Pregnancy Hypertension: An International Journal of Womens Cardiovascular Health 2 (2012) 139142

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Pregnancy Hypertension: An International

Journal of Womens Cardiovascular Health
journal homepage: www.elsevier.com/locate/preghy

Original Article

The maternal cardiovascular effect of carbetocin compared to oxytocin

in women undergoing caesarean section
I. Pisani a,, G.M. Tiralongo a, G. Gagliardi a, R.L. Scala a, C. Todde b, M.G. Frigo b, H. Valensise a
a
b

Department of Obstetrics and Gynecology, University of Tor Vergata, Rome, Italy

UOS Anesthesia and Reanimation in Obstetrics and Gynecology, Fatebenefratelli San Giovanni Calibita Hospital, Rome, Italy

a r t i c l e

i n f o

Article history:
Received 24 October 2011
Received in revised form 24 December 2011
Accepted 17 January 2012
Available online 31 January 2012
Keywords:
Carbetocin
Cardiovascular effect
Oxytocin
Post partum haemorrhage
Preeclampsia

a b s t r a c t
Objective: To compare haemodynamic changes, measured noninvasively using the USCOM
monitor, after combined spino-epidural anaesthesia and after administration of two different uterotonic drugs, oxytocin and carbetocin, in a population of pregnant women during
elective caesarean delivery.
Methods: Haemodynamic measurements were obtained with the USCOM system, by positioning a probe at maternal suprasternal notch (SSN) until the aortic valve ows prole
was optimally identied. Evaluations of the haemodynamic prole were obtained in seven
different moments: before anaesthesia; during skin incision; 60, 180 and 300 s after
administration of uterotonic drug, at closure of the uterus, at closure of the skin. Doses
of uterotonic drugs were: Oxytocin 5 UI in 500 cc NaCl eV, Carbetocin 100 mcg in bolus
eV. Main measured parameters were: heart rate, mean blood pressure, stroke volume,
cardiac output and total vascular resistance.
Results: We enrolled 32 pregnant women. Patients were randomized in two groups: oxytocin and carbetocin. A reduction in mean blood pressure, a reduction of total vascular
resistance and an increase of cardiac output and of stroke volume were seen, while heart
rate values remained stable in both treatment groups. No statistically signicant differences were found.
Discussion: Administration of carbetocin is associated with a substantial global haemodynamic stability in patients undergoing elective caesarean section without any difference
with oxytocin. This observation allows us to consider carbetocin comparable to oxytocin,
with minimum haemodynamic impact on the maternal circulation. This minimal effect
on global haemodynamic stability might extend the use of this uterotonic drug in patients
at high haemorrhagic risk with preeclampsia.
2012 International Society for the Study of Hypertension in Pregnancy. Published by
Elsevier B.V. All rights reserved.

Introduction
The prevalence of postpartum haemorrhage (PPH) is
about 6% of all deliveries [1] and represents an important
cause of maternal morbidity and mortality worldwide
[26], particularly after caesarean section [7]. One of the

Corresponding author. Tel.: +39 3204674575.

E-mail address: ilaria_pisani@hotmail.it (I. Pisani).

main causes of PPH is represented by uterine atony [4,5].

The prophylactic use of uterotonic agents to enhance uterine contraction is the most common strategy to prevent
PPH [1,46]. Oxytocin is the most widely used uterotonic
drug [1,57] in a dose of 5 IU, but with a short half-life of
about 7 min [9,11]. In fact it must be used in a continuous
intravenous infusion to sustain uterotonic contraction.
Recent interest has focused on carbetocin, a synthetic
long-acting analogue of oxytocin, with an increased
half-life, 410 times longer than reported for oxytocin,

2210-7789/$ - see front matter 2012 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.preghy.2012.01.002

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I. Pisani et al. / Pregnancy Hypertension: An International Journal of Womens Cardiovascular Health 2 (2012) 139142

and a rapid onset of the activity. In the clinical practice carbetocin can be administered as a single-dose injection,
intravenously or intramuscularly in an optimal dose of
100 mcg [8]. Currently preeclampsia is still a contraindication to the administration of carbetocin. In fact even if its
effectiveness on uterine contraction is widely present in
literature, data about its cardiovascular effects are still
limited. Nevertheless available studies are encouraging to
suggest that carbetocin might become useful for the prevention of postpartum haemorrhage even in preeclamptic
pregnant women [9]. We investigated the haemodynamic
effects of carbetocin and oxytocin, during elective caesarean section, in patients at high haemorrhagic risk, to
evaluate the cardiovascular impact of both drugs.

Materials and methods

We conducted a randomized clinical trial. The study
took place at the San Giovanni Calibita Fatebenefratelli
Hospital, Department of Obstetrics and Gynaecology in
Rome. The study protocol was approved by the ethic committee and signed informed consent was obtained from all
women. We enrolled 32 consecutive women undergoing
elective caesarean section with at least one haemorrhagic
risk factor. The inclusion criteria were: twin pregnancy,
placenta praevia, two or more previous caesarean sections,
previous uterine atony or uterine rupture, multiple myomas, large for gestational age fetuses. The exclusion criteria
were: patient refusal, urgency caesarean section, maternal
internistic diseases, foetal diseases. We randomly divided
the patients in two groups: group A received oxytocin,
group B received carbetocin during caesarean section.
The randomisation criteria were the day of the week in
which the caesarean section was performed. Carbetocin
and oxytocin were administered by the anaesthetist after
the delivery of the baby as intravenous bolus (100 lg)
and as intravenous infusion (5 UI in 500 ml 0.9% NaCl solution), respectively. Monitoring and anaesthetic techniques
followed the same protocol. For a uid preload, 500 ml
Ringers solution was administered. The combined spinoepidural anaesthesia was performed according to the usual
protocol of the Department, using 10 mg ropivacain and
3 lg of sufentanyl. After application the anaesthesia
women were positioned in a left-tilted recumbent position
to minimize aorto-caval compression. Block height was
assessed using cold sensitivity to 70% ethanol solution.
We obtained all haemodynamic measurements with the
USCOM system, a noninvasive method [12]. USCOM calculates the cardiac output by continuous wave Doppler ultrasound using a probe at the level of patients suprasternal
notch. This method is based on the assumption that the
outow tract diameter correlates linearly with height;
through patients height, cardiac output and derived haemodynamic parameters are calculated. The accuracy of
the system has been proven through numerous studies in
laboratory, compared with other methods and in various
clinical applications. Only two trained operators were
responsible for taking measurements. USCOM comparisons
with ow probes in computer controlled ow simulator
demonstrated a variation of less than 5% and, as shown

in a previous study [13], the mean difference between

observers was 0.16 0.59 l/min/m, and Lins concordance
correlation coefcient was 0.87. Haemodynamic measurements included recordings of heart rate (HR), mean blood
pressure (MBP), cardiac output (CO), stroke volume (SV)
and total vascular resistance (TVR). Haemodynamic
parameters were obtained at seven main time points: before anaesthesia in a left-tilted recumbent position, at the
incision of the skin, 60, 180, 300 s after the administration
of the uterotonic drugs, at the closure of the uterus and at
skins closures.
We hypothesized that both drugs have the same haemodynamic prole after administration and considering
the prevalence of PPH we calculated that we would need
30 women (15 for each group) to detect signicant differences with a power of 95%.
All analyses were performed using the statistical software program SPSS 13. Demographic and clinical data
were compared by means of independent samples Students t-test. Differences were considered as signicant
with p < 0.05.
Results
The study was conducted over a continuous six month
period, from November 2010 to April 2011. In total 32 women were selected, divided in two groups (A, B) of 15 patients each. Two patients, one for each group, were
excluded for a bad signal obtained with the USCOM. The
remaining patients were analysed in the study. All important maternal characteristics of both groups are compared
in Table 1. The absolute values of the haemodynamic measures are shown in Table 2, expressed as mean SD. No
signicant differences were found between two groups.
Figs. 15 show haemodynamic parameters progress
during caesarean section.
A decrease in mean blood pressure was found during all
measurements with a peak during the incision of the skin
in both groups (Fig. 1). No statistically signicant differences were found for all the evaluations between the two
groups. A reduction in TVR was seen during all the measurements with a peak 60 s after the administration of
the uterotonic drug in both groups (Fig. 2). No statistically
signicant differences were found for all the evaluations

Table 1
Characteristics of study population (EGA: effective gestational age, BMI:
body mass index, BSA: body surface area).

No. patients
Age
Parity
EGA
BMI
BSA
Multiple pregnancy
Placenta Previa
2 previous CS
LGA
Multiple myomas
a

Students t-test.

Group A

Group B

Comparisona

15
39 4
2
37 2
26 3
1.8 0.1
6
3
4
1
1

15
39 3
3
36 1
26 3
1.9 0.3
5
3
5
1
1

p:ns
p:ns
p:ns
p:ns
p:ns
p:ns
p:ns
p:ns
p:ns
p:ns
p:ns

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I. Pisani et al. / Pregnancy Hypertension: An International Journal of Womens Cardiovascular Health 2 (2012) 139142
Table 2
Results of hemodynamic measures expressed as mean SD.

Syntocinon
Carbetocin
p

Syntocinon
Carbetocin
p

Syntocinon
Carbetocin
p

Syntocinon
Carbetocin
p

Syntocinon
Carbetocin
p

CO1

CO2

CO3

CO4

CO5

CO6

CO7

8.8 1.8
7.91 1.4
ns (0.44)

7.96 2
7.7 2.5
ns (0.42)

9.68 1.9
10.1 2.4
ns (0.40)

9.34 1.7
9.67 1.7
ns (0.40)

9.99 2.3
9.69 1.6
ns (0.42)

9.93 2.3
9.8 1.7
ns (0.42)

9.81 2.2
9.16 1.8
ns (0.43)

RVS1

RVS2

RVS3

RVS4

RVS5

RVS6

RVS7

924.59 1.8
1016.03 249
ns (0.40)

879.11 2
788.45 158.5
ns (0.44)

747.03 1.9
618.07 175.9
ns (0.47)

740.75 1.7
634.14 147.8
ns (0.45)

692.97 2.3
621.55 132.2
ns (0.44)

681.15 2.3
612.26 129.8
ns (0.44)

682.9 2.2
698.77 145
ns (0.40)

SV1

SV2

SV3

SV4

SV5

SV6

SV7

101.4 29.3
96.75 19.1
ns (0.42)

108.ll 37.l
91.99 31.6
ns (0.46)

115.52 24.4
110.9 22.6
ns (0.42)

112.59 27.7
112.36 14
ns (0.41)

116.46 28.5
110.01 16.6
ns (0.43)

115.21 26.2
111.64 16.7
ns (0.42)

115.58 28.3
110.39 15.2
ns (0.42)

HR1

HR2

HR3

HR4

HR5

HR6

HR7

90.02 19.7
89.33 15
ns (0.44)

76.03 10.9
86.37 17.3
ns (0.38)

84.58 11
86.87 7.7
ns (0.39)

84.48 12.1
86.37 4
ns (0.41)

86.54 10.9
85.62 3.4
ns (0.41)

86.43 7.7
85.62 7
ns (0.41)

85.56 9
80.84 11.8
ns (0.42)

MBP1

MBP2

MBP3

MBP4

MBP5

MBP6

MBP7

94.97 16.5
96.19 12.5
ns (0.42)

82.5 13.4
71.19 13.7
ns (0.45)

85.77 14.1
77.68 19.9
ns (0.44)

83.73 12.5
73.9 8.6
ns (0.45)

82.2 12.1
72.81 8.1
ns (0.44)

81.33 12.6
72.62 8.8
ns (0.44)

80.47 11.9
77.05 8.3
ns (0.42)

Fig. 1. Mean blood pressure decreases after the anaesthesia with a peak
during skins incision in both groups.

Fig. 3. An increase of cardiac output was seen after uterotonic drug in

both groups.

Fig. 2. The reduction of TVR after administration of uterotonic drugs in

both groups.

Fig. 4. An increase of stroke volume was seen after uterotonic drug in

both groups.

between the two groups. An increase of cardiac output was

seen 60 s after the administration of uterotonic drug in
both groups and values remain stable at this level all along

the evaluation (Fig. 3). No statistically signicant

differences were found between the two groups. An
increase of the stroke volume was found 60 s after the

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Fig. 5. The stability in the heart rate in both groups.

administration of the uterotonic drug in both groups and

the values remain stable at this level all along the measurements (Fig. 4). No statistically signicant differences were
found between the two groups. As regard the heart rate,
we found stability all along the measurements (Fig. 5).
The difference of 6 bpm between the two groups, in second
measurement is not statistically signicant.
Discussion
This randomized trial was designed to compare the effect of carbetocin and oxytocin on maternal haemodynamic parameters through the USCOM (UltraSound
Cardiac Output Monitor) system, a noninvasive device, in
patients with high haemorrhagic risk undergoing elective
caesarean section. The USCOM method was validated
across an extremely broad range of patients and clinical
conditions. The PPH is one of the most important causes
of maternal morbidity and mortality worldwide [26],
and its prevalence was signicantly reduced thanks to
the use of uterotonic drugs. In particular, oxytocin is the
most recommended drug in clinical practice [10,11]. Carbetocin, a synthetic derivate of the oxytocin with structural modications, is reported to improve in a single
dose the uterine contraction, with cardiovascular side effects comparable to the oxytocin.
Results of our clinical trial show in both groups of patients, treated with oxytocin and carbetocin, a reduction
of total vascular resistance, an increase of cardiac output
and an increase of stroke volume. These changes are associated with a global haemodynamic stability, dened as
the absence of clinically signicant hypotension, with a
change in the blood pressure < 30% and no requiring vasopressor therapy. The haemodynamic prole of both groups
did not show signicant differences according to the drug
used. In conclusion, our observations allow us to consider

the use of carbetocin comparable to the oxytocin, with

high therapeutic potential and minimum haemodynamic
impact in patient with the condition of haemorrhagic risk
undergoing caesarean section.
This minimal effect on global haemodynamic stability
might extend the use of this uterotonic drug in patients
with haemorrhagic risk factors as those included in the
study and, at the same time, with preeclampsia or hypertensive disorder, which are actually a contraindication to
the administration of the carbetocin. We believe that the
experience reported might be helpful in the future to extend the indication to pregnancies with preeclampsia that
show a multifactorial etiopathogenesis in PPH. However,
further studies would be needed to conrm these results
in a population of women with hypertensive disorder in
pregnancy. Nevertheless, in these patients, evaluations of
total vascular resistance and cardiac output would be recommended in order to identify the haemodynamic prole
before the administration of carbetocin.
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