Abstract

Background

Numerous studies have shown that women emerge faster from general anaesthesia than men, and differ in their postoperative recovery profile. The extent and underlying mechanisms for these sex-related differences in general anaesthesia are unclear.

Methods

In a multicentre, prospective, matched cohort study, 500 ASA physical status I or II patients of either sex undergoing general anaesthesia for elective surgery were recruited. All subjects received a general anaesthetic through inhalation. Anaesthetic drugs and doses used, bispectral index (BIS) scores, recovery times, pain scores, and 40-item quality of recovery (QoR-40) scores for 3 days after general anaesthesia were recorded.

Results

Women had higher BIS scores at similar concentrations of anaesthesia (P<0.05). Time to eye-opening (P<0.01) and time to obeying commands (P<0.01) were shorter in women. Duration of recovery room stay was longer in women, who also had higher pain scores and need for treatment of nausea and vomiting (all P<0.001). QoR-40 scores for the first 3 days after general anaesthesia were lower in women (P<0.001). Plasma progesterone concentrations in women negatively correlated with the time to eye-opening (ρ=−0.53, P=0.01).

Conclusions

Patient sex is an independent factor influencing the response to anaesthesia and recovery after surgery. Women emerged faster from general anaesthesia but their overall quality of recovery was poorer. Female sex hormones, particularly progesterone, might be involved, with premenopausal women having faster recovery time but poor overall recovery.

Editor's key points

  • Evidence suggests that patient sex might affect recovery from general anaesthesia.

  • Speed and quality of anaesthetic recovery were studied in a multicentre, prospective, matched cohort study of 500 subjects undergoing general anaesthesia for elective surgery.

  • Women were less sensitive to general anaesthetic drugs as assessed by BIS score, emerged faster, and had worse quality of recovery compared with men.

  • Involvement of sex hormones such as progesterone and oestrogen is postulated as a mechanism.

A growing body of evidence suggests that patient sex is an independent factor influencing the response to general anaesthesia.1–3 Women appear to be less sensitive to hypnotic drugs as assessed by doses required to achieve similar hypnotic depth4 and faster recovery times after the cessation of anaesthetic drug delivery.5–8 An apparent increased risk of awareness in women could in part be owing to this reduced susceptibility to anaesthetic drugs.9,10 In addition, women are at greater risk of other adverse outcomes postoperatively.6,8

Sex hormones are neurosteroids and, like pregnanolone,11 have anaesthetic properties.12,13 Increased production of progesterone during the luteal phase of the menstrual cycle14 and pregnancy15,16 can decrease anaesthetic drug requirements. It remains unclear if sex-related reductions in sensitivity to general anaesthesia are primarily because of pharmacokinetic (faster clearance) or pharmacodynamic (less response at equal effect site concentrations) mechanisms.2,3 Some studies, however, have been unable to identify sex-specific differences in anaesthetic drug requirements.17,18

Most previous studies were not specifically designed to investigate sex-related differences in general anaesthesia, instead relying upon post hoc analyses of the existing data.5,6,8,19 In view of the incomplete and contradictory nature of previous studies, we set out to examine the effect of patient sex on requirements and response to general anaesthesia, and recovery from anaesthesia, in a matched cohort study in adults undergoing general anaesthesia for elective surgery.

Methods

Study design

After ethics committee approval and informed consent, 500 adult subjects undergoing elective non-cardiac surgery with general anaesthesia were enrolled in this matched cohort study. The study was conducted at several hospitals in Melbourne, Australia over a 5 yr period from February 2002 to May 2007. We matched each female patient to the next eligible male patient, according to age within 5 yr, American Society of Anesthesiologists (ASA) physical status score, and type of surgery.

Subjects were included in the study if they were aged between 18 and 70 yr, were ASA physical status I or II, and were undergoing elective general, orthopaedic, urologic, plastic, or ear, nose or throat surgery. They were excluded if they did not receive a general anaesthetic through inhalation, were undergoing sex-specific (gynaecological or prostatic surgery), emergency or high-risk surgery, were being treated with a major tranquilizer or lithium, or had a neurological condition.

Preoperative demographic characteristics including details of medical and surgical history, smoking status, and current medications were recorded. Operative data including the type and dose of anaesthetic drugs used, airway management, adverse intraoperative events, type and extent of surgery (minor, intermediate, major), and duration of anaesthesia were recorded. Postoperative sequelae including recovery room stay, adverse events, and pain scores using a 10-point numerical rating scale were recorded.

Female subjects had their menstrual cycle history recorded, including the day of cycle on the day of surgery, cycle length, duration of menses, age of menopause and menarche, and oral contraceptive or other exogenous hormone use. To examine a possible effect of female sex hormones, waist-to-hip ratios were recorded in all subjects. Female waist-to-hip ratio is a reliable indicator of female sex hormone profile;20 women with a lower ratio have higher concentrations of oestrogen and progesterone.21 We defined premenopausal status as age less than 52 yr22 and having menstrual periods. Post-menopausal state was determined clinically by permanent (>6 months) cessation of menses23 and confirmed where possible by elevated plasma follicle stimulating hormone and low oestrogen concentrations. These criteria were validated in a random selection of 23 premenopausal and 5 postmenopausal women using blood collected for the measurement of plasma oestradiol, progesterone, luteinizing hormone, and follicle stimulating hormone.

Most aspects of anaesthetic and perioperative management were left to the discretion of the anaesthetist, but all relevant data were collected. We planned to do sub-group analyses in order to ascertain whether the main study findings were consistent across the range of anaesthetic regimens used in contemporary practice. General anaesthesia was induced with either propofol or thiopental titrated to loss of consciousness and maintained using volatile anaesthesia (isoflurane, sevoflurane, or desflurane) with or without nitrous oxide. Non-depolarizing neuromuscular blocking agents, when used, were antagonized with neostigmine and atropine. End-tidal inhalation agent monitoring was done using the Datex-Ohmeda Aisys Carestation® (GE Healthcare, Helsinki, Finland), which has an accuracy of ±0.2%. Bispectral index (BIS) monitoring was used to measure the hypnotic component of depth of anaesthesia, though administration of anaesthesia was not titrated to BIS. BIS measurements were made every 5 min for the first hour and then every 10 min. A time-averaged mean BIS score was then calculated for the duration of general anaesthesia. Intraoperative age-adjusted minimum alveolar concentration (MACage) was determined using the following nomogram:24 

formula
where MAC40 represents MAC at age 40. The total age-adjusted MAC for volatile agents used in each patient (ktotal) was determined by the formula:25 
formula
where FE,volatile is the end-expired concentration of the volatile agent used and forumla is the end-expired concentration of nitrous oxide.

Cessation of administration of general anaesthesia was timed for the subject to emerge from anaesthesia after final wound closure. Emergence from anaesthesia was timed from the completion of wound dressing (=time 0) and included the time to spontaneous eye-opening, time to obeying commands, and the time spent in the recovery room (until eligible for discharge to the surgical ward).

Quality of recovery was assessed on each of the first 3 days after surgery using the 40-item quality of recovery (QoR-40) score26–28 completed during recovery. The QoR-40 encompasses most aspects of a good quality of recovery after surgery and anaesthesia, consisting of five dimensions (physical comfort, emotional state, physical independence, psychological support, and pain). The QoR-40 score ranges from 40 (extremely poor quality of recovery) to 200 (excellent quality of recovery).

Definition of outcomes

The main study outcomes were: (i) quality of recovery, using the QoR-40 and verbal rating pain scores, and (ii) speed of recovery, using time to eye-opening, time to obeying commands, and time spent in the recovery room. The sample size was calculated to detect an 8% (sd 20%) improvement in the QoR-40, with a type I error of 0.05 and a type II error of 0.2 for which we needed to enrol at least 111 patients per group. Allowing for dropouts and to account for sub-group analyses, we planned to enrol 500 subjects (250 females, 250 males).

Statistical analysis

Descriptive statistics are expressed as number (%) or mean (sd). Differences between women and men were examined using Student's t-test, Mann–Whitney U-test, χ2 test, or repeated analyses of variance, as appropriate. Sex differences in recovery times were plotted as Kaplan–Meier curves. Cox proportional hazards were used to adjust for covariates in order to identify the effects of age and sex on the pattern of recovery. The hazard ratio derived was denoted as a positive event and referred to as the recovery ratio. Thus, a recovery ratio greater than 1.0 indicates an increased likelihood of faster recovery. Spearman rank correlation (ρ) was used to examine the association between measured sex hormone concentrations and patterns of recovery. All analyses were performed using STATA/MP v10 (Stata Corporation, College Station, TX, USA). P<0.05 was considered statistically significant.

Results

Male and female subjects had comparable demographic and perioperative characteristics including age, ASA physical status, and type and extent of surgery (Tables 1 and 2). Male subjects were heavier and taller than their female counterparts, and reported a lower incidence of previous history of postoperative nausea and vomiting (PONV) and motion sickness (Table 1).

Table 1

Subject characteristics and clinical details. Values are mean (sd) or number (%). ENT, ear, nose, or throat; PONV, postoperative nausea and vomiting

Variable Male (n=253) Female (n=247) P-value 
Mean (range) (yr) 39.5 (18–70) 39.5 (17–75) 0.50 
Height (m) 1.78 (0.07) 1.64 (0.07) <0.0005 
Weight (kg) 85.5 (13.3) 67.7 (12.7) <0.0005 
ASA physical status 
 I 190 (78) 193 (75)  
 II 54 (22) 63 (25)  
Waist-to-hip ratio 1.00 (0.05) 0.85 (0.05) <0.0005 
Type of surgery 
 General 89 (35) 99 (41) 0.02 
 Orthopaedic 120 (47) 86 (35) 
 Urological 11 (4.3) 6 (2.5) 
 ENT 17 (6.6) 15 (6.2) 
 Plastics 14 (5.5) 30 (12) 
 Other 5 (2.0) 8 (3.3) 
Extent of surgery 
 Minor 72 (28) 30 (12) <0.0005 
 Intermediate 169 (66) 204 (84) 
 Major 15 (5.9) 10 (4.1) 
Previous PONV 10 (3.9) 74 (30) <0.0005 
Previous motion sickness 13 (5.1) 41 (17) <0.0005 
Smoking status 
 Non-smoker 119 (46) 156 (64) <0.0005 
 Smoker 60 (23) 31 (13) 
 Ex-smoker 77 (31) 57 (23) 
Alcohol use 
 Non-drinker 19 (7.4) 43 (18) <0.0005 
 Social 218 (85) 197 (81) 
 Heavy 19 (7.4) 4 (1.6) 
Variable Male (n=253) Female (n=247) P-value 
Mean (range) (yr) 39.5 (18–70) 39.5 (17–75) 0.50 
Height (m) 1.78 (0.07) 1.64 (0.07) <0.0005 
Weight (kg) 85.5 (13.3) 67.7 (12.7) <0.0005 
ASA physical status 
 I 190 (78) 193 (75)  
 II 54 (22) 63 (25)  
Waist-to-hip ratio 1.00 (0.05) 0.85 (0.05) <0.0005 
Type of surgery 
 General 89 (35) 99 (41) 0.02 
 Orthopaedic 120 (47) 86 (35) 
 Urological 11 (4.3) 6 (2.5) 
 ENT 17 (6.6) 15 (6.2) 
 Plastics 14 (5.5) 30 (12) 
 Other 5 (2.0) 8 (3.3) 
Extent of surgery 
 Minor 72 (28) 30 (12) <0.0005 
 Intermediate 169 (66) 204 (84) 
 Major 15 (5.9) 10 (4.1) 
Previous PONV 10 (3.9) 74 (30) <0.0005 
Previous motion sickness 13 (5.1) 41 (17) <0.0005 
Smoking status 
 Non-smoker 119 (46) 156 (64) <0.0005 
 Smoker 60 (23) 31 (13) 
 Ex-smoker 77 (31) 57 (23) 
Alcohol use 
 Non-drinker 19 (7.4) 43 (18) <0.0005 
 Social 218 (85) 197 (81) 
 Heavy 19 (7.4) 4 (1.6) 
Table 2

Intraoperative characteristics. Values are number (%) or mean (sd). MAC, minimum alveolar concentration; BIS, bispectral index; LA, local anaesthesia

Variable Male (n=253) Female (n=247) P-value 
Airway 
 Face mask 1(0.39) 0(0) 0.001 
 Laryngeal mask 176 (69) 131 (54)  
 Tracheal tube 79 (31) 113 (46)  
Induction agent 
 Propofol 254 (99) 243 (99) 0.59 
 Thiopental 2 (0.8) 1 (0.4)  
Induction dose of propofol (mg kg−12.8 (5.8) 2.5 (0.6) 0.23 
Midazolam co-induction dose (µg kg−1237 (93) 225 (93) 0.73 
 29 (19–33) 30 (22–34) 0.72 
Neuromuscular blocking agent 83 (32) 116 (48) 0.001 
Volatile agent 
 Isoflurane 28 (11) 23 (9.4) 0.06 
 Sevoflurane 196 (77) 169 (69)  
 Desflurane 32 (13) 51 (21)  
Nitrous oxide 154 (60) 114 (47) 0.003 
Age-adjusted MAC 1.31 (0.3) 1.26 (0.3) 0.08 
Average BIS 36 (7) 38 (8) 0.02 
Fentanyl 140 (54) 124 (51) 0.39 
Fentanyl dose (µg kg−10.63 (2.0) 0.72 (0.8) 0.24 
Additional opioid 
 None 78 (30) 65 (29) 0.01 
 Morphine 175 (68) 164 (67)  
 Pethidine 3 (1.2) 15 (6.2)  
Extra opioid dose (mg kg−1
 Morphine 0.12 (0.04) 0.13 (0.04) <0.0005 
 Pethidine 1.2 (0.9) 1.3 (0.4) 0.41 
Tramadol 99 (39) 96 (40) 0.79 
Antiemetic prophylaxis 71 (28) 209 (86) <0.0005 
LA infiltration 237 (93) 232 (95) 0.25 
Neuromuscular block-reversal agent used 80 (31) 67 (48) <0.0005 
Duration of anaesthesia (min) 65.0 (43.5) 70.8 (42.5) 0.13 
Variable Male (n=253) Female (n=247) P-value 
Airway 
 Face mask 1(0.39) 0(0) 0.001 
 Laryngeal mask 176 (69) 131 (54)  
 Tracheal tube 79 (31) 113 (46)  
Induction agent 
 Propofol 254 (99) 243 (99) 0.59 
 Thiopental 2 (0.8) 1 (0.4)  
Induction dose of propofol (mg kg−12.8 (5.8) 2.5 (0.6) 0.23 
Midazolam co-induction dose (µg kg−1237 (93) 225 (93) 0.73 
 29 (19–33) 30 (22–34) 0.72 
Neuromuscular blocking agent 83 (32) 116 (48) 0.001 
Volatile agent 
 Isoflurane 28 (11) 23 (9.4) 0.06 
 Sevoflurane 196 (77) 169 (69)  
 Desflurane 32 (13) 51 (21)  
Nitrous oxide 154 (60) 114 (47) 0.003 
Age-adjusted MAC 1.31 (0.3) 1.26 (0.3) 0.08 
Average BIS 36 (7) 38 (8) 0.02 
Fentanyl 140 (54) 124 (51) 0.39 
Fentanyl dose (µg kg−10.63 (2.0) 0.72 (0.8) 0.24 
Additional opioid 
 None 78 (30) 65 (29) 0.01 
 Morphine 175 (68) 164 (67)  
 Pethidine 3 (1.2) 15 (6.2)  
Extra opioid dose (mg kg−1
 Morphine 0.12 (0.04) 0.13 (0.04) <0.0005 
 Pethidine 1.2 (0.9) 1.3 (0.4) 0.41 
Tramadol 99 (39) 96 (40) 0.79 
Antiemetic prophylaxis 71 (28) 209 (86) <0.0005 
LA infiltration 237 (93) 232 (95) 0.25 
Neuromuscular block-reversal agent used 80 (31) 67 (48) <0.0005 
Duration of anaesthesia (min) 65.0 (43.5) 70.8 (42.5) 0.13 

Despite similar doses of drugs used to induce anaesthesia and similar age-adjusted MAC of inhaled agent administered for the maintenance of anaesthesia, the average BIS score of women was slightly higher than that of men (Table 2). Women emerged faster than men from general anaesthesia as reflected by times to eye-opening and obeying commands after cessation of anaesthesia (Table 3). This was also reflected by higher BIS scores at the completion of wound dressing (Table 3). However, despite a faster speed of recovery, women had higher pain scores, higher incidence of adverse sequelae such as shivering and PONV, and delayed recovery room discharge times (Table 3). The adverse effects continued in the days after surgery, with poorer quality of recovery as reflected in the postoperative QoR-40 and pain scores in the 3 days after surgery (Tables 4 and 5).

Table 3

Recovery characteristics. Values are mean (sd), number (%) or median (IQR). *Pain scores using a verbal rating scale of 0 (no pain) to 10 (worst pain imaginable). BIS, bispectral index; PONV, postoperative nausea and vomiting; IQR, interquartile range

Characteristic Male (n=253) Female (n=247) P-value 
BIS score at wound closure 51.2 (9.0) 53.2 (10.7) 0.03 
Time to eye-opening, min 7.7 (4.0) 5.3 (3.5) <0.0005 
BIS score at eye-opening 78.4 (15.7) 75.6 (13.5) 0.18 
Time to obeying commands, min 8.3 (5.1) 6.80 (7.3) 0.01 
Recovery room stay, min 33.7 (11.8) 38.8 (16.1) <0.0005 
Shivering 17 (6.6) 39 (16) <0.0005 
Nausea 2 (0.8) 24 (9.9) <0.0005 
Vomiting 1 (0.4) 10 (4.1) 0.01 
Treatment PONV 2 (0.8) 24 (9.9) <0.0005 
Pain scores* 
 Pain score in recovery room 0 (0–5) 4 (0–6) <0.0005 
 Discharge pain score from recovery room 0 (0–3) 2 (0–4) <0.0005 
 Postoperative day 1 3 (2–5) 4 (3–6) <0.0005 
 Postoperative day 2 2 (0–4) 3 (2–5) <0.0005 
 Postoperative day 3 1 (0–3) 2 (1–4) <0.0005 
Characteristic Male (n=253) Female (n=247) P-value 
BIS score at wound closure 51.2 (9.0) 53.2 (10.7) 0.03 
Time to eye-opening, min 7.7 (4.0) 5.3 (3.5) <0.0005 
BIS score at eye-opening 78.4 (15.7) 75.6 (13.5) 0.18 
Time to obeying commands, min 8.3 (5.1) 6.80 (7.3) 0.01 
Recovery room stay, min 33.7 (11.8) 38.8 (16.1) <0.0005 
Shivering 17 (6.6) 39 (16) <0.0005 
Nausea 2 (0.8) 24 (9.9) <0.0005 
Vomiting 1 (0.4) 10 (4.1) 0.01 
Treatment PONV 2 (0.8) 24 (9.9) <0.0005 
Pain scores* 
 Pain score in recovery room 0 (0–5) 4 (0–6) <0.0005 
 Discharge pain score from recovery room 0 (0–3) 2 (0–4) <0.0005 
 Postoperative day 1 3 (2–5) 4 (3–6) <0.0005 
 Postoperative day 2 2 (0–4) 3 (2–5) <0.0005 
 Postoperative day 3 1 (0–3) 2 (1–4) <0.0005 
Table 4

Quality of recovery, using the 40-item quality of recovery (QoR-40) score. The maximal score is 200, indicating a perfect recovery. Values are mean (sd)

Time period Male (n=225) Female (n=232) P-value 
Preoperative 199 (3.2) 197 (7.6) <0.0005 
Day 1 190 (12) 180 (19) <0.0005 
Day 2 194 (11) 186 (17) <0.0005 
Day 3 195 (10) 190 (17) <0.0005 
Time period Male (n=225) Female (n=232) P-value 
Preoperative 199 (3.2) 197 (7.6) <0.0005 
Day 1 190 (12) 180 (19) <0.0005 
Day 2 194 (11) 186 (17) <0.0005 
Day 3 195 (10) 190 (17) <0.0005 
Table 5

Dimensions of the QoR-40 before and after surgery. The maximal score for each dimension are reported in parentheses. Values are mean (sd)

QoR dimension and time after surgery Male (n=225) Female (n=232) P-value 
Physical comfort (60) 
 Before surgery 59.8 (1.5) 59.2 (2.6) 0.006 
 Day 1 55.8 (6.1) 51.2 (7.5) 0.001 
 Day 2 58.3 (4.7) 54.6 (6.3) <0.0005 
 Day 3 58.9 (3.7) 56.3 (6.1) <0.0005 
Emotional state (45) 
 Before surgery 44.7 (1.5) 44.2 (4.3) 0.014 
 Day 1 41.6 (6.0) 40.3 (5.9) 0.003 
 Day 2 43.4 (5.2) 40.1 (6.2) <0.0005 
 Day 3 43.9 (5.2) 43.4 (6.2) <0.0005 
Physical independence (25) 
 Before surgery 25.0 (0.2) 25.0 (1.1) 0.99 
 Day 1 22.0 (2.1) 20.6 (3.6) 0.003 
 Day 2 23.1 (2.0) 21.8 (2.6) <0.0005 
 Day 3 23.9 (1.8) 22.9 (2.8) 0.0012 
Psychological support (35) 
 Before surgery 35.0 (0.4) 34.7 (1.5) 0.033 
 Day 1 34.8 (0.8) 34.5 (1.7) 0.15 
 Day 2 34.9 (0.5) 34.6 (1.6) 0.069 
 Day 3 34.9 (0.5) 34.8 (1.2) 0.148 
Pain (35) 
 Before surgery 34.9 (0.7) 34.6 (1.4) 0.033 
 Day 1 32.4 (3.1) 30.1 (4.5) 0.0001 
 Day 2 33.6 (2.2) 31.3 (3.6) <0.0005 
 Day 3 34.1 (2.2) 32.3 (3.4) <0.0005 
QoR dimension and time after surgery Male (n=225) Female (n=232) P-value 
Physical comfort (60) 
 Before surgery 59.8 (1.5) 59.2 (2.6) 0.006 
 Day 1 55.8 (6.1) 51.2 (7.5) 0.001 
 Day 2 58.3 (4.7) 54.6 (6.3) <0.0005 
 Day 3 58.9 (3.7) 56.3 (6.1) <0.0005 
Emotional state (45) 
 Before surgery 44.7 (1.5) 44.2 (4.3) 0.014 
 Day 1 41.6 (6.0) 40.3 (5.9) 0.003 
 Day 2 43.4 (5.2) 40.1 (6.2) <0.0005 
 Day 3 43.9 (5.2) 43.4 (6.2) <0.0005 
Physical independence (25) 
 Before surgery 25.0 (0.2) 25.0 (1.1) 0.99 
 Day 1 22.0 (2.1) 20.6 (3.6) 0.003 
 Day 2 23.1 (2.0) 21.8 (2.6) <0.0005 
 Day 3 23.9 (1.8) 22.9 (2.8) 0.0012 
Psychological support (35) 
 Before surgery 35.0 (0.4) 34.7 (1.5) 0.033 
 Day 1 34.8 (0.8) 34.5 (1.7) 0.15 
 Day 2 34.9 (0.5) 34.6 (1.6) 0.069 
 Day 3 34.9 (0.5) 34.8 (1.2) 0.148 
Pain (35) 
 Before surgery 34.9 (0.7) 34.6 (1.4) 0.033 
 Day 1 32.4 (3.1) 30.1 (4.5) 0.0001 
 Day 2 33.6 (2.2) 31.3 (3.6) <0.0005 
 Day 3 34.1 (2.2) 32.3 (3.4) <0.0005 

Oestrogen concentrations in premenopausal and postmenopausal women were 232 (103–508) and 48 (44–50) pmol litre−1, respectively [median (IQR)] (P<0.05). Progesterone concentrations in premenopausal and postmenopausal women were 2.1 (1–14.6) and 2.6 (2.3–2.9) nmol litre−1, respectively (P<0.05). When correlated to plasma oestrogen and progesterone concentrations adjusting for subject age and anaesthetic dose (Table 6), only eye-opening time was negatively correlated to plasma progesterone (ρ=−0.53, P=0.01). When patient waist-to-hip ratio was examined, adjusting for subject age and anaesthetic dose, eye-opening time, time-to-obeying commands, and quality of recovery Day 1 (QoR day 1) were significantly correlated to waist-to-hip ratios (Table 7).

Table 6

Correlation of plasma sex steroid concentrations with perioperative indices adjusted for age and inhalation agent MAC in a random sample of 28 women. BIS, bispectral index; QoR, quality of recovery

  Oestrogen
 
Progesterone
 
Waist:hip ratio
 
ρ P-value ρ P-value ρ P-value 
Average BIS score −0.22 0.29 0.86 0.38 0.02 0.94 
Eye-opening time −0.04 0.83 −0.53 0.01 0.26 <0.001 
Time to obeying commands 0.13 0.55 0.04 0.62 0.20 <0.001 
QoR-40 score day 1 −0.22 0.29 −0.01 0.96 0.33 <0.001 
  Oestrogen
 
Progesterone
 
Waist:hip ratio
 
ρ P-value ρ P-value ρ P-value 
Average BIS score −0.22 0.29 0.86 0.38 0.02 0.94 
Eye-opening time −0.04 0.83 −0.53 0.01 0.26 <0.001 
Time to obeying commands 0.13 0.55 0.04 0.62 0.20 <0.001 
QoR-40 score day 1 −0.22 0.29 −0.01 0.96 0.33 <0.001 
Table 7

Comparison of average intraoperative BIS score relative to males age-matched with females according to menopausal status. Values are mean (sd). BIS, bispectral index

Patient group BIS score P-value 
Males <52 yr 36.0 (6.8)  
Premenopausal females 37.5 (8.5) 0.18 
Post-menopausal females 38.9 (7.2) 0.04 
Patient group BIS score P-value 
Males <52 yr 36.0 (6.8)  
Premenopausal females 37.5 (8.5) 0.18 
Post-menopausal females 38.9 (7.2) 0.04 

Premenopausal women had lower average intraoperative BIS scores relative to postmenopausal females with and without adjustment for age and ASA, but higher than that of age-matched males (Table 7). In terms of recovery from general anaesthesia, premenopausal women woke faster, 4.9 (3.2) vs 6.7 (4.0) and 7.7 (4.0) min; P<0.005 (Fig. 1) and were obeying commands quicker, 6.3 (7.0) vs 8.5 (8.0) and 8.2 (5.0) min; P<0.005 (Fig. 2) than postmenopausal women and men, respectively. These faster recovery times persisted after adjusting for age, ASA physical status, smoking history, daily alcohol intake, use of neuromuscular blocking agents, and extent of surgery (Table 8). Duration of recovery room stay was not significantly different between the two groups of women, but was longer when compared with males, respectively, 39.1 (14.5) compared with 39.4 (21.2) and 33.9 (11.8) min; P<0.005. Premenopausal women had higher pain scores recorded in the recovery room when compared with postmenopausal women and men, respectively, 3.5 (3.0) compared with 3.0 (2.8) and 2.2 (2.6); P<0.005. Premenopausal women had poorer rates of recovery compared with postmenopausal women and men (Fig. 3).

Table 8

Relationship between sex and time adjusted for age and ASA status using Cox proportional hazards. *Derived from the hazard ratio, where a value greater than 1.0 indicates an increased likelihood of faster recovery time. Using male patients as a reference

 Recovery ratio (95% CI)* P-value 
Eye-opening 
 Premenopausal female 1.90 (1.54–2.33) <0.005 
 Postmenopausal female 1.12 (0.80–1.56) 0.53 
 Age 1.00 (1.0–1.01) 0.28 
 ASA 0.90 (0.71–1.16) 0.43 
 Smoking status 
  Ex-smoker 1.0 (0.76–1.29) 0.95 
  Smoker 1.1 (0.88–1.38) 0.39 
 Alcohol intake 
  Social 0.98 (0.74–1.30) 0.90 
  Heavy 0.73 (0.44–1.22) 0.23 
 Extent of surgery 
  Intermediate 1.12 (0.87–1.43) 0.38 
  Major 0.99 (0.61–1.63) 0.98 
 Neuromuscular blocking agent use 1.08 (0.89–1.31) 0.45 
Obeying commands 
 Premenopausal female 1.69 (1.30–2.20) <0.0005 
 Postmenopausal female 0.71 (0.44–1.14) 0.92 
 Age 1.01 (1.0–1.02) 0.10 
 ASA physical status 0.84 (0.61–1.16) 0.28 
 Smoking status 
  Ex-smoker 1.19 (0.86–1.65) 0.29 
  Smoker 0.90 (0.67–1.19) 0.46 
 Alcohol intake 
  Social 0.74 (0.49–1.12) 0.14 
  Daily 0.50 (0.28–0.92) 0.03 
 Extent of surgery 
  Intermediate 0.89 (0.66–1.20) 0.45 
  Major 0.97 (0.51–1.84) 0.91 
 Neuromuscular blocking agent use 1.22 (0.94–1.57) 0.14 
 Recovery ratio (95% CI)* P-value 
Eye-opening 
 Premenopausal female 1.90 (1.54–2.33) <0.005 
 Postmenopausal female 1.12 (0.80–1.56) 0.53 
 Age 1.00 (1.0–1.01) 0.28 
 ASA 0.90 (0.71–1.16) 0.43 
 Smoking status 
  Ex-smoker 1.0 (0.76–1.29) 0.95 
  Smoker 1.1 (0.88–1.38) 0.39 
 Alcohol intake 
  Social 0.98 (0.74–1.30) 0.90 
  Heavy 0.73 (0.44–1.22) 0.23 
 Extent of surgery 
  Intermediate 1.12 (0.87–1.43) 0.38 
  Major 0.99 (0.61–1.63) 0.98 
 Neuromuscular blocking agent use 1.08 (0.89–1.31) 0.45 
Obeying commands 
 Premenopausal female 1.69 (1.30–2.20) <0.0005 
 Postmenopausal female 0.71 (0.44–1.14) 0.92 
 Age 1.01 (1.0–1.02) 0.10 
 ASA physical status 0.84 (0.61–1.16) 0.28 
 Smoking status 
  Ex-smoker 1.19 (0.86–1.65) 0.29 
  Smoker 0.90 (0.67–1.19) 0.46 
 Alcohol intake 
  Social 0.74 (0.49–1.12) 0.14 
  Daily 0.50 (0.28–0.92) 0.03 
 Extent of surgery 
  Intermediate 0.89 (0.66–1.20) 0.45 
  Major 0.97 (0.51–1.84) 0.91 
 Neuromuscular blocking agent use 1.22 (0.94–1.57) 0.14 
Fig 1

Time to eye-opening after cessation of general anaesthesia in males, premenopausal women, and postmenopausal women.

Fig 1

Time to eye-opening after cessation of general anaesthesia in males, premenopausal women, and postmenopausal women.

Fig 2

Time to obeying commands after cessation of general anaesthesia in males, premenopausal women, and postmenopausal women.

Fig 2

Time to obeying commands after cessation of general anaesthesia in males, premenopausal women, and postmenopausal women.

Fig 3

Differences in the 40-item quality of recovery (QoR-40) scores after general anaesthesia in males, premenopausal females, and postmenopausal females. Day 0 indicates baseline (preoperative) state. Error bars are ±se.

Fig 3

Differences in the 40-item quality of recovery (QoR-40) scores after general anaesthesia in males, premenopausal females, and postmenopausal females. Day 0 indicates baseline (preoperative) state. Error bars are ±se.

Discussion

We found that patient sex is an independent factor influencing both responsiveness to general anaesthesia and recovery after anaesthesia. After matching subjects in our cohort for age, ASA physical status, type and extent of surgery, and other factors known to influence recovery, and adjusting for anaesthetic drug concentration, sex-related differences existed for several features of general anaesthesia maintenance and recovery. Contrary to some suggestions,29 our findings suggest that these sex-related differences extend beyond a theoretical interest to encompass factors deemed clinically important to both anaesthetists and their patients. The apparently small (2–3 min) difference in recovery time for consciousness between women and men is of comparable size to that seen when comparing inhalation agents such as isoflurane and sevoflurane.30

Although similar anaesthetic and opioid doses were needed to induce and maintain general anaesthesia, women generally had lighter anaesthetic states as reflected by slightly higher intraoperative BIS scores. The lighter hypnotic state continued up until the time of application of wound dressings and can explain the faster initial recovery times in women. Higher BIS scores at equivalent concentrations of general anaesthesia suggest that women are less sensitive to the hypnotic effects of anaesthetics, reinforcing previous findings,8 and helping to explain why female sex might be a risk factor for awareness.9,10 The underlying mechanisms for this are less clear. Differences in pharmacokinetic action of anaesthetic drugs due to physiological differences between the sexes cannot account for all of these discrepancies.1,2 Our findings, including the observed association between plasma progesterone concentrations and recovery time, suggest that sex-related differences in response and recovery from general anaesthesia are, at least in part, pharmacodynamic in nature.

Despite experiencing faster emergent times, the overall rate and quality of recovery from general anaesthesia for women was poorer than that of men. Longer recovery room stays, higher pain scores, and increased rate of PONV were observed and consistent with previous studies.19,31,32 Moreover, women also had poor quality of recovery for the 3 days after surgery and general anaesthesia. The sex differences were more persistent in premenopausal women, with differences apparent on the third postoperative day in this group but not in postmenopausal women. This indicates that patient sex is an important factor influencing not only rate but also the quality of recovery from general anaesthesia. A 10-point difference in the QoR-40 score is typical of that seen in patients with and without a major complication after surgery, or when comparing minor with major surgery.26–28

Sex hormones appear to play a role in modulating sex-related differences in general anaesthesia and postoperative recovery. When the subjects were subdivided into three groups according to oestrogen status, progesterone status, or both, premenopausal women differed not only from age-matched men in terms of their response to general anaesthesia and recovery from anaesthesia, but also differed when compared with postmenopausal women. Faster recovery was observed in premenopausal women, yet interestingly, lighter states of anaesthesia were observed in postmenopausal women. Correlations between female sex hormone concentrations and recovery times indicate potential anaesthetic drug interactions of these hormones. Our findings are consistent with earlier studies using volatile anaesthetics in animal models33 and human volunteers,34 including the capacity to induce sleep.12 Lower progesterone concentrations in postmenopausal women could explain the lighter states of anaesthesia measured by intraoperative BIS scores seen in postmenopausal when compared with premenopausal women. Interestingly, female waist-to-hip ratio, which more accurately reflects chronic effects of oestrogen and progesterone, was also correlated with recovery times, further supporting a role of female sex hormones in the recovery from general anaesthesia.

Oestrogen, progesterone, and androgen receptors have been identified in mammalian brain and possess actions distinct from reproductive behaviour and function.35 Progesterone and its metabolites, in particular, have hypnotic effects that are thought to occur via direct action on the GABAA receptor complex.34,35 Oestrogen, however, has the opposite effect by suppressing GABAA receptor-mediated inhibition.34,36 Unlike progesterone, oestrogen increases excitatory transmission at NMDA-type glutamate receptors, increasing NMDA receptor density in the hippocampus37 and increasing the binding of glutamate to NMDA receptors.38

Sex-based differences in nociception could explain the differences in both the depth of anaesthesia and recovery from anaesthesia. This suggests differences in the neuronal circuitry involved in pain perception between sexes.39 Oestrogen and progesterone are thought to play a role by influencing excitability in both the brain and spinal cord.40 As the state of general anaesthesia appears to be dependent on drug effects at different receptor types in the brain and spinal cord, it is possible that altered modulation of these receptors by sex steroid hormones could explain some of the sex-related differences seen during and after general anaesthesia and surgery. Determining the effect of different concentrations of oestrogen and progesterone, and different stages of the menstrual cycle, on the response to and recovery from general anaesthesia warrant further investigation.

There are several limitations to our study. Eligible patients were recruited only when research staff were available, and with the aim to match men and women. We excluded patients who received total i.v. anaesthesia. These steps might limit general validity of our study. We did not confirm menopausal status with hormone assays in all participants, although this is not required to define menopause.41 Misclassification is possible but unlikely to bias the study. Although end-tidal concentrations of volatile agents were recorded at the time of cessation of general anaesthesia, concentrations at the time of emergence were not. This limited our ability to discriminate between pharmacokinetic and pharmacodynamic effects in nature. However, given the similarity between the groups studied in terms of subject characteristics and doses of drugs used, pharmacodynamic differences seem the most plausible explanation.

In conclusion, patient sex is an independent factor influencing both state of general anaesthesia and recovery from general anaesthesia. Women wake faster from general anaesthesia than men, suggesting an apparent resistance to the hypnotic effect, but their overall rate of recovery is slower because of more pain, PONV, and diminished quality of recovery, consistent with a pharmacodynamic rather than pharmacokinetic effect. The female sex hormones progesterone (in particular) and oestrogen may be contributing to these sex-related differences.

Conflict of interest

None.

Funding

The study was funded by an Australian and New Zealand College of Anaesthetists project grant (02/014). Dr Frank Buchanan was supported by an Australian and New Zealand College of Anaesthetists Scholarship. Professor Paul Myles is supported by an Australian National Health and Medical Council Practitioner Fellowship.

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