Acta Anaesthesiol Scand 2013; 57: 2936

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2012 The Authors

Acta Anaesthesiologica Scandinavica
2012 The Acta Anaesthesiologica Scandinavica Foundation
ACTA ANAESTHESIOLOGICA SCANDINAVICA

doi: 10.1111/j.1399-6576.2012.02723.x

Review Article

Maternal and foetal effects of remifentanil for general

anaesthesia in parturients undergoing caesarean section:
a systematic review and meta-analysis
M. Heesen1, S. Klhr1, T. Hofmann1, R. Rossaint2, S. Devroe3 S. Straube4 and M. Van de Velde3
1
Department of Anaesthesia, Klinikum Bamberg, Bamberg, Germany, 2Department of Anaesthesia, Universittsklinkum Aachen, Aachen,
Germany, 3Department of Anaesthesia, Universitair Zieckenhuis Leuven, Leuven, Belgium, and 4Department of Occupational, Social and
Environmental Medicine, University Medical Center Gttingen, Gttingen, Germany

Background: Remifentanil has been suggested for the induction of general anaesthesia for caesarean section. We aimed to
define remifentanil effects on maternal stress response as well as
neonatal effects.
Methods: Relevant articles were retrieved by a systematic literature search. Randomized, controlled trials comparing
remifentanil use before delivery with placebo were selected.
Maternal outcome parameters were blood pressure and heart
rate; neonatal effects included the need for mask ventilation and
intubation, base excess, pH values, Apgar < 7 at 1 and 5 min. The
random effects model was used for meta-analysis; risk ratio or
weighted mean difference (WMD) and 95% confidence interval
(95% CI) were calculated.
Results: Five articles including 186 patients were identified.
Highest and lowest systolic blood pressure were significantly
lower in the remifentanil group (WMD: -29.98, -50.90 to
-9.07 mmHg, 95% CI; P = 0.005; and WMD: -12.46, -18.21 to
-6.71 mmHg, 95% CI; P < 0.0001), the lowest heart rate was

eneral anaesthesia can become necessary for

caesarean section if spinal anaesthesia, the
anaesthetic technique of first choice, is impossible
because of contraindications, failure of block or
urgency. It is current clinical practice to avoid opioids
for the induction of general anaesthesia1 because of a
potential for respiratory depression of the neonate.
Remifentanil, a short-acting m-receptor agonist is
degraded by esterases,2 resulting in a half-time of
a few minutes.3 As a consequence of its beneficial
pharmacokinetic profile, remifentanil4 has been suggested for the use in parturients undergoing caesarean section.5 Remifentanil crosses the placenta and is
cleared rapidly from the neonatal plasma.6 We therefore sought to define neonatal and maternal effects of
remifentanil use in parturients undergoing caesar-

significantly lower after remifentanil treatment (WMD: -8.22,

-11.67 to -4.78, 95% CI; P < 0.00001). Base excess was significantly higher in infants of remifentanil-treated mothers (WMD:
1.15, -0.27 to 2.03, 95% CI; P = 0.01); pH was also higher in the
remifentanil group, but significance was missed (P = 0.07). No
differences were observed for Apgar values or the need of airway
assist.
Conclusion: Remifentanil was found to attenuate the maternal
circulatory response to intubation and surgery. Higher base
excess and pH suggest a beneficial effect on the neonatal acidbase status. A trial with adequate power is warranted that
addresses neonatal side-effects of remifentanil.
Accepted for publication 18 May 2012
2012 The Authors
Acta Anaesthesiologica Scandinavica
2012 The Acta Anaesthesiologica Scandinavica Foundation

ean section by performing a systematic review and

meta-analysis of the available data.

Methods
Literature search
A systematic literature search was performed on 10
September 2011 in PubMed and Embase with the
search terms: caesarean section, c section, caesarean
delivery or operative delivery, and remifentanil. In
addition, we checked the reference lists of retrieved
articles for relevant literature, and we handsearched the abstract bands of the annual congresses
of the American and European society of anaesthesiology and regional anaesthesia from 1998 until
2011. We chose this period because the first article

29
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M. Heesen et al.

on the use of remifentanil in pregnant patients was

published in 1998.6 Articles were considered for
further analysis when they reported the use of
remifentanil for the induction of general anaesthesia
before delivery of the baby and when a placebo
group was included. We tried to contact the authors
of three of the reports79 but did not get further
information.

Quality assessment
The Oxford quality scale was used to score each
trial.10 Two authors (MH, TH) independently scored
the trials.

Data extraction and meta-analysis

For the binary variables mask/bag ventilation and
intubation, the number of events and total number
of subjects per group (remifentanil, control group)
were extracted. Data extraction was done by means
of a form and was independently done by two
authors (MH, SK).
Apgar values were dichotomized (Apgar < 7 or
7). Mean and standard deviation were extracted
from tables or figures for the continuous outcome
parameters pH, base excess (BE), highest and lowest
systolic blood pressure, and heart rate.
We used the software program Review Manager
(RevMan) (Computer program) (version 5.1, The
Nordic Cochrane Centre, The Cochrane Collaboration, 2008, Copenhagen, Denmark). The random
effects model was applied for meta-analysis of binary
and continuous variables. The pooled risk ratio (RR)
and 95% confidence interval (95% CI) were calculated for binary variables, and the weighted mean
difference (WMD) of the pooled continuous data.

Results
Our literature search identified 135 articles of which
five reports79,11,12 including 186 patients were considered eligible for further analysis (Fig. 1). The
remifentanil regimes were heterogenous in the
identified trials. Two trials studied pre-eclamptic
women, and three reports non-pre-eclamptic parturients. Four studies were full papers,7,8,11,12 and one
study was an abstract publication.9 Details of the
trials are given in Table 1.
In the trial by Bouattour et al.,7 standard deviations were not given so that data of this report were
not included into the analyses of blood pressure and
heart rate. Moreover, Apgar scores < 7 or 7 could
not be retrieved from this study. No Apgar or pH
data were given in the study by Orhan Sungur et al.9

30

Maternal outcome
The highest systolic blood pressure was significantly
lower in the remifentanil group (WMD: -29.98,
-50.90 to -9.07, 95% CI; P = 0.005; Fig. 2A). The
WMD for the lowest systolic blood pressure was
also significant (-12.46, -18.21 to -6.71, 95% CI;
P < 0.00001; Fig. 2B). Also, the lowest heart rate was
lower in the remifentanil-treated women (WMD:
-8.22, -11.67 to -4.78, 95% CI; P < 0.000001; Fig. 2C),
whereas no significant difference was found for the
highest heart rate (WMD: -10.43, -22.91 to 2.05, 95%
CI; P = 0.10). Catecholamine plasma concentrations
were measured in two reports.8,12 The time points of
sample taking was different in the two studies so
that these data could not be used for meta-analysis.
In one study, norepinephrine plasma levels were
higher in the placebo compared with the remifentanil group and increased significantly from
baseline to 1 min after intubation; epinephrine
decreased in the remifentanil group from baseline to
this time point.12 At delivery, norepinephrine was in
both groups higher than the respective baseline;
epinephrine was higher in the control patients.12
Draisci et al.8 did not find significant changes in the
catecholamine plasma levels, neither within one
group nor between groups at uterine incision or at
end of surgery. In this study, Adrenocorticotropic
hormone (ACTH) levels increased significantly
from baseline to uterine incision.8

Neonatal outcome
Base excess was significantly higher in infants of
remifentanil-treated mothers (WMD: 1.15, -0.27
2.03, 95% CI; P = 0.01). Also, pH values were higher
in the remifentanil group (WMD 0.01, 0.000.03),
but significance level was just missed (P = 0.07). No
difference was observed for arterial partial pressure
of carbon dioxide data. The open RR for mask ventilation or intubation as well as Apgar values at 1
and 5 min did not differ between groups. Neonatal
outcome data are given in Fig. 3.

Discussion
As a major result, we found that remifentanil is
highly effective in blunting the blood pressure
and heart rate response to intubation and surgery.
Base excess was significantly higher in infants of
remifentanil-treated mothers. pH data were also
higher, although statistical significance was not
reached. No difference was observed by our metaanalysis for the neonatal outcome parameters mask
ventilation, intubation and Apgar values.

Identification

Meta-analysis of remifentanil for caesarean section

Records identified through database

searching
n = 135

Additional records
identified through other
sources
n=1

Eligibility

Screening

Records after duplicates removed

n = 136

Records screened
n = 136

Full-text articles assessed for

eligibility
n=6

Records excluded
reports on labour analgesia
n = 64
Reviews/Editorials/Letters to
the editor n = 29
Case reports/series n = 34
Animal/in vitro studies n = 3

Records excluded, with reasons

No placebo group n = 1

Included

Studies included in qualitative

synthesis
n=5

Studies included in quantitative

synthesis (meta-analysis)
n=5

A large population-based study including 987,010

women revealed that caesarean section was an independent risk factor for stroke.13 Subsequent analyses
in pre-eclamptic women showed that the adjusted
hazard ratio (HR) for stroke after general anaesthesia was 2.83 when comparing with neuraxial blockade.14 The unadjusted HR for stroke after general
anaesthesia for caesarean section in non-preeclamptic women was also significantly increased,
but significance was no longer given after adjusting
for confounders.14 No differences were seen
between spinal and epidural anaesthesia.14 The
increased stroke risk after general anaesthesia could
be a consequence of higher stress hormones and
blood pressure values. By contrast, neuraxial blockade was reported to attenuate the stress response of
pre-eclamptic and non-pre-eclamptic women.15,16

Fig. 1. Flow diagram.

It is tempting to speculate that an effective reduction of the haemodynamic response by remifentanil

administration for the induction of general anaesthesia could help to reduce the risk of stroke.
Whereas we found a significant reduction of blood
pressure and heart rate, the results for stress hormones were not consistent. This inconsistency is
probably due to the fact that blood pressure reaction
to intubation is mediated not only by hormonal
mechanisms but also by autonomic neuronal activation. A significant attenuation of the catecholamine
response was seen in one study8 but not in another.12
This could be due to the short half-time of catecholamines in plasma and the differences in time-points
of plasma sampling between the two studies.
A remarkable reduction of the haemodynamic
response has been reported by the use of intrave-

31

32

paper

paper

paper

paper

abstract

Ngan Kee et al.11

Bouattour et al.7

Draisci et al.8

Yoo et al.12

Orhan Sungur9
RCT

RCT

RCT

RCT

RCT

Study
design

double-blinded

single-blinded
(anaesthetist and
pediatrist not
blinded)
double-blinded

double-blinded

double-blinded

Blinding

not mentioned

not mentioned

not mentioned

not mentioned

appropriate

Randomization

severe
pre-eclampsia,
elective or urgent
c-section
severe
pre-eclampsia,
c-section

singleton term
pregnancy, elective
c-section

singleton term
pregnancy, elective
c-section
pregnancy at term,
elective c-section

Patients

1 mg/kg bolus

1 mg/kg bolus

0.5 mg/kg bolus,

followed by infusion
of 0.2 mg/kg/min
0.5 mg/kg bolus,
followed by infusion
of 0.15 mg/kg/min

1 mg/kg bolus

Intervention

RCT, randomized,controlled trial; SAP, systolic arterial pressure; MAP, mean arterial pressure; c-section, caesarean section.

Publication

Author

Characteristics of the trials included in the meta-analysis.

Table 1

R:11 C:11

R: 21 C: 21

R: 21 C: 21

R: 20 C: 20

R: 20 C: 20

Sample size
remifentanil/control

not defined

MAP

stress hormone
concentration

not defined

SAP

Primary
outcome

M. Heesen et al.

Meta-analysis of remifentanil for caesarean section

A

B
Study or Subgroup
Ngan Kee et al.11
Draisci et al.8
Yoo, et al.12

Remifentanil
Control
Mean
SD Total Mean SD Total Weight
85 11.4
113
14
136
19

Total (95% CI)

20
21
19

102 19.5
118
16
154
17

60

20
21
21

Mean Difference
IV, Random, 95% CI Year

33.8% 17.00 [26.90, 7.10] 2006

36.3%
5.00 [14.09, 4.09] 2008
29.9% 18.00 [29.22, 6.78] 2009

62 100.0% 12.94 [21.46, 4.41]

Heterogeneity: Tau = 30.52; Chi = 4.33, df = 2 (P = 0.11); I = 54%

Test for overall effect: Z = 2.97 (P = 0.003)

C
Study or Subgroup
Ngan Kee et al.11
Draisci et al.8
Yoo et al.12
Total (95% CI)

Remifentanil
Control
SD Total Mean SD Total Weight
Mean
76
74
76.7

8.2
14
9.2

20
21
19
60

Mean Difference
IV, Random, 95% CI

79 15.7
77
17
87.5 1.8

20
21
21

50
25
0
25
Favours Remifentanil Favours control

Mean Difference
IV, Random, 95% CI Year

50

Mean Difference
IV, Random, 95% CI

3.00 [10.76, 4.76] 2006

29.6%
3.00 [12.42, 6.42] 2008
23.8%
46.6% 10.80 [15.01, 6.59] 2009

62 100.0%

Heterogeneity: Tau = 14.72; Chi = 4.36, df = 2 (P = 0.11); I = 54%

Test for overall effect: Z = 2.21 (P = 0.03)

6.63 [12.51, 0.75]

50
25
0
25
Favours Remifentanil Favours control

50

Fig. 2. Maternal outcome parameters. (A) Highest systolic blood pressure. (B) Lowest systolic blood pressure. (C) Lowest heart rate. CI,
confidence interval; SD, standard deviation; IV, inverse variance.

nous lidocaine for general anaesthesia for caesarean

section.17 We feel that a trial comparing intravenous
lidocaine with remifentanil in terms of maternal
stress reaction and neonatal side-effects would be
interesting.
In addition to maternal effects, the consequences
of remifentanil for the neonate are of particular
interest. Our analysis found a higher base excess
(statistically significant) as well as pH (not significant) after remifentanil administration to the
mother. Remifentanil blunts the sympathoadrenal
activation that may have two opposite effects.18 High
adrenergic activity may compromise the uteroplacental perfusion, and its attenuation may be beneficial. On the other side, the adrenergic activity plays
an important role for pulmonary and metabolic
adaptation of the neonate. Our results suggesting
that remifentanil is associated with alkalotic acidbase status in infants should be interpreted with
caution: the differences between groups were
1.15 mmol/L for base excess and 0.01 units for pH,
which questions the clinical relevance.
Recently, remifentanil use in labouring women
has been subject of a systematic review19 and was

found to effectively reduce maternal pain. This

study, however, was unable to provide unambiguous conclusions about the effects of remifentanil on
foetal pH. In a previous paper,20 we showed that it is
more important to look at the number of babies with
a pH < 7.20 than at the absolute pH values. Malin
and colleagues21 clearly defined the role of foetal
acidosis by demonstrating that a pH < 7.20
increased mortality by the factor four and doubled
the risk of morbidity. Therefore, future studies
should give these values because the incidence of
true foetal acidosis is more meaningful.
Our analysis failed to find differences in Apgar
values or the need for intubation or mask ventilation of the infant. Four of the five trials included
into our analysis were powered for the haemodynamic outcome of the mother rather than for neonatal side-effects. The low number of patients as
well as the low event rate is the most likely reason
for the lack of differences between opioid-treated
mothers and the control group. To come to a clinically meaningful conclusion, approximately 500
patients per group and a total of 200 events are
required.22,23

33

M. Heesen et al.
A

B
Study or Subgroup
Ngan Kee et al.11
Bouattour et al.7
Draisci et al.8
Yoo et al.12
Total (95% CI)

Remifentanil
Control
SD Total Weight
SD Total Mean
Mean

Mean Difference
IV, Random, 95% CI

22.2%
32.1%
38.2%
7.5%

0.00 [0.03, 0.03]

0.01 [0.01, 0.03]
0.02 [0.00, 0.04]
0.02 [0.03, 0.07]

78 100.0%

0.01 [0.00, 0.03]

7.29
7.26
7.36
7.28

0.05
0.03
0.03
0.07

20
17
21
18
76

7.29
7.25
7.34
7.26

0.04
0.04
0.04
0.08

20
18
21
19

Heterogeneity: Tau = 0.00; Chi = 1.37, df = 3 (P = 0.71); I = 0%

Test for overall effect: Z = 1.83 (P = 0.07)

Mean Difference
IV, Random, 95% CI

0.2
0.1
0
0.1
0.2
Favours Remifentanil Favours control

Fig. 3. Neonatal outcome. (A) Base excess (BE) data of the neonate. (B) pH data of the neonate. (C) Partial pressure of carbon dioxide data
of the neonate. (D) Mask ventilation of the neonate. (E) Intubation of the neonate. (F) Apgar < 7 at 1 min. (G) Apgar < 7 at 5 min. CI,
confidence interval; SD, standard deviation; IV, inverse variance; M-H, Mantel-Haenszel.

Another issue of our analysis is the heterogeneity

with two reports of pre-eclamptic women vs. three
studies of non-pre-eclamptic women. Tight haemodynamic control should be considered in preeclamptic women, in pre-eclamptic and otherwise
healthy parturients; however, this should be balanced against the potential risks of hypotension. In
addition, remifentanil dosage regimens differed
among the studies and doseresponse effects should
be further defined in order to find the optimal dosage
for both mother and infant. The number of infants

34

needing ventilatory assist was remarkably higher in

the study by Yoo et al.12 of pre-eclamptic parturients
compared with the other reports, and this fact was
probably due to a sedative effect of volatile anaesthetics in pre-term babies with or without respiratory
distress syndrome. The need for brief mask ventilation has already been described in an initial study on
the use of remifentanil for caesarean section24 in 6 out
of 10 babies.
In summary, remifentanil can attenuate the blood
pressure and heart rate response to endotracheal

Meta-analysis of remifentanil for caesarean section

E

Fig. 3. Continued

intubation and surgery in parturients undergoing

caesarean section under general anaesthesia. Our
analysis suggests that remifentanil induces an alkalotic acid-base status. We were unable to define the
effects of remifentanil on Apgar values and the need
for airway assist because of the low number of
patients and events. A trial with adequate power to
detect differences between infants of remifentaniltreated parturients and control patients is warranted
before remifentanil can be recommended for clinical
routine use.
Conflict of interest: None.
Funding: Departmental funds.

References
1. Tsen LC. Anesthesia for cesarean delivery. In: Chestnut DH,
Polley LS, Tsen LC, Wong CA eds. Obstetric anesthesia, 4th
edn. Philadelphia, PA: Mosby-Elsevier, 2009: 52174.
2. Egan TD. Remifentanil pharmacokinetics and pharmacodynamics. A preliminary appraisal. Clin Pharmacokinet 1995;
29: 8094.

3. Kapila A, Glass PS, Jacobs JR, Muir KT, Hermann DJ, Shiraishi M, Howell S, Smith RL. Measured context-sensitive halftimes of remifentanil and alfentanil. Anesthesiology 1995;
83: 96875.
4. Buerkle H, Wilhelm W. Remifentanil for gynaecological and
obstetric procedures. Curr Opin Anaesthesiol 2000; 13:
2715.
5. Bdard JM, Richardson MG, Wissler RN. General anesthesia
with remifentanil for Cesarean section in a parturient
with an acoustic neuroma. Can J Anaesth 1999; 46: 576
80.
6. Kan RE, Hughes SC, Rosen MA, Kessin C, Preston PG, Lobo
EP. Intravenous remifentanil: placental transfer, maternal
and neonatal effects. Anesthesiology 1998; 88: 146774.
7. Bouattour L, Ben Amar H, Bouali Y, Kolsi K, Gargouri A,
Khemakhem K, Kallel N, Trabelsi K, Guermazi M, Rekik A,
Karoui A. Maternal and neonatal effects of remifentanil for
general anaesthesia for caesarean delivery. Ann Fr Anesth
Reanim 2007; 26: 299304.
8. Draisci G, Valente A, Suppa E, Frassanito L, Pinto R, Meo F,
De Sole P, Boss E, Zanfini BA. Remifentanil for cesarean
section under general anesthesia: effects on maternal stress
hormone secretion and neonatal well-being: a randomized
trial. Int J Obstet Anesth 2008; 17: 1306.
9. Orhan Sungur M, Ozkan Seyhan T, Parlak H, Altuntas E,
Tugrul M. The effects of remifentanil during general anaes-

35

M. Heesen et al.

10.

11.

12.

13.

14.

15.

16.

17.

36

thesia induction for caesarean delivery of severe preeclamptic patients. Eur J Anaesthesiol 2009; 26 (Suppl 45): 151.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ,
Gavaghan DJ, McQuay HJ. Assessing the quality of reports of
randomized clinical trials: is blinding necessary? Control
Clin Trials 1996; 17: 112.
Ngan Kee WD, Khaw KS, Ma KC, Wong AS, Lee BB, Ng FF.
Maternal and neonatal effects of remifentanil at induction of
general anesthesia for cesarean delivery: a randomized,
double-blind, controlled trial. Anesthesiology 2006; 104:
1420.
Yoo KY, Jeong CW, Park BY, Kim SJ, Jeong ST, Shin MH, Lee
J. Effects of remifentanil on cardiovascular and bispectral
index responses to endotracheal intubation in severe preeclamptic patients undergoing caesarean delivery under
general anaesthesia. Br J Anaesth 2009; 102: 8129.
Lin SY, Hu CJ, Lin HC. Increased risk of stroke in patients
who undergo cesarean section delivery: a nationwide
population-based study. Am J Obstet Gynecol 2008; 198:
391.e17.
Huang CJ, Fan YC, Tsai PS. Differential impacts of modes of
anaesthesia on the risk of stroke among preeclamptic
women who undergo caesarean delivery: a populationbased study. Br J Anaesth 2010; 105: 81826.
Ramanathan J, Coleman P, Sibai B. Anesthetic modification
of hemodynamic and neuroendocrine stress responses to
cesarean delivery in women with severe preeclampsia.
Anesth Analg 1991; 73: 7729.
Loughran PG, Moore J, Dundee JW. Maternal stress
response associated with caesarean delivery under general
and epidural anaesthesia. Br J Obstet Gynaecol 1986; 93:
9439.
El-Tahan MR, Warda OM, Diab DG, Ramzy EA, Matter MK.
A randomized study of the effects of perioperative i.v. lidocaine on hemodynamic and hormonal responses for cesarean section. J Anesth 2009; 23: 21521.

18. Irestedt L, Lagercrantz H, Belfrage P. Causes and consequences of maternal and fetal sympathoadrenal activation
during parturition. Acta Obstet Gynecol Scand 1984; 118:
1115.
19. Leong WL, Sng BL, Sia AT. A comparison between remifentanil and meperidine for labor analgesia: a systematic
review. Anesth Analg 2011; 113: 81825.
20. Veeser M, Hofmann T, Roth R, Klhr S, Rossaint R, Heesen
M. Vasopressors for the management of hypotension after
spinal anaesthesia for elective caesarean section. Systematic
review and cumulative meta-analysis. Acta Anaesth Scand
2012; doi: 10.1111/j.1399-6576.2011.02646.x. [E-pub ahead of
print].
21. Malin GL, Morris RK, Khan KS. Strength of association
between umbilical cord pH and perinatal and long term
outcomes: systematic review and meta-analysis. BMJ 2010;
340: c1471.
22. Moore RA, Gavaghan D, Tramer MR, Collins SL, McQuay
HJ. Size is everything-large amounts of information are
needed to overcome random effects in estimating direction
and magnitude of treatment effects. Pain 1998; 78: 20916.
23. Straube S, Moore RA, Derry S, Wiffen PJ. Small studies in
meta-analyses. Making the best of a little. BMJ 2010; 24: c4463.
24. Van de Velde M, Teunkens A, Kuypers M, Dewinter T, Vandermeersch E. General anaesthesia with target controlled
infusion of propofol for planned caesarean section: maternal
and neonatal effects of a remifentanil-based technique. Int J
Obstet Anesth 2004; 13: 1538.
Address:
Prof. Dr. Michael Heesen
Department of Anaesthesia
Klinikum Bamberg Buger Str. 80
96049 Bamberg
Germany
Email: michael.heesen@sozialstiftung-bamberg.de