. No preoperative sedation or analgesics were administered. Once in the operating room, standard anesthesia monitors were placed, including electrocardiogram, pulse oximetry, noninvasive blood pressure cuff, BIS of the electroencephalogram (EEG), and end-tidal gas monitors. The BIS A2000 monitor (version 3.2; Aspect Medical Systems, Inc, Natick, MA) uses three adhesive electrodes to the forehead (single channel: Fp1-Fpz). BIS, raw EEG, hemodynamic variables, and end-tidal gas measurements were automatically recorded to a computer at 5-s intervals during the course of the experiment. BIS and other EEG-based variables reported here are an average of recordings taken for 1 min before the administration of the sedation scale.

Either sevoflurane (tightly sealed mask via semiclosed circuit) or propofol (IV) were administered to achieve predetermined end-tidal or effect-site concentrations for each patient. Propofol was administered via a target-controlled infusion (TCI) device (Duke University, Durham, NC), which used a three-compartment population pharmacokinetic model targeting drug effect-site concentration (12). This technology is able to rapidly achieve and maintain stable serum and effective brain concentrations of propofol. The initial target effect-site concentrations were 2.5 µg/mL of propofol or an end-tidal sevoflurane concentration of 0.6%. After 10 min at the target concentration, the modified observer’s assessment of awareness and sedation (OAA/S) was administered (9,13). LOC was defined as an OAA/S of <2 (loss of responsiveness to light tapping on left shoulder or mild shaking with voice command to open eyes). An arousal response and opening the eyes was considered positive, whereas nonspecific motor responses were considered negative. After OAA/S assessment, the study was concluded, and anesthesia was continued at the discretion of the anesthesiologist.

Propofol and sevoflurane target concentration for a given patient were determined by the response of the previous patient. Target concentrations were increased by 10% if the previous patient’s OAA/S score was 2 and decreased by 10% if <2. The concentrations at which LOC was in 50% of patients (LOC₅₀) were determined by the Dixon method (14). LOC₅₀ was defined as the mean of independent crossover pairs within each group. A crossover represents a unique pair of sequential patients in which the first patient lost consciousness and the next patient did not or vice versa. The investigator administering the OAA/S was not blinded to the sevoflurane or propofol dose.

Frequency data (gender) were analyzed with the ² test. Kruskal-Wallis test was also used to detect significant differences in ranked categorical variables such as ASA status. Multifactorial analysis of variance with post hoc Bonferroni test was used to determine the LOC₅₀ and average BIS for propofol and sevoflurane and to examine significant cofactors (gender, age, weight, etc.) using a standard statistical software package (SPSS version 11; SPSS Inc, Chicago, IL). P < 0.05 was considered statistically significant.

	Results

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Ten independent, crossover pairs were collected in each experimental group except for the male sevoflurane group (nine crossover pairs; Table 1), representing 78 of 115 enrolled patients. The average age (mean ± sd) of male patients was 29 ± 7 yr and 31 ± 6 yr for female patients. No statistically significant differences were found between genders or drug groups. Weight was also not significantly different between men and women (81 ± 16 kg versus 74 ± 15 kg, respectively) and was not different between drug groups. Men were significantly taller (177 ± 8 cm) than women (164 ± 8 cm) in both drug groups. No difference in heart rate, end-tidal carbon dioxide, and systolic blood pressure measured before the administration of the OAA/S during spontaneous ventilation was found between men and women or between drug groups (Table 1). In the sevoflurane group, diastolic blood pressure (DBP) was significantly higher in men (74 ± 15 mm Hg) than women (59 ± 14 mm Hg). No gender difference in DBP was found in the propofol group. Administration of the OAA/S did not significantly change heart rate, systolic blood pressure, or DBP in any group when examined by repeated-measures analysis of variance (data not shown). OAA/S was administered 11 ± 1 min after starting the propofol infusion and 11 ± 3 min after sevoflurane administration via mask. There were no significant differences in the time the OAA/S was administered between genders or drug groups.

The sevoflurane dose at LOC₅₀ measured by loss of response to mild prodding or shaking (OAA/S <2) was 0.83% ± 0.13% in men and 0.92% ± 0.09% in women (Fig. 1). No statistical difference was found between genders (92% power to detect a mean difference of 10%). Propofol effect-site target at LOC₅₀ was significantly different between men (2.9 ± 0.2 µg/mL) and women (2.7 ± 0.2 µg/mL). This comparison had a 95% power to detect a significant difference. After equilibration, and 1 min before the administration of the OAA/S administration, BIS at 50% LOC (BIS₅₀) was not significantly different between men and women in either drug group. However, the average BIS at LOC was statistically different between patients receiving sevoflurane (74 ± 9) and those receiving propofol (62 ± 11) (Table 2; Fig. 1). Average signal quality index (SQI) remained more than 80% (SQI <70% indicates BIS calculation may be influenced by artifact) and electromyographic (EMG) less than 50 dB. No difference in EMG activity in the frontalis muscle, the electrode impedance, or overall SQI between gender or hypnotic drug were identified during automated BIS recordings (Table 2).

View larger version (20K): [in this window] [in a new window]   Figure 1. Bispectral index (BIS) versus hypnotic dose at loss of consciousness in 50% of subjects (LOC50) for sevoflurane or propofol. Patients breathed spontaneously and were maintained at stable end-tidal concentrations of sevoflurane by mask or by target-controlled infusions (TCI) of propofol for 10 min. LOC50 for sevoflurane was 0.83% ± 0.13% in men and 0.92% ± 0.09% in women. LOC50 for propofol was 2.9 ± 0.2 µg/mL effect-site target concentration in men and 2.7 ± 0.1 µg/mL in women. Data are mean ± sd (represented by error bars) of crossover pairs. Statistically significant (P < 0.05) gender differences are indicated (*). Average BIS at LOC for sevoflurane was significantly different than that of propofol (#; Table 2).

	Discussion

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This study examined the hypnotic requirements for LOC₅₀ to mild prodding or shaking at near steady-state conditions using either sevoflurane by mask or propofol by TCI in healthy patients undergoing outpatient surgery randomized by gender. No statistically significant difference was noted in the LOC₅₀ for sevoflurane between men and women. This experimental design provided adequate statistical power (92%) to detect a 10% difference in the mean values between these groups. Katoh et al. (11) found similar results using the LOC₅₀ for loss of response to loud verbal command (OAA/S <3) of 0.65% end-tidal sevoflurane at an average BIS of 75. Gender was not a significant cofactor in their experiment. In our study, men required significantly more propofol (+7% TCI effect-site target concentration) than women at LOC₅₀. Measured serum propofol levels can vary ±30% from the predicted target values, and serum levels have been found to be a poor predictor of brain effect (15–17). Although effect-site concentrations could not be obtained, BIS provided a dynamic measure of anesthetic effect. Men and women had no significant difference in BIS₅₀ values at LOC, indicating equivalent hypnotic states between genders for either anesthetic. Based on these facts, we conclude that gender has no clinically significant impact on the propofol or sevoflurane requirements for LOC under our experimental conditions.

Our study used the same pharmacokinetic variables for propofol and TCI software as Glass et al. (9). They concluded that the correlation of BIS value and measured effect was independent of the choice of sedative/hypnotic drug, with no statistically significant differences between IV and volatile anesthetics. However, they defined LOC as loss of response to verbal command (OAA/S <3), which is similar to Zbinden et al.’s (18) definition of MAC_awake. They reported LOC₅₀ for propofol 2.35 µg/mL with a BIS₅₀ of 63 for OAA/S <3 (loss of response to verbal command). Reexamination of their data for OAA/S <2 found an LOC₅₀ for propofol 2.4 µg/mL with a BIS₅₀ of 56 for OAA/S (J. Sigl, personal communication) similar to our average value for propofol of 2.8 µg/mL at a BIS₅₀ of 62. Gan et al. (8) reported a reanalysis of the Glass et al. (9) data showing that women had consistently higher BIS values at similar plasma propofol concentrations to men. Our data do not support this conclusion. Although sevoflurane was not used in the Glass et al. (9) study, the LOC₅₀ for isoflurane for OAA/S <2 was 0.57% end-tidal at a BIS₅₀ of 63 (J. Sigl, personal communication). Stimulus-response scales, such as the OAA/S, provide only a ranked-ordered set of tests of increasing sedation with significant overlapping definitions. The OAA/S scale does not represent clearly defined increments or units of hypnosis and cannot clearly differentiate between pure cortical and spinally mediated motor responses. The sedative concentrations of propofol and sevoflurane for loss of response to mild prodding or shaking (OAA/S <2) and those reported for loss of response to loud voice command (OAA/S <3 or MAC_awake) were very similar.

A higher average, prestimulus BIS at LOC₅₀ for the volatile anesthetic sevoflurane was found compared with propofol. BIS was averaged for one minute before the administration of the OAA/S. It is possible that the BIS is higher in patients receiving volatile anesthetics because of increased EMG activity in the frontalis muscle of the forehead, and this may be increased in spontaneously breathing patients. The BIS value can be artifactually increased by high EMG activity (>50 dB), electrocautery, or high frequency signals (SQI <50%) because of the increased noise below the high-pass filter. In our study, an adequate signal quality was maintained throughout the experiment, and there was no difference in EMG between genders or anesthetic. Many studies fail to report these data and consider sources of potential signal contamination. The explanation of this statistically significant difference between propofol and sevoflurane at the transition from OAA/S 2 to 1 is unclear.

In summary, we conclude that there are no clinically significant differences between genders for LOC defined by lack of response to mild prodding for sevoflurane or propofol in spontaneously breathing patients at conditions approximating steady-state. However, at the clinical end-point of loss of response to mild prodding or shaking, sevoflurane and propofol have differing neurophysiologic effects, as determined by BIS.

	Footnotes

 
Dr. Sebel is a paid consultant to and Dr. Johansen has received speaking honoraria and educational grants from Aspect Medical Systems, Inc (Natick, MA).

Accepted for publication December 13, 2006.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Pleym H, Spigset O, Kharasch ED, Dale O. Gender differences in drug effects: implications for anesthesiologists. Acta Anaesthesiol Scand 2003;47:241–59.[Web of Science][Medline]
2. Vuyk J, Oostwouder CJ, Vletter AA, et al. Gender differences in the pharmacokinetics of propofol in elderly patients during and after continuous infusion. Br J Anaesth 2001;86:183–8.[Abstract/Free Full Text]
3. Chan MT, Gin T. Postpartum changes in the minimum alveolar concentration of isoflurane. Anesthesiology 1995;82:1360–3.[Web of Science][Medline]
4. Gin T, Chan MTV. Decreased minimum alveolar concentration of isoflurane in pregnant humans. Anesthesiology 1994;81:829–32.[Web of Science][Medline]
5. Zhou HH, Norman P, DeLima LG, et al. The minimum alveolar concentration of isoflurane in patients undergoing bilateral tubal ligation in the postpartum period. Anesthesiology 1995;82:1364–8.[Web of Science][Medline]
6. Eger EI II, Laster MJ, Gregory GA, et al. Women appear to have the same minimum alveolar concentration as men: a retrospective study. Anesthesiology 2003;99:1059–61.[Web of Science][Medline]
7. Tanifuji Y, Mima S, Yasuda N, et al. Effect of menstrual cycle on MAC. Masui 1988;37:1240–2.[Medline]
8. Gan TJ, Glass PSA, Sigl J, et al. Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology 1999;90:1283–7.[Web of Science][Medline]
9. Glass PS, Bloom M, Kearse L, et al. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology 1997;86:836–47.[Web of Science][Medline]
10. Ward DS, Norton JR, Guivarc’h PH, et al. Pharmacodynamics and pharmacokinetics of propofol in a medium-chain triglyceride emulsion. Anesthesiology 2002;97:1401–8.[Web of Science][Medline]
11. Katoh T, Bito H, Sato S. Influence of age on hypnotic requirement, bispectral index, and 95% spectral edge frequency associated with sedation induced by sevoflurane. Anesthesiology 2000;92:55–61.[Web of Science][Medline]
12. Smith C, McEwan AI, Jhaveri R, et al. The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. Anesthesiology 1994;81:820–8.[Web of Science][Medline]
13. Chernik DA, Gillings D, Laine H, et al. Validity and reliability of the observer’s assessment of alertness/sedation scale: study with intravenous midazolam. J Clin Psychopharmacol 1990;10:244–51.[Web of Science][Medline]
14. Dixon WJ. The up-and-down method for small samples. Am Stat Assoc J 1965;60:967–78.
15. Hoymork SC, Raeder J, Grimsmo B, Steen PA. Bispectral index, serum drug concentrations and emergence associated with individually adjusted target-controlled infusions of remifentanil and propofol for laparoscopic surgery. Br J Anaesth 2003;91:773–80.[Abstract/Free Full Text]
16. Mortier E, Struys M. Effect site modelling and its application in TCI. Adv Exp Med Biol 2003;523:239–44.[Medline]
17. Shafer SL. Towards optimal intravenous dosing strategies. Semin Anesth 1993;12:222–34.
18. Zbinden AM, Maggiorini M, Petersen-Felix S, et al. Anesthetic depth defined using multiple noxious stimuli during isoflurane/oxygen anesthesia: motor reactions. Anesthesiology 1994;80:253–60.[Web of Science][Medline]

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