British Journal of Anaesthesia 106 (6): 8329 (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
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

Editors key points

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.

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 eyeopening (r 20.53, P0.01).
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 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

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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Evidence suggests that

patient sex might affect
recovery from general
anaesthesia.

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.

BJA

Effect of patient sex

Methods
Study design

MACage = MAC40 100.00269(age40)

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
ktotal =

FE,volatile
FE,N2 O
+
MACage,volatile MACage,N2 O

where FE,volatile is the end-expired concentration of the volatile 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 (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

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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 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 anaesthesia. Intraoperative age-adjusted minimum alveolar concentration (MACage) was determined using the following
nomogram:24

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Buchanan et al.

using Students t-test, Mann Whitney U-test, x 2 test, or

repeated analyses of variance, as appropriate. Sex differences in recovery times were plotted as KaplanMeier
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 (r) 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.

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).
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

Table 2 Intraoperative characteristics. Values are number (%) or

mean (SD). MAC, minimum alveolar concentration; BIS, bispectral
index; LA, local anaesthesia
Variable

Results

Female
(n5247)

P-value

Airway
Face mask
Laryngeal mask

1(0.39)

0(0)

0.001

176 (69)

131 (54)

79 (31)

113 (46)

254 (99)

243 (99)

2 (0.8)

1 (0.4)

Induction dose of
propofol (mg kg21)

2.8 (5.8)

2.5 (0.6)

0.23

Midazolam
co-induction dose
(mg kg21)

237 (93)

225 (93)

0.73

Tracheal tube
Induction agent

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
(n5253)

Mean (range) (yr)

39.5 (18 70)

39.5 (17 75)

Height (m)

1.78 (0.07)

1.64 (0.07)

Weight (kg)

Female
(n5247)

85.5 (13.3)

67.7 (12.7)

190 (78)

193 (75)

II

54 (22)

63 (25)

1.00 (0.05)

0.85 (0.05)

P-value
0.50
,0.0005

Isoflurane
,0.0005

89 (35)

99 (41)

120 (47)

86 (35)

Urological

11 (4.3)

6 (2.5)

ENT

17 (6.6)

15 (6.2)

Plastics

14 (5.5)

30 (12)

5 (2.0)

8 (3.3)

72 (28)

30 (12)

169 (66)

204 (84)

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

Orthopaedic

Other

0.02

Intermediate
Major

119 (46)

156 (64)

Smoker

60 (23)

31 (13)

Ex-smoker

77 (31)

57 (23)

834

19 (7.4)

43 (18)

Social

218 (85)

197 (81)

Heavy

19 (7.4)

4 (1.6)

30 (22 34)
116 (48)

0.72
0.001

28 (11)

23 (9.4)

196 (77)

169 (69)

0.06

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

36 (7)

38 (8)

0.02

Fentanyl

140 (54)

124 (51)

0.39

Fentanyl dose (mg

kg21)

0.63 (2.0)

0.72 (0.8)

0.24

0.01

None
,0.0005

78 (30)

65 (29)

Morphine

175 (68)

164 (67)

Pethidine

3 (1.2)

15 (6.2)

Extra opioid dose (mg kg21)

,0.0005

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

237 (93)

232 (95)

0.25

80 (31)

67 (48)

,0.0005

65.0 (43.5)

70.8 (42.5)

0.13

LA infiltration

Alcohol use
Non-drinker

83 (32)

Additional opioid

Smoking status
Non-smoker

Sevoflurane

Average BIS

Extent of surgery
Minor

29 (19 33)
Neuromuscular
blocking agent

0.59

Volatile agent

Type of surgery
General

Thiopental

,0.0005

ASA physical status

Waist-to-hip ratio

Propofol

,0.0005

Neuromuscular
block-reversal agent
used
Duration of
anaesthesia (min)

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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
(n5253)

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Effect of patient sex

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
Male
(n5253)

Female
(n5247)

BIS score at wound

closure

51.2 (9.0)

53.2 (10.7)

0.03

7.7 (4.0)

5.3 (3.5)

,0.0005

78.4 (15.7)

75.6 (13.5)

0.18

8.3 (5.1)

6.80 (7.3)

0.01

33.7 (11.8)

38.8 (16.1)

,0.0005

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

Time to eye-opening,
min
BIS score at eye-opening
Time to obeying
commands, min
Recovery room stay, min
Shivering

P-value

Pain scores*
4 (0 6)

Time period

Male (n5225)

Female (n5232)

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
(n5225)

Female
(n5232)

P-value

Before surgery

59.8 (1.5)

59.2 (2.6)

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
0.014

Physical comfort (60)

0.006

Pain score in recovery

room

0 (0 5)

Discharge pain score

from recovery room

0 (0 3)

Postoperative day 1

3 (2 5)

4 (3 6)

,0.0005

Before surgery

44.7 (1.5)

44.2 (4.3)

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
0.99

2 (0 4)

,0.0005
,0.0005

Emotional state (45)

Physical independence (25)

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).
Oestrogen concentrations in premenopausal and postmenopausal women were 232 (103 508) and 48 (44 50) pmol
litre21, 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 litre21,
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 (r 20.53,
P0.01). 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).
Premenopausal women had lower average intraoperative
BIS scores relative to postmenopausal females with and
without adjustment for age and ASA, but higher than that

Before surgery

25.0 (0.2)

25.0 (1.1)

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

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

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

Psychological support (35)

Pain (35)

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

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Characteristic

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)

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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

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

0.13

0.55

0.04

0.62

0.20

,0.001

20.22

0.29

20.01

0.96

0.33

,0.001

Time to obeying commands

QoR-40 score day 1

P-value

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

36.0 (6.8)

Premenopausal females

37.5 (8.5)

0.18

Post-menopausal females

38.9 (7.2)

0.04

1.00

P-value

Proportion

BIS score

Males ,52 yr

KaplanMeier estimates for time

to obeying commands

0.75
0.50
Male
Menopausal female
Premenopausal female

0.25
0.00
0

KaplanMeier estimates for time

to eye-opening

10

15

20

25

Analysis time (min)

Proportion

1.00
Fig 2 Time to obeying commands after cessation of general
anaesthesia in males, premenopausal women, and postmenopausal women.

0.75
0.50
0.25

Male
Postmenopausal female
Premenopausal female

0.00
0

5
10
Analysis time (min)

15

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. 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).

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

836

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

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Patient group

P-value

BJA

Effect of patient sex

200

QoR-40 score

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

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

170

ASA

0.90 (0.71 1.16)

0.43

Ex-smoker

1.0 (0.76 1.29)

0.95

Smoker

1.1 (0.88 1.38)

0.39

Eye-opening

Smoking status

Alcohol intake
0.98 (0.74 1.30)

0.90

Heavy

0.73 (0.44 1.22)

0.23

Intermediate

1.12 (0.87 1.43)

0.38

Major

0.99 (0.61 1.63)

0.98

1.08 (0.89 1.31)

0.45

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

Ex-smoker

1.19 (0.86 1.65)

0.29

Smoker

0.90 (0.67 1.19)

0.46

Social

0.74 (0.49 1.12)

0.14

Daily

0.50 (0.28 0.92)

0.03

Intermediate

0.89 (0.66 1.20)

0.45

Major

0.97 (0.51 1.84)

0.91

1.22 (0.94 1.57)

0.14

P<0.0005
0

2
Postoperative day

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.

Extent of surgery

Neuromuscular blocking
agent use
Obeying commands

Smoking status

Alcohol intake

Extent of surgery

Neuromuscular blocking
agent use

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 sexrelated 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 agematched 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

837

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Social

Male
Premenopausal female
Postmenopausal female

BJA

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

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: 24159
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 anaesthesia 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,
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
8 Buchanan FF, Myles PS, Leslie K, Forbes A, Cicuttini F. Gender and
recovery after general anaesthesia combined with neuromuscular blocking drugs. Anesth Analg 2006; 102: 291 7
9 Domino KB, Posner KL, Caplan RA, Cheney FW. Awareness during
anaesthesiaa 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: 18997
12 Merryman W, Boiman R, Barnes L, Rothchild I. Progesterone
anaesthesia in human subjects. J Clin Endocrinol Metab 1954;
14: 15679
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 production 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: 7826
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: 10625
19 Myles PS, Hunt JO, Moloney JT. Postoperative minor complications. 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. NeuroEndocrinol Lett 2002; 23(Suppl 4): 81 91

Downloaded from http://bja.oxfordjournals.org/ by guest on September 29, 2016

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.

Buchanan et al.

Effect of patient sex

32 Harmon D, OConnor P, Gleasa O, Gardiner J. Menstrual cycle irregularity and the incidence of nausea and vomiting after laparoscopy. Anaesthesia 2000; 55: 11647
33 Datta S, Migliozzi RP, Flanagan HL, Krieger N. Chronically administered 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: 80814
36 Gee KW, Bolger MB, Brinton RE, Coirini H, McEwen BS. Steroid
modulation of the chloride ionophore in rat brain: structureactivity
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: 299307
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: 27483
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 dendritic spine density. J Neurosci 1997; 17: 1848 59
40 Woolley CS, Schwartzkroin PA. Hormonal effects on the brain.
Epilepsia 1998; 39: S2S8
41 Rymer J, Morris EP. Extracts from Clinical evidence: Menopausal
symptoms. Br Med J 2000; 321: 15169

839

Downloaded from http://bja.oxfordjournals.org/ by guest on September 29, 2016

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: 1812
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: 1679
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. Anesthesiology 2001; 95: 862 7
28 Leslie K, Troedel S, Irwin K, et al. Quality of recovery from
anaesthesia in neurosurgical patients. Anesthesiology 2003; 99:
115865
29 Moller DH, Glass PSA. Should a patients gender alter the anaesthetic plan? Curr Opin Anaesthesiol 2003; 16: 37983
30 Myles PS, Hunt JO, Fletcher H, Smart J, Jackson T. Propofol, thiopental, sevoflurane and isoflurane: a randomized controlled trial
of effectiveness. Anesth Analg 2000; 91: 11639
31 Taenzer AH, Clark C, Curry CS. Gender affects report of pain and
function after arthroscopic anterior cruciate ligament reconstruction. Anesthesiology 2000; 93: 6705

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