British Journal of Anaesthesia 106 (6): 832–9 (2011)

Advance Access publication 9 May 2011 . doi:10.1093/bja/aer094

NEUROSCIENCES AND NEUROANAESTHESIA

Effect of patient sex on general anaesthesia and recovery

F. F. Buchanan 1, P. S. Myles 1,2* and F. Cicuttini 3
1
Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Commercial Road, Melbourne, Victoria 3004, Australia
2
Academic Board of Anaesthesia and Perioperative Medicine and 3 Department of Epidemiology and Preventive Medicine, Monash
University, Melbourne, Australia
* Corresponding author. E-mail: p.myles@alfred.org.au

Editor’s key points
† Evidence suggests that
patient sex might affect
recovery from general
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

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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.
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 (r ¼ 20.53, P¼0.01).
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.
Keywords: anaesthesia, general; complications; gender; vomiting, nausea
Accepted for publication: 17 March 2011

A growing body of evidence suggests that patient sex is an
independent factor influencing the response to general anaes-
thesia.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 anaes-
thetic 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 pro-
gesterone during the luteal phase of the menstrual cycle14
and pregnancy15 16 can decrease anaesthetic drug require-
ments. It remains unclear if sex-related reductions in sensitivity
to general anaesthesia are primarily because of pharmacoki-
netic (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.

& The Author [2011]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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Effect of patient sex
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 Mel-
bourne, Australia over a 5 yr period from February 2002 to
May 2007. We matched each female patient to the next eli-
gible 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 under-
going 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 under-
going sex-specific (gynaecological or prostatic surgery), emer-
gency 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 manage-
ment, adverse intraoperative events, type and extent of
surgery (minor, intermediate, major), and duration of anaes-
thesia 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 hor-
mones, 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 con-
centrations of oestrogen and progesterone.21 We defined pre-
menopausal 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 sti-
mulating hormone and low oestrogen concentrations. These
criteria were validated in a random selection of 23 premeno-
pausal 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 manage-
ment 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 find-
ings were consistent across the range of anaesthetic regi-
mens used in contemporary practice. General anaesthesia
was induced with either propofol or thiopental titrated to
loss of consciousness and maintained using volatile anaes-
thesia (isoflurane, sevoflurane, or desflurane) with or
without nitrous oxide. Non-depolarizing neuromuscular
BJA
blocking agents, when used, were antagonized with neostig-
mine and atropine. End-tidal inhalation agent monitoring
was done using the Datex-Ohmeda Aisys Carestationw (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 anaes-
thesia. Intraoperative age-adjusted minimum alveolar con-
centration (MACage) was determined using the following
nomogram:24
MACage = MAC40 × 10−0.00269(age−40)
where MAC40 represents MAC at age 40. The total
age-adjusted MAC for volatile agents used in each patient
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(ktotal ) was determined by the formula:25
FE,volatile FE,N2 O
ktotal = +
MACage,volatile MACage,N2 O
where FE,volatile is the end-expired concentration of the vola-
tile agent used and FE,N2 O 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 (¼time 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 calcu-
lated 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
833
BJA Buchanan et al.

using Student’s t-test, Mann –Whitney U-test, x 2 test, or Male subjects were heavier and taller than their female
repeated analyses of variance, as appropriate. Sex differ- counterparts, and reported a lower incidence of previous
ences in recovery times were plotted as Kaplan–Meier history of postoperative nausea and vomiting (PONV) and
curves. Cox proportional hazards were used to adjust for co- motion sickness (Table 1).
variates in order to identify the effects of age and sex on the Despite similar doses of drugs used to induce anaesthesia
pattern of recovery. The hazard ratio derived was denoted as and similar age-adjusted MAC of inhaled agent administered
a positive event and referred to as the recovery ratio. Thus, a for the maintenance of anaesthesia, the average BIS score of
recovery ratio greater than 1.0 indicates an increased likeli- women was slightly higher than that of men (Table 2).
hood of faster recovery. Spearman rank correlation (r) was Women emerged faster than men from general anaesthesia
used to examine the association between measured sex
hormone concentrations and patterns of recovery. All ana-
lyses were performed using STATA/MP v10 (Stata Corporation, Table 2 Intraoperative characteristics. Values are number (%) or
College Station, TX, USA). P,0.05 was considered statistically mean (SD). MAC, minimum alveolar concentration; BIS, bispectral
index; LA, local anaesthesia
significant.
Variable Male Female P-value
(n5253) (n5247)
Results
Airway
Male and female subjects had comparable demographic and Face mask 1(0.39) 0(0) 0.001

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perioperative characteristics including age, ASA physical Laryngeal mask 176 (69) 131 (54)
status, and type and extent of surgery (Tables 1 and 2). Tracheal tube 79 (31) 113 (46)
Induction agent
Propofol 254 (99) 243 (99) 0.59
Table 1 Subject characteristics and clinical details. Values are
mean (SD) or number (%). ENT, ear, nose, or throat; PONV, Thiopental 2 (0.8) 1 (0.4)
postoperative nausea and vomiting Induction dose of 2.8 (5.8) 2.5 (0.6) 0.23
propofol (mg kg21)
Variable Male Female P-value Midazolam 237 (93) 225 (93) 0.73
(n5253) (n5247) co-induction dose
Mean (range) (yr) 39.5 (18 – 70) 39.5 (17 – 75) 0.50 (mg kg21)

Height (m) 1.78 (0.07) 1.64 (0.07) ,0.0005 29 (19 –33) 30 (22 – 34) 0.72

Weight (kg) 85.5 (13.3) 67.7 (12.7) ,0.0005 Neuromuscular 83 (32) 116 (48) 0.001
blocking agent
ASA physical status
Volatile agent
I 190 (78) 193 (75)
Isoflurane 28 (11) 23 (9.4) 0.06
II 54 (22) 63 (25)
Sevoflurane 196 (77) 169 (69)
Waist-to-hip ratio 1.00 (0.05) 0.85 (0.05) ,0.0005
Desflurane 32 (13) 51 (21)
Type of surgery
Nitrous oxide 154 (60) 114 (47) 0.003
General 89 (35) 99 (41) 0.02
Age-adjusted MAC 1.31 (0.3) 1.26 (0.3) 0.08
Orthopaedic 120 (47) 86 (35)
Average BIS 36 (7) 38 (8) 0.02
Urological 11 (4.3) 6 (2.5)
Fentanyl 140 (54) 124 (51) 0.39
ENT 17 (6.6) 15 (6.2)
Fentanyl dose (mg 0.63 (2.0) 0.72 (0.8) 0.24
Plastics 14 (5.5) 30 (12)
kg21)
Other 5 (2.0) 8 (3.3)
Additional opioid
Extent of surgery
None 78 (30) 65 (29) 0.01
Minor 72 (28) 30 (12) ,0.0005
Morphine 175 (68) 164 (67)
Intermediate 169 (66) 204 (84)
Pethidine 3 (1.2) 15 (6.2)
Major 15 (5.9) 10 (4.1)
Extra opioid dose (mg kg21)
Previous PONV 10 (3.9) 74 (30) ,0.0005
Morphine 0.12 (0.04) 0.13 (0.04) ,0.0005
Previous motion 13 (5.1) 41 (17) ,0.0005
Pethidine 1.2 (0.9) 1.3 (0.4) 0.41
sickness
Tramadol 99 (39) 96 (40) 0.79
Smoking status
Antiemetic 71 (28) 209 (86) ,0.0005
Non-smoker 119 (46) 156 (64) ,0.0005
prophylaxis
Smoker 60 (23) 31 (13)
LA infiltration 237 (93) 232 (95) 0.25
Ex-smoker 77 (31) 57 (23)
Neuromuscular 80 (31) 67 (48) ,0.0005
Alcohol use block-reversal agent
Non-drinker 19 (7.4) 43 (18) ,0.0005 used
Social 218 (85) 197 (81) Duration of 65.0 (43.5) 70.8 (42.5) 0.13
Heavy 19 (7.4) 4 (1.6) anaesthesia (min)

834
Effect of patient sex BJA

Table 3 Recovery characteristics. Values are mean (SD), number Table 4 Quality of recovery, using the 40-item quality of recovery
(%) or median (IQR). *Pain scores using a verbal rating scale of 0 (QoR-40) score. The maximal score is 200, indicating a perfect
(no pain) to 10 (worst pain imaginable). BIS, bispectral index; recovery. Values are mean (SD)
PONV, postoperative nausea and vomiting; IQR, interquartile
range Time period Male (n5225) Female (n5232) P-value
Preoperative 199 (3.2) 197 (7.6) ,0.0005
Characteristic Male Female P-value
Day 1 190 (12) 180 (19) ,0.0005
(n5253) (n5247)
Day 2 194 (11) 186 (17) ,0.0005
BIS score at wound 51.2 (9.0) 53.2 (10.7) 0.03
Day 3 195 (10) 190 (17) ,0.0005
closure
Time to eye-opening, 7.7 (4.0) 5.3 (3.5) ,0.0005
min
BIS score at eye-opening 78.4 (15.7) 75.6 (13.5) 0.18
Time to obeying 8.3 (5.1) 6.80 (7.3) 0.01 Table 5 Dimensions of the QoR-40 before and after surgery. The
commands, min maximal score for each dimension are reported in parentheses.
Recovery room stay, min 33.7 (11.8) 38.8 (16.1) ,0.0005 Values are mean (SD)
Shivering 17 (6.6) 39 (16) ,0.0005
QoR dimension and Male Female P-value
Nausea 2 (0.8) 24 (9.9) ,0.0005
time after surgery (n5225) (n5232)
Vomiting 1 (0.4) 10 (4.1) 0.01

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Physical comfort (60)
Treatment PONV 2 (0.8) 24 (9.9) ,0.0005
Before surgery 59.8 (1.5) 59.2 (2.6) 0.006
Pain scores*
Day 1 55.8 (6.1) 51.2 (7.5) 0.001
Pain score in recovery 0 (0 –5) 4 (0 –6) ,0.0005
room Day 2 58.3 (4.7) 54.6 (6.3) ,0.0005
Discharge pain score 0 (0 –3) 2 (0 –4) ,0.0005 Day 3 58.9 (3.7) 56.3 (6.1) ,0.0005
from recovery room Emotional state (45)
Postoperative day 1 3 (2 –5) 4 (3 –6) ,0.0005 Before surgery 44.7 (1.5) 44.2 (4.3) 0.014
Postoperative day 2 2 (0 –4) 3 (2 –5) ,0.0005 Day 1 41.6 (6.0) 40.3 (5.9) 0.003
Postoperative day 3 1 (0 –3) 2 (1 –4) ,0.0005 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
as reflected by times to eye-opening and obeying commands Day 1 22.0 (2.1) 20.6 (3.6) 0.003
after cessation of anaesthesia (Table 3). This was also Day 2 23.1 (2.0) 21.8 (2.6) ,0.0005
reflected by higher BIS scores at the completion of wound Day 3 23.9 (1.8) 22.9 (2.8) 0.0012
dressing (Table 3). However, despite a faster speed of recov- Psychological support (35)
ery, women had higher pain scores, higher incidence of Before surgery 35.0 (0.4) 34.7 (1.5) 0.033
adverse sequelae such as shivering and PONV, and delayed Day 1 34.8 (0.8) 34.5 (1.7) 0.15
recovery room discharge times (Table 3). The adverse Day 2 34.9 (0.5) 34.6 (1.6) 0.069
effects continued in the days after surgery, with poorer Day 3 34.9 (0.5) 34.8 (1.2) 0.148
quality of recovery as reflected in the postoperative QoR-40 Pain (35)
and pain scores in the 3 days after surgery (Tables 4 and 5). Before surgery 34.9 (0.7) 34.6 (1.4) 0.033
Oestrogen concentrations in premenopausal and postme- Day 1 32.4 (3.1) 30.1 (4.5) 0.0001
nopausal women were 232 (103 –508) and 48 (44 –50) pmol Day 2 33.6 (2.2) 31.3 (3.6) ,0.0005
litre21, respectively [median (IQR)] (P,0.05). Progesterone Day 3 34.1 (2.2) 32.3 (3.4) ,0.0005
concentrations in premenopausal and postmenopausal
women were 2.1 (1– 14.6) and 2.6 (2.3 –2.9) nmol litre21,
respectively (P,0.05). When correlated to plasma oestrogen
and progesterone concentrations adjusting for subject age of age-matched males (Table 7). In terms of recovery from
and anaesthetic dose (Table 6), only eye-opening time was general anaesthesia, premenopausal women woke faster,
negatively correlated to plasma progesterone (r ¼ 20.53, 4.9 (3.2) vs 6.7 (4.0) and 7.7 (4.0) min; P,0.005 (Fig. 1) and
P¼0.01). When patient waist-to-hip ratio was examined, were obeying commands quicker, 6.3 (7.0) vs 8.5 (8.0) and
adjusting for subject age and anaesthetic dose, eye-opening 8.2 (5.0) min; P,0.005 (Fig. 2) than postmenopausal
time, time-to-obeying commands, and quality of recovery women and men, respectively. These faster recovery times
Day 1 (QoR day 1) were significantly correlated to persisted after adjusting for age, ASA physical status,
waist-to-hip ratios (Table 7). smoking history, daily alcohol intake, use of neuromuscular
Premenopausal women had lower average intraoperative blocking agents, and extent of surgery (Table 8). Duration
BIS scores relative to postmenopausal females with and of recovery room stay was not significantly different
without adjustment for age and ASA, but higher than that between the two groups of women, but was longer when

835
BJA Buchanan et al.

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

r P-value r P-value r P-value
Average BIS score 20.22 0.29 0.86 0.38 0.02 0.94
Eye-opening time 20.04 0.83 20.53 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 20.22 0.29 20.01 0.96 0.33 ,0.001

Table 7 Comparison of average intraoperative BIS score relative

to males age-matched with females according to menopausal Kaplan–Meier estimates for time
to obeying commands
status. Values are mean (SD). BIS, bispectral index 1.00
Patient group BIS score P-value
0.75

Proportion
Males ,52 yr 36.0 (6.8)

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Premenopausal females 37.5 (8.5) 0.18 0.50
Post-menopausal females 38.9 (7.2) 0.04
Male
0.25 Menopausal female
Premenopausal female
0.00
0 5 10 15 20 25
Kaplan–Meier estimates for time Analysis time (min)
to eye-opening
1.00
Fig 2 Time to obeying commands after cessation of general
0.75 anaesthesia in males, premenopausal women, and postmeno-
Proportion

pausal women.
0.50

0.25 Male for anaesthetic drug concentration, sex-related differences

Postmenopausal female
Premenopausal female
0.00
0 5 10
Analysis time (min)
Fig 1 Time to eye-opening after cessation of general anaesthesia
in males, premenopausal women, and postmenopausal women.
compared with males, respectively, 39.1 (14.5) compared
with 39.4 (21.2) and 33.9 (11.8) min; P,0.005. Premenopau-
sal 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).
Discussion
We found that patient sex is an independent factor influen-
cing both responsiveness to general anaesthesia and recov-
ery 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
existed for several features of general anaesthesia mainten-
ance and recovery. Contrary to some suggestions,29 our find-
15 ings 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 compar-
able 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 hyp-
notic 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 concen-
trations of general anaesthesia suggest that women are
less sensitive to the hypnotic effects of anaesthetics, reinfor-
cing 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 pharmaco-
kinetic 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

836
Effect of patient sex BJA

Table 8 Relationship between sex and time adjusted for age and
ASA status using Cox proportional hazards. *Derived from the 200
hazard ratio, where a value greater than 1.0 indicates an
increased likelihood of faster recovery time. †Using male patients

QoR-40 score
as a reference

Recovery ratio (95% P-value

CI)*
Eye-opening
Male
Premenopausal female† 1.90 (1.54 – 2.33) ,0.005
Premenopausal female
Postmenopausal female† 1.12 (0.80 – 1.56) 0.53 Postmenopausal female
Age 1.00 (1.0 –1.01) 0.28 170
P<0.0005
ASA 0.90 (0.71 – 1.16) 0.43 0
0 1 2 3
Smoking status
Postoperative day
Ex-smoker 1.0 (0.76 – 1.29) 0.95
Smoker 1.1 (0.88 – 1.38) 0.39
Alcohol intake
Fig 3 Differences in the 40-item quality of recovery (QoR-40)
scores after general anaesthesia in males, premenopausal
Social 0.98 (0.74 – 1.30) 0.90
females, and postmenopausal females. Day 0 indicates baseline

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Heavy 0.73 (0.44 – 1.22) 0.23 (preoperative) state. Error bars are + SE.
Extent of surgery
Intermediate 1.12 (0.87 – 1.43) 0.38
Major 0.99 (0.61 – 1.63) 0.98 anaesthesia. A 10-point difference in the QoR-40 score is
Neuromuscular blocking 1.08 (0.89 – 1.31) 0.45 typical of that seen in patients with and without a major
agent use complication after surgery, or when comparing minor with
Obeying commands major surgery.26 – 28
Premenopausal female† 1.69 (1.30 – 2.20) ,0.0005 Sex hormones appear to play a role in modulating sex-
Postmenopausal female† 0.71 (0.44 – 1.14) 0.92 related differences in general anaesthesia and postoperative
Age 1.01 (1.0 –1.02) 0.10 recovery. When the subjects were subdivided into three
ASA physical status 0.84 (0.61 – 1.16) 0.28 groups according to oestrogen status, progesterone status,
Smoking status or both, premenopausal women differed not only from age-
Ex-smoker 1.19 (0.86 – 1.65) 0.29 matched men in terms of their response to general anaes-
Smoker 0.90 (0.67 – 1.19) 0.46 thesia and recovery from anaesthesia, but also differed
Alcohol intake when compared with postmenopausal women. Faster recov-
Social 0.74 (0.49 – 1.12) 0.14 ery was observed in premenopausal women, yet interest-
Daily 0.50 (0.28 – 0.92) 0.03 ingly, lighter states of anaesthesia were observed in
Extent of surgery postmenopausal women. Correlations between female sex
Intermediate 0.89 (0.66 – 1.20) 0.45 hormone concentrations and recovery times indicate poten-
Major 0.97 (0.51 – 1.84) 0.91 tial anaesthetic drug interactions of these hormones. Our
Neuromuscular blocking 1.22 (0.94 – 1.57) 0.14 findings are consistent with earlier studies using volatile
agent use
anaesthetics in animal models33 and human volunteers,34
including the capacity to induce sleep.12 Lower progesterone
concentrations in postmenopausal women could explain the
and recovery time, suggest that sex-related differences in lighter states of anaesthesia measured by intraoperative BIS
response and recovery from general anaesthesia are, at scores seen in postmenopausal when compared with pre-
least in part, pharmacodynamic in nature. menopausal women. Interestingly, female waist-to-hip
Despite experiencing faster emergent times, the overall ratio, which more accurately reflects chronic effects of oes-
rate and quality of recovery from general anaesthesia for trogen and progesterone, was also correlated with recovery
women was poorer than that of men. Longer recovery times, further supporting a role of female sex hormones in
room stays, higher pain scores, and increased rate of PONV the recovery from general anaesthesia.
were observed and consistent with previous studies.19 31 32 Oestrogen, progesterone, and androgen receptors have
Moreover, women also had poor quality of recovery for the been identified in mammalian brain and possess actions
3 days after surgery and general anaesthesia. The sex differ- distinct from reproductive behaviour and function.35 Pro-
ences were more persistent in premenopausal women, with gesterone and its metabolites, in particular, have hypnotic
differences apparent on the third postoperative day in this effects that are thought to occur via direct action on the
group but not in postmenopausal women. This indicates GABAA receptor complex.34 35 Oestrogen, however, has the
that patient sex is an important factor influencing not only opposite effect by suppressing GABAA receptor-mediated
rate but also the quality of recovery from general inhibition.34 36 Unlike progesterone, oestrogen increases

837
BJA
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 Oestro-
gen and progesterone are thought to play a role by influen-
cing 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 recov-
ery 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 par-
ticipants, although this is not required to define meno-
pause.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 anaesthe-
sia, 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, pharmaco-
dynamic differences seem the most plausible explanation.
In conclusion, patient sex is an independent factor influ-
encing 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 dimin-
ished quality of recovery, consistent with a pharmacody-
namic 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.
838
Buchanan et al.
References
1 Holdcroft A. Females and their variability. Anaesthesia 1997; 52:
931– 34
2 Buchanan FF, Myles PS, Cicuttini F. Patient sex and its influence on
general anaesthesia. Anaesth Intensive Care 2009; 37: 207– 18
3 Pleym H, Spigset O, Kharasch ED, Dale O. Gender differences in
drug effects: implications for anaesthetists. Acta Anaesthesiol
Scand 2003; 47: 241–59
4 Goto T, Nakata Y, Morita S. The minimum alveolar concentration
of xenon in the elderly is sex-dependent. Anesthesiology 2002;
97: 1129– 32
5 Gan TJ, Glass PS, Sigl J, et al. Women emerge from general anaes-
thesia with propofol/alfentanil/nitrous oxide faster than men.
Anesthesiology 1999; 90: 1283– 7
6 Myles PS, McLeod A, Hunt JO, Fletcher H. Sex differences in speed
of emergence differences in speed of emergence and quality of
recovery after anaesthesia: cohort study. Br Med J 2001; 322:
710– 11
7 Hoymork SC, Raeder J, Grimsmo B, Steen PA. Bispectral index,
Downloaded from http://bja.oxfordjournals.org/ by guest on September 29, 2016
serum drug concentrations and emergence associated with indi-
vidually adjusted target-controlled infusions of remifentanil and
propofol for laparoscopic surgery. Br J Anaesth 2003; 91: 773– 80
8 Buchanan FF, Myles PS, Leslie K, Forbes A, Cicuttini F. Gender and
recovery after general anaesthesia combined with neuromuscu-
lar blocking drugs. Anesth Analg 2006; 102: 291– 7
9 Domino KB, Posner KL, Caplan RA, Cheney FW. Awareness during
anaesthesia—a closed claims analysis. Anesthesiology 1999; 90:
1053– 61
10 Ghoneim MM, Block RI, Haffarnan M, Mathews MJ. Awareness
during anaesthesia: risk factors, causes and sequelae. A review
of reported cases in the literature. Anesth Analg 2009; 108:
529– 35
11 Carl P, Hogskilde S, Nielsen JW, et al. Pregnanolone emulsion: a
preliminary pharmacokinetic and pharmacodynamic study of a
new intravenous anaesthetic agent. Anaesthesia 1990; 45: 189–97
12 Merryman W, Boiman R, Barnes L, Rothchild I. Progesterone
‘anaesthesia’ in human subjects. J Clin Endocrinol Metab 1954;
14: 1567–9
13 Bittran D, Purdy RH, Kellogg CK. Anxiolytic effect of progesterone
is associated with increases in cortical allopregnanolone and
GABAA receptor function. Pharmacol Biochem Behav 1993; 45:
423– 8
14 Erden V, Yangin Z, Erkalp K, et al. Increased progesterone pro-
duction during the luteal phase of menstruation may decrease
anaesthetic requirement. Anesth Analg 2005; 101: 1007– 11
15 Gin T, Chan MT. Decreased minimum alveolar concentration of
isoflurane in pregnant humans. Anesthesiology 1994; 81: 829– 32
16 Chan MTV, Mainland P, Gin T. Minimum alveolar concentration of
halothane and enflurane are decreased in early pregnancy.
Anesthesiology 1996; 85: 782–6
17 Eger EI II, Laster MJ, Gregory GA, Katoh T, Sonner JM. Women
appear to have the same minimum alveolar concentration as
men. Anesthesiology 2003; 99: 1059– 61
18 Wadhwa A, Durrani J, Sengupta P, Doufas AG, Sessler DI.
Women have the same desflurane minimum alveolar concentration
as men: a prospective study. Anesthesiology 2003; 99: 1062–5
19 Myles PS, Hunt JO, Moloney JT. Postoperative ‘minor’ compli-
cations. Comparison between men and women. Anaesthesia
1997; 52: 300– 6
20 Singh D. Female mate value at a glance: relationship of
waist-to-hip to health, fecundity and attractiveness. NeuroEndo-
crinol Lett 2002; 23(Suppl 4): 81 –91
Effect of patient sex
21 Jasienska G, Ziomkiewicz A, Ellison PT, Lipson SF, Thune I. Large
breasts and narrow waists indicate high reproductive potential
in women. Proc Biol Sci 2004; 22: 1213– 7
22 Walsh RJ. The age of menopause in Australian women. Med J
Aust 1978; 215: 181–2
23 Burger HG. The endocrinology of the menopause. J Steroid
Biochem Mol Biol 1999; 69: 31– 5
24 Mapleson WW. Effect of age on MAC in humans: a meta-analysis.
Br J Anaesth 1996; 76: 179– 85
25 White DC. Uses of MAC. Br J Anaesth 2003; 91: 167–9
26 Myles PS, Weitkamp B, Jones K, Melick J, Hensen S. Validity and
reliability of a postoperative quality of recovery score: the
QoR-40. Br J Anaesth 2000; 84: 11– 5
27 Myles PS, Hunt JO, Fletcher H, Solly R, Kelly S, Woodward D.
Relationship between quality of recovery in hospital, and
quality of life at three months after cardiac surgery. Anesthesiol-
ogy 2001; 95: 862– 7
28 Leslie K, Troedel S, Irwin K, et al. Quality of recovery from
anaesthesia in neurosurgical patients. Anesthesiology 2003; 99:
1158–65
29 Moller DH, Glass PSA. Should a patient’s gender alter the anaes-
thetic plan? Curr Opin Anaesthesiol 2003; 16: 379–83
30 Myles PS, Hunt JO, Fletcher H, Smart J, Jackson T. Propofol, thio-
pental, sevoflurane and isoflurane: a randomized controlled trial
of effectiveness. Anesth Analg 2000; 91: 1163–9
31 Taenzer AH, Clark C, Curry CS. Gender affects report of pain and
function after arthroscopic anterior cruciate ligament reconstruc-
tion. Anesthesiology 2000; 93: 670–5
BJA
32 Harmon D, O’Connor P, Gleasa O, Gardiner J. Menstrual cycle irre-
gularity and the incidence of nausea and vomiting after laparo-
scopy. Anaesthesia 2000; 55: 1164–7
33 Datta S, Migliozzi RP, Flanagan HL, Krieger N. Chronically adminis-
tered progesterone decreases halothane requirements in rabbits.
Anesth Analg 1989; 68: 46 –50
34 Manber R, Armitage R. Sex, steroids and sleep: a review. Sleep
1999; 22: 540– 55
35 Pfaff DW, McEwen BS. Actions of oestrogens and progestins on
nerve cells. Science 1983; 219: 808–14
36 Gee KW, Bolger MB, Brinton RE, Coirini H, McEwen BS. Steroid
modulation of the chloride ionophore in rat brain: structure-
activity requirements, regional dependence and
mechanisms of action. J Pharmacol Exp Ther 1988; 246:
803– 12
37 McEwen BS, Alves SE. Etrogen actions in the central nervous
system. Endocr Rev 1999; 20: 299–307
38 Rudick CN, Woolley CS. Estradiol induces a phasic Fos response in
the hippocampal CA1 and CA3 regions of adult female rats.
Hippocampus 2000; 10: 274–83
Downloaded from http://bja.oxfordjournals.org/ by guest on September 29, 2016
39 Woolley CS, Weiland NG, McEwen BS, Schwartzkroin PA. Estradiol
increases the sensitivity of hippocampal CA1pyramidal cells to
NMDA-receptor mediated synaptic input: correlation with dendri-
tic spine density. J Neurosci 1997; 17: 1848– 59
40 Woolley CS, Schwartzkroin PA. Hormonal effects on the brain.
Epilepsia 1998; 39: S2–S8
41 Rymer J, Morris EP. ‘Extracts from Clinical evidence’: Menopausal
symptoms. Br Med J 2000; 321: 1516–9
839