Patient gender may be an important factor influencing recovery from general anesthesia (1–5). Women emerge faster from general anesthesia than men (4–6), but it is unclear whether this is a result of gender differences in pharmacokinetics or pharmacodynamics or differences in type or extent of surgery (5,6). In addition, whether faster emergence is related to women receiving less anesthetic than men remains uncertain.
Women require more propofol than men to lose consciousness (7,8) and to maintain anesthesia during surgery (8,9). This suggests gender-related differences in drug disposition and/or sensitivity to propofol (5) and, in either case, may result in a lighter hypnotic state of anesthesia and possibly awareness. Awareness with recall is an infrequent yet significant complication of general anesthesia (10–12). Women are more likely to report awareness than men (13), suggesting a relative insensitivity to hypnotic drugs in women, that they may have received less anesthetic than men, or that men do not report it as often.
The bispectral index (BIS; Aspect Medical Systems, Natick, MA) was developed as a measure of hypnotic depth of anesthesia (14). It is derived from the electroencephalogram using unilateral frontoparietal electrodes and is displayed as a number from 0 (reflecting deep anesthesia) to 100 (reflecting awake state) (14). A BIS value between 40 and 60 is suitable for surgical anesthesia (15). A recent trial found that BIS-guided anesthesia reduced the risk of awareness in surgical patients at high risk of awareness (10). This confirms the ability of BIS monitoring as a measure of the hypnotic depth of anesthesia.
In this study, we analyzed recovery characteristics of a subset of these patients and compared recovery times between women and men.
We analyzed a subset of patients previously enrolled in a large multicenter, randomized, controlled trial of patients at increased risk of awareness (10). Patients at risk of awareness included those whose anesthetic drug dose administration was constrained by concern for marked hemodynamic instability or delayed recovery time (16,17). Study patients included those undergoing rigid bronchoscopy, cesarean delivery with general anesthesia, emergency surgery for acute trauma, those with significant impairment of cardiovascular status, severe end-stage lung disease, history of awareness, known or suspected heavy alcohol intake, chronic benzodiazepine or opioid use, or those treated with protease inhibitors and therefore midazolam was contraindicated (10,16,17). Patients undergoing general anesthesia combined with neuromuscular blockade whose tracheas were extubated and who were admitted to the recovery room were included in the study. We excluded all patients receiving postoperative sedation and/or mechanical ventilation in the intensive care unit and patients with missing recovery data.
After ethics committee approval and informed patient consent, patients were randomly assigned to receive either BIS-guided anesthesia or routine anesthesia care. All other aspects of perioperative care, including choice and usage of anesthetic drugs, were left to the discretion of the anesthesiologist. In patients allocated to the BIS group, the delivery of anesthesia was adjusted to maintain a BIS of 40–60 from the time of laryngoscopy and tracheal intubation until the commencement of wound closure. In both groups of patients, reduction and cessation of anesthesia was timed to allow for early recovery after final wound closure. For BIS-monitored patients, hypnotic drug administration was adjusted to allow a BIS of 55–70 during wound closure in order to facilitate early recovery (15). We recorded the BIS value at 5 min intervals for the first hour, and every 10 min thereafter, for each patient allocated to the BIS group. The time-averaged mean BIS value was calculated (10).
The times to eye opening from cessation of anesthesia after completion of wound closure and eligibility for discharge after arrival in the postanesthesia care unit (PACU) were recorded. Recovery times were defined in the study protocol and were measured from the time of completion of wound dressing. Eligibility for PACU discharge was met when the patient was awake and orientated, had stable vital signs, and pain and emesis were controlled. For institutions using the Aldrete score, a modified Aldrete score ≥9 was used to define eligibility for PACU discharge. These times were recorded by research or PACU nursing staff unaware of whether BIS monitoring was used intraoperatively.
Patient demographics, preoperative characteristics, details of medical and surgical history, and risk factors for awareness were collected. Operative characteristics collected included anesthetic drugs and dosages used, airway management, adverse intraoperative events, duration of anesthesia, and type and extent of surgery (minor, intermediate, major). Extent of surgery was determined by the anesthesiologist based on a consideration of the likely metabolic stress, pain imposed, and hospitalization required. For calculation of anesthetic drug administration during maintenance, we asked anesthesiologists to record the time-averaged end-tidal anesthetic concentrations for volatile drugs, and infusion rate or target plasma concentration when total IV anesthesia was used. We were interested in a possible effect of female sex hormones on recovery characteristics, and so we included a surrogate measure for active hormonal (premenopausal) status in the analysis by coding patient age <52 yr, the average age of menopause in Australian women (18).
Descriptive statistics are expressed as number (%), mean (sd), or median (interquartile range). Differences between women and men were examined using Student’s t-test, Mann-Whitney U-test, χ2 test or analysis of variance, as appropriate. Gender differences in recovery times were plotted as Kaplan-Meier curves, and compared with log-rank tests. We anticipated differences in baseline variables between the gender groups and so we explored the influence of each variable on recovery times using univariate testing. Significant covariates affecting recovery times were included with premenopausal status and gender in a multivariable analysis using Cox proportional hazards. This enabled adjustment for each potential confounding variable and allowed determination of an independent effect of gender on recovery times. The hazard ratio subsequently derived was denoted as a positive event and duly referred to as a recovery ratio. Thus, a hazard ratio >1.0 indicates an increased likelihood of a faster recovery time. All analyses were performed using SPSS for Windows, version 12.0. A P value of < 0.01 was considered statistically significant.
Of the 2463 patients recruited to the randomized trial, 1079 patients (584 males, 495 females) were eligible for inclusion in this cohort study (522 in the BIS group and 557 in the routine care group). Female patients were younger, had less preexisting medical disease and lower ASA scores, and underwent less extensive surgery than male patients (all P < 0.01). The average BIS during anesthesia were higher in women than men (P = 0.005) (Table 1).
Women had faster recovery times than men: time to eye opening: women 11 (12) min versus men 14 (13) min for men, P < 0.0005; time to eligibility for discharge from the PACU: women 78 (106) min versus men 133 (209) for men, P < 0.0005 (Figs. 1 and 2). Corresponding median (95% confidence interval) values were 8 (7.3–8.7) min versus 10 (9.3–10.7) min, and 60 (55–65) min versus 75 (71–79) min, respectively. Differences between women and men were consistent across a range of subgroups (Figs. 3 and 4).
In multivariate analyses, patient gender, ASA status, emergency surgery, and benzodiazepine premedication predicted longer time to eye opening (all P ≤ 0.001) (Table 2). Patient gender, duration and extent of surgery, and ASA status predicted time to eligibility for discharge from the PACU (all P < 0.001) (Table 3).
We found that gender was an important factor influencing recovery times in patients undergoing general anesthesia with neuromuscular blockade. Times to eye opening after cessation of anesthesia and duration of recovery room stay were shorter in women compared with men. Although the size of this effect might be considered to be small (median differences, 2 minutes and 15 minutes, respectively), it is equivalent to the effect of sedative premedication on these variables. Our results suggest that the influence of patient gender on recovery from general anesthesia is significant and not subtle, as suggested previously (2). Importantly, our results indicate a possible hormonal influence on the effect of hypnotic drugs. This finding is consistent with previous studies (4–6) but has improved reliability in our study because of the diverse range of surgical procedures undertaken and the large sample size, which allowed adjustment for many confounding factors. Subgroup analyses of each of the main factors known to affect recovery times supported a consistent gender effect.
BIS-guided anesthesia hastens recovery by improving titration of anesthesia (10,15). Because BIS numbers correlate well with the hypnotic state of anesthesia, larger average values indicate a lighter depth of anesthesia. Therefore, women either received less hypnotic drug administration than men in our study, or women were intrinsically less sensitive to the hypnotic effects of anesthetic drugs (as indicated by larger BIS values). Previously, women had a threefold more frequent incidence of reported awareness (8), and in our study women were more likely to have reported awareness during previous anesthesia. Their faster rate of recovery may account for these observations. Women recover faster than men even when their measured BIS levels are equivalent (6), suggesting that both pharmacokinetic and pharmacodynamic variables may be involved.
The evidence supporting pharmacokinetic differences between women and men is substantial. Women have a larger proportion of body fat and smaller water content than men (3). This affects the volume of distribution and therefore the initial concentration of many drugs used in anesthesia (3). For lipid-soluble drugs, such as opioids and benzodiazepines, the volume of distribution is generally larger in women (3); conversely, for water-soluble drugs such as muscle relaxants, it is smaller (3). For most IV anesthetics, hepatic metabolism is the major route of elimination, with gender-related differences reported in the cytochrome P450 system (3). Female sex hormones, in particular, modulate the activity of this system (19,20) and may influence drug clearance. With alfentanil, clearance is dependent almost entirely on hepatic CYP3A4 activity (21), and sex-related differences in clearance have been reported (22). Hormonal influences may be involved (23), as clearance of alfentanil was 70% more rapid in women younger than 50 years than older women (22). A larger volume of distribution and more rapid rate of metabolism would facilitate faster cessation of drug action and enhance speed of emergence. This can explain, at least in part, the faster rate of recovery seen in women after general anesthesia (4,5).
There are also gender differences with the pharmacodynamic effects of drugs used in anesthesia. Women have less sensitivity to propofol (6,8) and, at similar blood concentrations of propofol, women consistently record larger BIS values (8). As BIS measures pharmacodynamic effect, it is plausible that decreased sensitivity to the hypnotic actions of propofol may account for faster recovery times seen in our study. Similar pharmacodynamic differences have been reported with remifentanil, where larger blood concentrations have been required in conjunction with nitrous oxide to achieve the same depth of anesthesia in women than in men (24). The minimum alveolar concentration (MAC) of a volatile anesthetic is another measure of pharmacodynamic effect that may be gender-dependent. Women required larger desflurane concentrations than men to prevent movement in response to noxious electrical stimulation at baseline conditions (25). The MAC of xenon in elderly patients is also sex-dependent with women, who require 26% less xenon than men to prevent movement (26). These findings were not supported by a retrospective study of 258 patients previously anesthetized with desflurane, diethyl ether, halothane, methoxyflurane, and sevoflurane (27). Using logistic regression to normalize the MAC of these drugs, Eger and Laster (27) found no difference between women and men. One possible explanation is that these studies on the MAC of volatile anesthetics were small and thus may have been underpowered. Whether gender influences MAC thus remains unclear.
As menopause normally heralds the natural decline in the level of circulating female sex hormones, age <52 years can be used as a surrogate marker of active sex hormonal status (18). In our study, the gender differences seem to be accentuated in younger patients, suggesting a hormonal influence. This finding is significant, as it may allude to a possible female sex hormone role on the modulation of anesthetic action. Pregnancy decreases the MAC of isoflurane, halothane, and enflurane (28,29). The female sex hormone, progesterone, has been shown to increase the potency of inhaled anesthetics (30) and to induce sleep in humans (31). This and other steroid hormones have hypnotic and analgesic effects (32). Altered modulation of the γ-hydroxy butyric acidA receptor complexes, one of the purported sites of action of anesthetic drugs, has been demonstrated during the menstrual cycle in rats (33). This evidence reinforces the view that underlying physiological differences induced by sex hormones may account for some of the variation in the effects of anesthesia (4). However, this proposition requires direct measurement of likely hormones during and after anesthesia.
Recovery from general anesthesia is dependent on factors influencing drug sensitivity and drug disposition (5). Because the two groups being compared in this study could not be randomized, there is the possibility of differences in important baseline characteristics. Such differences can mask the true effect of patient gender and thus alternative explanations for our findings (34,35). We therefore used univariate analyses to explore associations with recovery times of such possible confounders and used multivariate analysis to adjust for significant covariates (36). This confirmed that patient gender affects recovery times. In addition, we examined the effect of gender in a number of subgroups selected on the basis of variables that may represent potential confounders. In most of these subgroups, female gender remained a significant risk factor (Figs. 3 and 4). Despite this, we believe more work is needed to better define the role of gender on recovery using groups of patients matched in baseline characteristics and type of surgery. A possible role of sex hormones needs to be further validated by studies correlating recovery times and overall quality of recovery with measurement of female sex hormone levels.
In conclusion, this study found that gender is an independent factor influencing recovery from general anesthesia: despite similar amounts of anesthetic drug administration, women recover faster and are eligible for discharge from the recovery room sooner than men.
1. Holdcoft A. Females and their variability. Anesthesia 1997;52:931–4.
2. Moller DH, Glass PSA. Should a patient’s gender alter the anaesthetic plan? Curr Opin Anesthesiol 2003;16:379–83.
3. Pleym H, Spigset O, Kharasch ED, Dale O. Gender differences in drug effects: implications for anesthesiologists. Acta Anaesthiol Scand 2003;47:241–59.
4. Myles PS, McLeod A, Hunt J, Fletcher H. A cohort study of gender differences in speed of emergence and quality of recovery after anesthesia. BMJ 2001;322:710–1.
5. Gan TJ, Glass PS, Sigl J, et al. Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology 1999;90:1283–7.
6. 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.
7. Leslie P, Drover DR. Women patients require more propofol for general anesthesia than men. Anesthesiology 2001;95:A481.
8. 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.
9. Kodaka M, Asano K, Miyao H. The propofol Cp50 of women for loss of consciousness is higher than that of men. Anesthesiology 2002;96:A446.
10. Myles PS, Leslie K, McNeil J et al. Bispectral index monitoring to prevent awareness during anesthesia: the B-Aware randomised controlled trial. Lancet 2004;363:1757–63.
11. Sandin R, Enlund G, Samuelsson P, Lennmarken C. Awareness during anesthesia: a prospective case study. Lancet 2000;355:707–11.
12. Sebel PS, Bowdle TA, Ghoneim MM et al. The incidence of awareness during anesthesia: a multicenter United States study. Anesth Analg 2004;99:833–9.
13. Domino KB, Posner KL, Caplan RA, Cheney FW. Awareness during anesthesia – a closed claims analysis Anesthesiology 1999;90:1053–61.
14. Sigl JC, Chamoun NS. An introduction to bispectral analysis for the EEG. J Clin Mon 1994;10:392–404.
15. Gan TJ, Glass PS, Windsor A, et al. Bispectral Index allows faster emergence and improved recovery from propofol, alfentanil and nitrous oxide anesthesia. BIS Utility Study Group. Anesthesiology 1997;87:808–15.
16. Ranta S, Laurila R, Saario J, et al. Awareness with recall during general anesthesia: incidence and risk factors. Anesth Analg 1998;86:1084–9.
17. Lubke GH, Kerssens C, Phaf RH, Sebel PS. Dependence of explicit and implicit memory on hypnotic state in trauma patients. Anesthesiology 1999;90:670–80.
18. Walsh RJ. The age of the menopause in Australian women. Med J Aust 1978;215:181–2.
19. Wadelius M, Darj E, Frenne G, Rane A. Induction of CYP2D6 in pregnancy. Clin Pharmacol Ther 1997;62:400–7.
20. Oram M, Wilson K, Burnett D. The influence of the oral contraceptive on the metabolism of methaqualone in man. Br J Clin Pharmacol 1982;14:341–5.
21. Kharasch ED, Russell M, Mautz D, et al. The role of cytochrome P450 3A4 in alfentanil clearance: implications for interindividual variability in disposition and perioperative drug interactions. Anesthesiology 1997;87:36–50.
22. Lemmens H, Burm A, Hennis P et al. Influence of age on pharmacokinetics of alfentanil. Gender dependence. Clin Pharmacokinetic 1990;19:416–22.
23. Rubio A, Cox C. Sex, age and alfentanil pharmacokinetics. Clin Pharmacol Ther 1991;21:81–2.
24. Drover DR, Lemmens HJ. Population pharmacodynamics of remifentanil as a supplement to nitrous oxide anesthesia for elective abdominal surgery. Anesthesiology 1998;89:869–77.
25. Greif R, Laciny S, Mokhtarani M, et al. Transcutaneous electrical stimulation of an auricular acupuncture point decreases anaesthetic requirement. Anesthesiology 2002;96:306–12.
26. Goto T, Nakata Y, Morita S. The minimum alveolar concentration of xenon in the elderly is sex-independent. Anesthesiology 2002;97:1129–32.
27. Eger EI II, Laster MJ. Women appear to have the same minimum alveolar concentration as men. Anesthesiology 2003;99:1059–61.
28. Gin T, Chan MT. Decreased minimum alveolar concentration of isoflurane in pregnant humans. Anesthesiology 1994;81:829–32.
29. Chan MTV, Mainland P, Gin T. Minimum alveolar concentration of halothane and enflurane are decreased in early pregnancy. Anesthesiology 1996;85:782–6.
30. Datta S, Migliozzi RP, Flanagan HL, Krieger NR. Chronically administered progesterone decreases halothane requirements in rabbits. Anesth Analg 1989;68:46–50.
31. Merryman W, Boiman R, Barnes L, Rothchild I. Progesterone “anesthesa” in human subjects. J Clin Endocrinol Metab 1954;14:1567–9.
32. Frye CA, Duncan JE. Progesterone metabolites, effective at the GABAA
receptor complex, attenuate pain sensitivity in rats. Brain Res 1994;643:194–203.
33. Finn DA, Gee KW. The influence of oestrous cycle on nonsteroid potency in the GABAA
receptor complex. J Pharm Exp Therap 1993;265:374–9.
34. Altman DG. Comparability of randomised groups. Statistician 1985;34:125–36.
35. Datta M. You cannot exclude the explanation you have not considered. Lancet 1993;342:345–7.
© 2006 International Anesthesia Research Society
36. Katz MH. Multivariable analysis: a primer for readers of medical research. Ann Intern Med 2003;138:644–50.