International Journal of Obstetric Anesthesia (2008) 17, 130136

ORIGINAL ARTICLE

Remifentanil for cesarean section under general

anesthesia: effects on maternal stress hormone secretion
and neonatal well-being: a randomized trial
G. Draisci, * A. Valente, E. Suppa, L. Frassanito, R. Pinto, F. Meo,
P. De Sole, E. Bossu`, B. A. Zanni
Istituto di Anestesiologia e Rianimazione, Dipartimento di Emergenza e Accettazione Istituto di Chimica Clinica,
Universita` Cattolica del Sacro Cuore, Istituto Superiore di Sanita`, Rome, Italy

KEYWORDS

Abstract
Background: Remifentanil may attenuate maternal hemodynamic response during
cesarean section under general anesthesia, but could cause transient but signicant
neonatal depression. We investigated the effect of low-dose remifentanil on maternal
neuroendocrine response and fetal wellbeing.
Methods: Forty-two ASA I-II parturients undergoing cesarean section at term under
general anesthesia were randomized to receive either fentanyl after delivery (n = 21,
group C) or remifentanil bolus 0.5 lg/kg before induction followed by a continuous
infusion at 0.15 lgkg 1min 1 until peritoneal incision, then restarted after delivery
(n = 21, group R). Maternal heart rate and blood pressure, and epinephrine, norepinephrine, adrenocorticotropic hormone (ACTH), and growth hormone levels were measured at baseline, uterine incision, and the end of surgery. Remifentanil was measured in
maternal and umbilical arterial and venous blood. One- and 5-minute Apgar scores and
umbilical arterial and venous pH were recorded.
Results: ACTH was signicantly higher in group C at uterine incision (P < 0.01). No
signicant differences were observed in hemodynamics, catecholamines or growth hormone. Apgar scores at 1 (P < 0.05) and 5 min (P <0.01) were signicantly higher in
group C. Mean umbilical pH values were within normal range but signicantly higher
in group C. Three neonates in group R required intubation but recovered at 5 min without naloxone. Mean SD maternal remifentanil concentration was 1.67 1.04 ng/mL.
Conclusions: Remifentanil administration before peritoneal incision partially reduced
the hormonal stress response. Maternal benets must be weighed against transitory
but signicant neonatal respiratory depression. Neonatal resuscitation facilities are
mandatory when remifentanil is used.
c 2008 Elsevier Ltd. All rights reserved.

Analgesics; Opioid;
Anesthesia; Obstetrical;
Cesarean section;
Hormones; Piperidines/
adverse effects;
Anesthesia; General;
Infant/Newborn
Accepted 1 October 2007

G. Draisci, A. Valente, E. Suppa, L. Frassanito, R. Pinto, F. Meo, B. A. Zanni, Universita` Cattolica del Sacro Cuore, Dipartimento di
Emergenza e Accettazione, Istituto di Anestesiologia e Rianimazione, P. De Sole, Universita` Cattolica del Sacro Cuore, Istituto di Chimica
Clinica, E. Bossu`, Istituto Superiore di Sanita`, Rome, Italy.
* Correspondence to: G. Draisci, Largo A. Gemelli 8, 00168 Rome, Italy. Tel.: +39 06 30154507.
E-mail address: gdraisci@inwind.it

0959-289X/$ - see front matter c 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ijoa.2008.01.002

Effect of remifentanil at cesarean section on mother and baby

Introduction
Regional anesthesia is preferred for cesarean section
because of reduced maternal mortality.1 However,
general anesthesia may be indicated if regional anesthesia fails or is contraindicated, or for emergency
delivery. In a recent meta-analysis, general anesthesia
was shown to be associated with transient neonatal
sedation and essentially benign effects on neonatal
acid-base balance.2
The neuroendocrine stress response to surgery appears less well controlled with general than with regional anesthesia.3 The use of systemic opioids obtunds
the hormonal stress response during lower abdominal
procedures under general anesthesia.4 However, during cesarean section opioid administration is usually
avoided until after delivery to reduce the risk of neonatal depression.5,6 If opioid administration before
delivery is thought to be advantageous, remifentanil
with its fast onset and rapid metabolism appears to
be a suitable agent. It provides hemodynamic stability
in patients undergoing cesarean section under general
anesthesia,7 and has been successfully used in cases of
maternal cardiac disease,8,9 neurological conditions,
preeclampsia and liver disease.1012 However, previous studies showed that the use of remifentanil to
control the hemodynamic response to intubation
and surgery is associated with transitory but signicant neonatal depression.7,13 Since this effect could
be dose-dependent,14 the aim of our study was to
investigate whether administration of low-dose remifentanil could control the neuroendocrine response at
cesarean section under general anesthesia without
adverse effect on the neonate.

Methods
The study was designed as a randomized, controlled,
single-blind trial. Anesthetists and pediatricians were
not blinded to anesthetic technique. Approval from
the local research ethics committee was obtained
and written informed consent was given by all patients who participated in the study.
Forty-two ASA I-II women with singleton term
pregnancy scheduled for elective cesarean section
were enrolled. All patients had absolute or relative
contraindications to regional anesthesia. Exclusion
criteria were active labor, preeclampsia, neurological
disease, substance abuse, predicted difcult airway
management, known congenital abnormalities or
signs of fetal compromise.
Patients were randomly assigned to receive remifentanil infusion (group R) before and after delivery,
or fentanyl bolus (group C) only after delivery. Sub-

131

jects were randomized by computer-generated codes

in closed envelopes opened just before surgery. After
randomization, two i.v. lines were established, one of
which was used exclusively for either remifentanil
(group R) or saline (group C) infusion. Intravenous
ranitidine 100 mg and metoclopramide 10 mg were
given 60 min before induction of anesthesia. Standard
monitoring included electrocardiography, pulse
oximetry, non-invasive blood pressure, carbon dioxide, sevourane and nitrous oxide end-tidal concentrations, and bispectral index electroencephalogram
(EEG). Blood pressure and heart rate were measured
every 2 min and values at baseline, induction (immediately before thiopental administration), immediately after intubation, skin incision, uterine incision
and at the end of surgery, were used for analysis.
Patients were placed supine with left uterine displacement, and underwent pre-oxygenation through
a face mask for three minutes. Ultrasonographic fetal
heart rate monitoring was continued until surgical
skin disinfection. Anesthesia was induced with thiopental 4 mg/kg and suxamethonium 1 mg/kg. After
direct laryngoscopy and tracheal intubation, anesthesia was maintained with 1.5% end-tidal sevourane
and 50% nitrous oxide in oxygen. Neuromuscular
block was continued with vecuronium bromide 0.05
mg/kg. Patients were ventilated to maintain an endtidal CO2 of 3.7-4.3 kPa (28-32 mmHg).
In group C, patients received fentanyl 5 lg/kg just
after delivery. In group R, a 0.5-lg/kg remifentanil
bolus was infused over 30 s immediately before thiopental injection. This was followed by an infusion of
0.15 lgkg 1min 1 stopped at peritoneal incision.
After delivery, remifentanil 0.15-0.25 lgkg 1min 1
was re-infused until the end of surgery and titrated
to maintain median arterial pressure close to preoperative values.
After delivery, oxytocin 20 units was administered
in 500 mL of 5% glucose solution. Postoperative
analgesia was managed with intravenous paracetamol
1 g (repeated up to 4 g at six-hourly intervals), morphine 3-mg bolus at the end of surgery and i.v. morphine PCA (1-mg bolus on demand, 8-min lock-out,
maximal dose 30 mg/4 h).
Apgar scores were recorded at 1 and 5 min and the
newborns were evaluated and resuscitated in accordance with published guidelines15 by the on-call
attending pediatrician, who was informed of the anesthetic technique but not directly involved in the
study. All neonates were observed in the nursery for
at least 24 h after birth, with SpO2 monitoring removed at 3 h if no episodes of desaturation had occurred. Blood sugar was checked on admission and
at two-hourly intervals for the rst 6 h of life. Temperature was monitored for 24 h.

132

Statistical analysis
A mean increase of 20% stress hormone concentration at uterine incision was dened as the primary
outcome of the study, with a study power of 90%
(b = 0.10) and a sensitivity of 95% (a = 0.05). Based
on past data on patient variation at baseline level
from our central laboratory, given the expected variability (r) of 20%, the sample size required was 21 per
group.17 Statistical analysis was performed with the
SPSS program package. Demographic and blood
gas analysis were compared using the unpaired t test.
Apgar score and maternal hormone data were compared using Wilcoxon and Students t test. Signicant
differences were conrmed using non-parametric
tests. P values <0.05 were considered signicant.

Table 1

Demographic data and indications for general anesthesia

Control
(n = 21)
Age (years)
Weight (kg)
Height (cm)
Gestation (weeks)
Birth weight (g)
Indication for general anesthesia
refusal of regional anesthesia
thrombocytopenia
previous spinal surgery

Forty-two women were recruited to and completed

the study. Maternal height, weight, gestational age,
and neonatal weight were similar in the two groups

34.5 4.6 30.5 3.8

77 6.4
76 8.2
164 5.5
161 6.9
37.5 1.5 38.3 0.7
2923 433 3238 454
13 (61.9%)
6 (28.6%)
2 (14.3%)

11 (52.4%)
6 (28.6%)
4 (19%)

(Table 1). Indications for general anesthesia are also

presented in Table 1.
There were no signicant differences between the
groups in heart rate or blood pressure at any time
(Figs. 1 & 2).
Maternal hormone concentrations for the three
sampling times are given in Table 2. Norepinephrine
(P <0.001 in group C and P <0.0001 in group R) and
epinephrine (P <0.05 in group C and P <0.01 in
group R) concentrations rose signicantly at uterine
incision, but there were no signicant differences
between groups at any sampling time. A signicant
increase in ACTH was seen in group C (P <0.0001).
ACTH concentration, was signicantly higher in
group C than in group R at uterine incision
(P <0.01). There were no signicant changes in
growth hormone concentration.

SAP Control

SAP Remifentanil

MAP Control

MAP Remifentanil

200

160

120
80

40

0
Baseline Induction

Results

Remifentanil
(n = 21)

Data are mean standard deviation or number (percent).

Arterial pressure (mmHg)

Maternal venous blood samples were taken for assay of norepinephrine and epinephrine, adrenocorticotropic hormone (ACTH), and growth hormone
30 min before surgery (baseline), just before uterine
incision, and at the end of surgery. Umbilical venous
and arterial blood samples were collected from a
segment of cord just after clamping to measure pH,
base excess, and remifentanil concentration. Remifentanil concentration was measured in maternal
blood taken at baseline and uterine incision. To
determine remifentanil concentration, blood samples
were collected in heparinized tubes containing 50%
(w/w) citric acid solution (10 lL/mL of blood), then
immediately placed on ice and centrifuged at 4C
for 15 min at 2000 rpm. Plasma was separated and
stored at 70C (catecholamines and remifentanil)
and at 20C (ACTH, growth hormone). Norepinephrine and epinephrine were measured by high
performance liquid chromatography (HPLC) and
quantied by an electrochemical-coulombmetric
method (HPLC-EG-ESA 5100 A, Coulochem, Bedford, MA, USA). Concentrations of ACTH and
growth hormone were measured by commercially
available radioimmunoassay kits. Umbilical blood
acid-base balance was analyzed on a Critical Care
Express Nova Biomedical blood gas analyzer. Remifentanil plasma concentrations were determined by a
validated HPLC-MS method after solid phase extraction.16 The quantitation range of the assay was 0.5 to
48.0 ng/mL; the estimated limit of detection was 0.18
ng/mL, and the limit of quantitation was 0.5 ng/mL.

G. Draisci et al.

After
Skin
Intubation Incision

Uterine
Incision

End
Surgery

Figure 1 Maternal arterial pressure. SAP Control: systolic arterial pressure of control group; SAP Remifentanil:
systolic arterial pressure of remifentanil group; MAP
control: mean arterial pressure of control group; MAP
remifentanil: mean arterial pressure of remifentanil group.

Effect of remifentanil at cesarean section on mother and baby

Control

Table 3

Remifentanil

133
Apgar scores and umbilical blood gas analysis

Heart rate (beats/min)

140
120
100
80
60
40
20
0
Baseline Induction After IOT

Figure 2
Table 2

Skin
Incision

Uterine
Incision

End
Surgery

Maternal heart rate.

Maternal hormone concentrations

Control
(n = 21)

Remifentanil
(n = 21)

Norepinephrine (pg/mL)
Baseline
Uterine incision
End of surgery

408 155
602 227
617 147

386 182
716 272
516 241

Epinephrine (pg/mL)
Baseline
Uterine incision
End of surgery

91.6 84.3
333 415
96 103

96.7 80.3
231 208
61 56

ACTH (pg/mL)
Baseline
Uterine incision
End of surgery

29 13
138 94
64 36

39 15
53 39*
44 25

Growth hormone (ng/mL)

Baseline
Uterine incision
End of surgery

0.22 0.14
0.32 0.19
0.42 0.6

0.21 0.20
0.33 0.32
0.37 0.4

Data are mean SD.

*
P <0.01.

Induction-to-delivery time (I-D time), uterine incision-to-delivery time (U-D time), and peritoneal incision-to-uterine incision time (P-U time) were similar
in the two groups. Apgar scores were signicantly
lower in group R at 1 min (P <0.05) and at 5 min
(P <0.01) (Table 3). Three neonates in the remifentanil group required tracheal intubation (Apgar score 2
at 1 min). Naloxone was not administered in any
case. At 5 min, Apgar scores were 8 or more in all
newborns and no further intervention was required.
Umbilical blood gas analysis was in the normal range
in both groups although umbilical vein pH was significantly lower in group R (P <0.01). There were no
episodes of desaturation, respiratory depression,
hypoglycemia or hypothermia in neonates from
either group after initial resuscitation.
Data from 16/21 patients who received remifentanil were analyzed to determine plasma remifentanil

Apgar at 1 min
<5
6-8
9-10
mean
Apgar a 5 min
<5
6-8
9-10
mean
Umbilical vein
pH
BE (mEq/L)
Umbilical Artery
pH
BE (mEq/L)
I-D time (min)
U-D time (min)
P-U time (min)

Control
(n = 21)

Remifentanil
(n = 21)

0
13 (61.9%)
8 (38.1%)
8.4 ( 0.96)

3 (14.3%)
18 (85.7%)
0
6.84 ( 2.44)*

0
0
21 (100%)
9.4 ( 0.51)

0
4 (19.%)
17 (81.%)
8.73 ( 0.45)*

7.40 0.05
0.03 3.46

7.36 0.04**
0.53 2.46

7.34 0.04
0.47 3.28
6.7 1.8
1.4 0.7
1.5 0.3

7.36 0.03
0.08 2.66
6.77 2.97
1.85 0.8
1.4 0.4

Apgar scores are number and percentage.

BE: base excess.
I-D time: Induction-to-delivery time (mean SD).
U-D time: Uterine incision-to-delivery time (mean SD).
P-U time: Peritoneal incision-to-uterine incision time (mean SD).
*
**

P < 0.05.
P < 0.01.

concentrations. Data from ve were excluded because

of incomplete or inadequate samples (n = 4) or storage (n = 1). Median maternal venous concentration
was 1.67 1.04 ng/mL. Remifentanil was not detectable in four umbilical venous samples, detected but
not quantied in nine and 1.22 1.09 ng/mL in the
remainder. Remifentanil was not detectable in eight
umbilical arterial samples, detected but not quantied
in four, and 0.72 0.42 ng/mL in the remainder. The
available data did not allow calculation of median
umbilical concentrations or UV/UA ratios nor to
investigate a correlation between remifentanil concentration and Apgar scores.
No patient had recall of intraoperative events
and BIS monitoring showed values less than 60
during the study period with no differences between
groups. No patient showed chest wall rigidity and
there was no difference between groups in nausea/
vomiting or 24 h morphine consumption (group C
mean 28.5 18.1 mg vs. group R mean 31.4 16.2 mg).

Discussion
Remifentanil, administered as a 0.5-lg/kg bolus before induction followed by an infusion of 0.15

134
lgkg 1min 1 until peritoneal incision, partially
obtunded the neuroendocrine response to surgery
with a decrease in ACTH rise. However, this was at
the expense of transient neonatal depression, with
Apgar scores signicantly lower in babies whose
mothers had received remifentanil, although all
scores improved to P8 within 5 min. Neonatal respiratory depression has previously been reported
following maternal remifentanil administration with
more than 10% of babies requiring intubation.7,13,18
Fortunately, respiratory depression was transient,
and umbilical cord pH values did not suggest fetal
asphyxia.
When cesarean section is performed under general
anesthesia, it is benecial to minimize both maternal
surgical stress and neonatal depression. As signicant
amounts of drugs used for general anesthesia cross
the placenta,19 opioids are usually administered after
umbilical cord clamping. Consequently, the maternal
neuroendocrine response is more pronounced during
induction of anesthesia and surgical incision.5,6 This
is undesirable when the mother has concomitant systemic disease and haemodynamic stability is required.
We administered remifentanil as a bolus and continuous infusion to blunt the maternal stress response. The infusion was stopped at peritoneal
incision to allow partial metabolism before uterine
incision and hopefully minimize effects on the baby.
The dose of remifentanil was derived from previous
studies in both obstetric and non-obstetric patients,
and was based on clinical safety and the ability to
limit secondary effects.712
In previous studies, both Ngan Kee and colleagues
and Van de Velde and colleagues showed transient
neonatal respiratory compromise lasting up to 5
min with remifentanil bolus in cesarean section under
general anesthesia7,13 We also observed a signicant
reduction in Apgar scores in the remifentanil group
at 1 and 5 min, with a concomitant difference in
umbilical vein pH values, even though these remained
in the normal range. These data indicate that, even at
low doses, remifentanil has the potential to cause
respiratory depression.7 However, all Apgar scores
were P8 at 5 min without naloxone administration,
indicating rapid resolution of respiratory depression
when present. No other adverse neonatal effects were
observed during the rst 24 h of life. We chose not to
blind anesthetists and pediatricians to the anesthetic
technique. As remifentanil is not part of our standard
technique we considered that it was safer for both
mother and baby if staff were aware of treatment
allocation.
Remifentanil transfer across the placenta has
been described.7,18 In our study, the mean remifentanil concentration in maternal venous blood was
1.67 1.04 ng/mL, a level similar to that reported

G. Draisci et al.
by Kan et al (1.32 0.80 ng/mL).18 Unfortunately,
we were unable to calculate UV/MV and UA/MV
ratios. No correlation between umbilical or maternal
remifentanil concentration and Apgar scores or pH
could be established. Babies of remifentanil-treated
mothers had a greater need for medical assistance
in the rst minutes after birth, but in no case
showed evidence of prolonged neurological insult
or damage.
Blood pressure and heart rate were not signicantly different between the remifentanil and control
groups although surgical stimulation resulted in a
similar increase in heart rate in both groups. Other
investigators have observed that remifentanil provided greater hemodynamic stability at induction of
anesthesia.7 This disparity could result from a lower
remifentanil dose in our study or alternatively lighter
anesthesia in control patients in previous studies.
Also it could be that we did not measure maternal
hemodynamic parameters sufciently frequently to
observe a difference. We did, however, record blood
pressure and heart rate at times to coincide with the
most noxious stimulation. Adequately deep hypnosis
seemed to have been assured by general anesthesia
with or without remifentanil, as evidenced by BIS
monitoring and by the absence of recall of intraoperative events.
Hemodynamic changes alone are less sensitive
indicators of surgical stress than are biochemical
markers.20 Reduced hormone secretion would indicate better control of surgical stress and potentially
of its adverse metabolic consequences, such as glucose tolerance reduction, catabolism enhancement,
and depressed immune function.3,21 Reduction in
stress hormone response with the present dosages of
remifentanil was limited to ACTH secretion. ACTH
is a sensitive index of stress, and correlates with the
severity of surgical trauma.22 It is partly inhibited
by the afferent neural blockade obtained with epidural or spinal anesthesia.23 ACTH is known to cause
increased muscle catabolism, and to affect immune
function. The transient immunosuppression induced
by surgical stress may be partially explained by activation of the ACTH-cortisol axis.24
In our study, signicant differences in ACTH concentration just before uterine incision may reect opioid-mediated suppression of CRH secretion,25 or a
combination of central and peripheral mechanisms.
The metabolic effect of growth hormone is in some
ways similar to that of ACTH-cortisol (glyconeogenic, anti-insulin effect), and in part the opposite
(anabolic effect with stimulation of protein synthesis
in non-muscle tissues). We were unable to identify
any differences between the groups suggesting that,
at the current dosages, remifentanil does not affect
growth hormone release.

Effect of remifentanil at cesarean section on mother and baby

The lack of difference in catecholamine levels between groups parallels the absence of a hemodynamic
effect. Opioids are known to reduce the hypothalamic-adrenal response to surgery,26 and to depress
sympathetic activity in a dose-dependent manner.27,28
Although norepinephrine secretion has been shown
to be reduced by opioid administration,29 in our
study the increase in norepinephrine was not attenuated by remifentanil infusion, as previously described.30 This supports the hypothesis that
norepinephrine, released mainly from sympathetic
nerve endings, is not signicantly affected by systemic
opioid administration.31
Epinephrine is secreted from the adrenal medulla
and not released from peripheral tissues.32 This
release is governed by sympathetic nervous system
activation. Although the difference was not signicant, the epinephrine concentration was lower in
group R than in group C at uterine incision, and
could have resulted from an opioid-mediated central
control of epinephrine secretion, limited by the lowdose of remifentanil.31 For women with signicant
disease such as valvular stenosis or severe hypertension, remifentanil should probably be administered
in a higher dose than that used in our study to minimize hemodynamic instability, and to achieve greater
control of the stress response to surgery.8,9 However,
this may occur at the cost of more intense neonatal
sedation, which was present in our patients even
though they were treated with a low dose.
At the dosage we used, remifentanil infusion may
not be considered suitable as a routine component
of general anesthesia for cesarean section in healthy
patients. It may be that a higher bolus dose and a
lower infusion rate or duration or remifentanil target
controlled infusion could improve surgical stress control with minimal neonatal sedation.
Administration of remifentanil before peritoneal
incision during cesarean section under general anesthesia partially reduced maternal stress hormone
secretion related to surgery. Remifentanil is probably
suitable for reducing the adverse consequences of surgery, but further optimization of remifentanil administration protocols is required to improve the risk/
benet ratio for both the mother and baby. If remifentanil is used, neonatal resuscitation facilities must
be immediately available. Further study to dene
the inuence of preventing surgical stress on general
maternal health status is necessary.

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