International Journal of Obstetric Anesthesia (2014) xxx, xxx–xxx


0959-289X/$ - see front matter c 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijoa.2014.01.005

ORIGINAL ARTICLE
www.obstetanesthesia.com

The effect of intravenous ondansetron on maternal

haemodynamics during elective caesarean delivery under spinal
anaesthesia: a double-blind, randomised, placebo-controlled
trial
J.R. Ortiz-Gómez,a F.J. Palacio-Abizanda,b F. Morillas-Ramirez,b I. Fornet-Ruiz,c
A. Lorenzo-Jiménez,b M.L. Bermejo-Albaresb
a
Department of Anaesthesiology, Hospital Virgen del Camino, Pamplona, Spain
b
Department of Anaesthesiology, Hospital Gregorio Marañón, Madrid, Spain
c
Department of Anaesthesiology, Hospital Puerta de Hierro, Madrid, Spain

ABSTRACT
Background: Spinal anaesthesia for caesarean delivery is frequently associated with adverse effects such as maternal hypotension
and bradycardia. Prophylactic administration of ondansetron has been reported to provide a protective effect. We studied the
effect of different doses of ondansetron in obstetric patients.
Methods: This prospective double-blind, randomised, placebo-controlled study included 128 healthy pregnant women scheduled
for elective caesarean delivery under spinal anaesthesia. Women were randomly allocated into four groups (n = 32) to receive
either placebo or ondansetron 2, 4 or 8 mg intravenously before induction of spinal anaesthesia. Demographic, obstetric, intraop-
erative timing and anaesthetic variables were assessed at 16 time points. Anaesthetic variables assessed included blood pressure,
heart rate, oxygen saturation, nausea, vomiting, electrocardiographic changes, skin flushing, discomfort or pruritus and vasopres-
sor requirements.
Results: There were no differences in the number of patients with hypotension in the placebo (43.8%) and ondansetron 2 mg
(53.1%), 4 mg (56.3%) and 8 mg (53.1%) groups (P = 0.77), nor the percentage of time points with systolic hypotension (7.3%
in the placebo group and 11.1%, 15.7% and 12.6% in the ondansetron 2, 4 and 8 mg groups, respectively, P = 0.32). There were
no differences between groups in ephedrine (P = 0.11) or phenylephrine (P = 0.89) requirements and the number of patients with
adverse effects.
Conclusions: In our study, prophylactic ondansetron had little effect on the incidence of hypotension in healthy parturients under-
going spinal anaesthesia with bupivacaine and fentanyl for elective caesarean delivery.
c 2014 Elsevier Ltd. All rights reserved.

Keywords: Ondansetron; Spinal anaesthesia; Hypotension; Caesarean delivery

Introduction may be associated with maternal nausea and vomiting

Spinal anaesthesia is the most widely used anaesthetic
technique for caesarean delivery. However, it is fre-
quently associated with adverse effects such as maternal
hypotension and bradycardia. Although there is no sin-
gle definition for hypotension, most authors agree that
hypotension is present when the systolic blood pressure
(SBP) decreases to <90–100 mmHg or when there is a
reduction from baseline of <20–30%.1,2 Hypotension
Accepted January 2014
Correspondence to: J. R. Ortiz-Gómez, Department of Anaesthesiol-
ogy, Hospital Virgen del Camino, Irunlarrea 4, Pamplona, 31008
Navarra, Spain.
E-mail address: j.r.ortiz.gomez.md.phd@gmail.com
and in severe cases unconsciousness, pulmonary aspira-
tion and placental hypoperfusion with fetal hypoxia,
acidosis and neurologic injury.2 The incidence of hypo-
tension after spinal anaesthesia is 33% in non-obstetric
patients3 and approximately twice this rate in the obstet-
ric population.2
Several studies have reported that intravenous
ondansetron (8 mg in the general population4 and
4 mg in obstetric patients5) could attenuate hypotension
in patients receiving spinal anaesthesia. Decreases in
cardiac output and systemic vascular resistance are the
main contributors to hypotension with sympathetic
nerve blockade and the Bezold–Jarisch and reverse

Please cite this article in press as: Ortiz-Gómez JR et al. The effect of intravenous ondansetron on maternal haemodynamics during elective
caesarean delivery under spinal anaesthesia: a double-blind, randomised, placebo-controlled trial. Int J Obstet Anesth (2014), http://
dx.doi.org/10.1016/j.ijoa.2014.01.005
2 Ondansetron and caesarean section
Bainbridge reflexes inducing bradycardia.6 The Bezold–
Jarisch reflex is caused by decreased filling of the right
atrium, which reduces outflow from some intrinsic chro-
notropic stretch mechanoreceptors in the ventricular
wall.7 Serotonin may be an important factor in inducing
this reflex,7–12 as has been described in hypovolaemic
animal models. Therefore, ondansetron may attenuate
arterial hypotension by blocking serotonin-induced bra-
dycardia. Experimental results also suggest that a func-
tional interaction between serotonergic and opioidergic
pathways in the rat brain is part of the complex, multi-
factorial system that regulates blood pressure in the cen-
tral nervous system.13–15 Therefore, both peripheral and
central mechanisms may be involved.
In this study, we evaluated the effect of three different
intravenous ondansetron doses (2, 4 and 8 mg) and pla-
cebo on the haemodynamic response and side effects
following spinal anaesthesia in healthy ASA I pregnant
women undergoing elective caesarean delivery. The pri-
mary outcome, hypotension, was defined as a systolic
blood pressure <75% of baseline.
Methods
This was a prospective double-blind, placebo-con-
trolled, randomised study. After institutional ethical
committee approval, 128 American Society of Anesthe-
siologists class I women scheduled for lower segment
caesarean delivery under spinal anaesthesia were en-
rolled during anaesthesia consultation or early in the
third trimester. Written informed consent was obtained
from all patients to participate in this study. Exclusion
criteria included refusal to participate, contraindication
to spinal anaesthesia, age <20 or >45 years, obesity
(body mass index (BMI) at term >30 kg/m2) and a his-
tory of allergy to or side effects from ondansetron.
Women were fasted for 8 h before surgery. They did
not receive premedication. Peripheral venous access
was secured with an 18-gauge cannula. Ten minutes
after arrival in the operating room, baseline values
for oxygen saturation, electrocardiography and non-
invasive blood pressure were recorded in the supine po-
sition with 15 degrees left tilt. These were considered
the baseline data.
Women were previously randomly allocated by our
Statistical Department into four groups to receive intra-
venous ondansetron (Zofran, GlaxoSmithKline, Parma,
Italy) or placebo. An anaesthesia nurse verified the
allocation and prepared the appropriate dose of ondan-
setron (2, 4 or 8 mg) with 0.9% saline solution to a total
volume of 10 mL or a placebo of 0.9% saline solution
10 mL. The syringes had no identifying markers indicat-
ing group allocation. The nurse injected the contents of
the syringe intravenously over 60 s, 5 min before the
lumbar puncture was performed. The anaesthetist caring
for the woman was blinded to group allocation.
Please cite this article in press as: Ortiz-Gómez JR et al. The effect of intravenous ondansetron on maternal haemodynamics during elective
caesarean delivery under spinal anaesthesia: a double-blind, randomised, placebo-controlled trial. Int J Obstet Anesth (2014), http://
dx.doi.org/10.1016/j.ijoa.2014.01.005
Spinal anaesthesia was induced in the sitting position
at the L3–4 or L4–5 interspace, with a 27-gauge Whit-
acre needle. We administered 0.5% hyperbaric bupiva-
caine, according to the following formula: bupivacaine
(mg) = height (cm) · 0.06, with fentanyl 20 lg. Follow-
ing injection, patients were immediately placed supine
with 15 degrees left tilt. All women were rapidly co-
loaded with hydroxyethyl starch (Voluven, Fresenius
Kabi, Barcelona, Spain) 8 mL/kg.
Sensory block height level was checked by assessing
the perception of coldness using an alcohol swab, and
motor block using the Bromage scale, both at 7 and
15 min after intrathecal injection.
Hypotension was defined as SBP <75% of baseline.1,2
Treatment was initiated with intravenous ephedrine
10 mg or phenylephrine 50 lg if the maternal heart rate
was >95 beats/min, given over 30 s to avoid bradycar-
dia. Intravenous atropine 0.01 mg/kg was administered
if the maternal heart rate was <45 beats/min.
The anaesthetist recorded demographic data (age,
height, body mass index), obstetric data (indication for
caesarean delivery, gestation, number of previous preg-
nancies, caesarean deliveries, uterine pathology), intra-
operative timing (time from dural puncture to skin
incision, time from skin incision to delivery, total time
of the surgery) and anaesthetic variables, (SBP, diastolic
blood pressure (DBP), mean arterial pressure (MAP),
heart rate (HR), oxygen saturation (SaO2)), adverse ef-
fects (nausea, vomiting, electrocardiographic changes,
skin flushing, discomfort, pruritus), need for atropine,
ephedrine or phenylephrine, and the initial and final
haemoglobin values. Anaesthetic variables were re-
corded before administration of the study drug and then
at 2 min intervals for 15 min and 5 min intervals for a
further 30 min after intrathecal injection, as well as at
the end of surgery.
Our protocol allowed the administration of intrave-
nous acetaminophen 1 g and supplementary doses of
fentanyl 50 lg (maximum of three doses) if the patient
felt pain during surgery. General anaesthesia could be
administered if anaesthesia was still inadequate. The
protocol dictated that women requiring supplementa-
tion were removed from the study.
Statistical analysis
Data were analysed using IBM SPSS 21 statistical soft-
ware package (IBM, New York NY, USA). Comparison
of means of independent samples was performed using
ANOVA, followed by Dunnett’s test for post hoc test-
ing, and repeated measures ANOVA was used for
paired data. Association between qualitative variables
was performed using the chi-square test with Fisher’s
exact test where appropriate. Trends were studied with
the chi-square for linear trend test. A P value <0.05
was considered significant. Haemodynamic data (SBP,
DBP, MAP, heart rate and oxygen saturation), were
J.R. Ortiz-Gómez et al. 3

re-plotted using a format where all values were ex-

pressed as the correspondent percentage related to the
baseline value (considered as 100%) to reveal a more dis-
crete pattern of change so that each patient served as her
own control.

Results
A total of 128 women were recruited into the study, 32
in each group (Appendix A). Patient characteristics and
anaesthetic data are presented in Tables 1 and 2. No dif-
ferences between groups were observed in obstetric data
including gestational age, previous pregnancies and cae-
sarean deliveries.
The incidence of maternal hypotension in this study
was 51.6%. There were no differences in the number of Fig. 1 Maternal blood pressure.
patients with hypotension: 14 patients (43.7%) in the
placebo group and 17 (53.1%), 18 (56.2%) and 17 100
(53.1%) patients in ondansetron 2, 4 and 8 mg groups, 90

Systolic Blood Pressure (mmHg)

respectively (P = 0.77). As a single patient could have 80

more than one hypotensive episode, we analysed the 70

60
percentage of time points with systolic hypotension:
50
these were 7.3% in the placebo group and 11.1%, 40
15.6% and 12.6% in the ondansetron 2, 4 and 8 mg 30
groups respectively. These differences were not statisti- 20

cally significant (P = 0.32). 10

0
Arterial pressures (SBP, MAP and DBP) are shown Basal 1 3 5 7 9 11 13 15 20 25 30 35 40 45 End
in Fig. 1. We found differences at 15 min in SBP Time (min)
(108 ± 13.4 mmHg in the placebo group compared with Placebo Ondansetron 2 mg Ondansetron 4 mg Ondansetron 8 mg

117 ± 12.1, 113 ± 13.4 and 113 ± 17.7 mmHg in the

ondansetron 2, 4 and 8 mg groups, respectively,
P = 0.03). There were no differences between groups
in HR and SaO2 values.
Differences between placebo and ondansetron 8 mg
groups were observed (Fig. 2) in the variation of SBP
Fig. 2 Variation in systolic blood pressure compared to
baseline.
from baseline at 9 min (85.2 ± 13.5 vs. 95.1 ± 17.3
mmHg, P = 0.02), 11 min (85.1 ± 10.6 vs. 91.1 ± 16.2

Table 1 Demographic data

Placebo Ondansetron 2 mg Ondansetron 4 mg Ondansetron 8 mg P value
(n = 32) (n = 32) (n = 32) (n = 32)
Age (years) 35 ± 5.6 34.7 ± 4.0 33.9 ± 4.8 35.3 ± 3.8 0.63
Weight (kg) 76.7 ± 12.3 75.5 ± 12.4 74.8 ± 14.4 76.8 ± 10.9 0.89
Height (cm) 162 ± 6.9 161.6 ± 5.6 160.9 ± 6.2 161.7 ± 5.3 0.90
Body mass index (kg/m2) 162 ± 6.9 162 ± 5.6 161 ± 6.2 162 ± 5.3 0.96
Data are mean ± SD.

Table 2 Anaesthetic data

Placebo Ondansetron 2 mg Ondansetron 4 mg Ondansetron 8 mg P value
(n = 32) (n = 32) (n = 32) (n = 32)
Dural puncture to skin incision (min) 9.8 ± 1.9 10.1 ± 2.9 10.8 ± 2.2 10.8 ± 2.1 0.25
Skin incision to fetal extraction (min) 8.9 ± 2.5 7.8 ± 2.8 7.8 ± 1.7 9.0 ± 3.5 0.43
Total time (min) 39.0 ± 7.0 38.1 ± 9.0 39.6 ± 8.1 41.1 ± 5.1 0.83
Sensory block height 15 min after intrathecal injection
T3–4 21 (65.6%) 23 (76.6%) 22 (73.3%) 19 (63.3%) 0.74
T5–6 11 (36.6%) 9 (30.0%) 10 (33.3%) 13 (43.3%)
Data are mean ± SD or number (%).

Please cite this article in press as: Ortiz-Gómez JR et al. The effect of intravenous ondansetron on maternal haemodynamics during elective
caesarean delivery under spinal anaesthesia: a double-blind, randomised, placebo-controlled trial. Int J Obstet Anesth (2014), http://
dx.doi.org/10.1016/j.ijoa.2014.01.005
 4 Ondansetron and caesarean section

100 differences were found between haemoglobin values at

90
the end of surgery (12.2 ± 1.5 g/dL, P = 0.28).
80
Mean Blood Pressure (mmHg)

70
60
50
40
30
20
10
0
Basal 1 3 5 7 9
Placebo Ondansetron 2 mg
Fig. 3 Variation in mean blood pressure compared to
baseline.
mmHg, P = 0.02), 13 min (85.5 ± 10.8 vs. 94.7 ±
15.7 mmHg, P = 0.02) and 35 min (82.7 ± 9.3 vs. 91.5
± 16.1 mmHg, P = 0.03). Differences between placebo
and ondansetron 8 mg groups were observed (Fig. 3) in
the variation of MAP from baseline at 9 min
(83.0 ± 13.7 vs. 91.4 ± 15.7 mmHg, P = 0.04). There
were no differences between groups in the variations
from baseline of DBP, HR and SaO2.
We found no differences between groups in the num-
ber of patients requiring ephedrine (P = 0.11) or phenyl-
ephrine (P = 0.89) (Table 3), or in the median [IQR]
dose requirement (ephedrine 0 [0,5] mg, P = 0.07), or
(phenylephrine 0 [0,0] lg, P = 0.87). There was a
significant dose-dependent trend in ephedrine dosing
with dose of ondansetron (P = 0.02). No atropine
was needed. The lowest value of heart rate was
46 beats/min at 9 min in one patient in the ondansetron
4 mg group.
There were no differences between groups in the
number of patients with adverse effects (Table 4). No
Discussion
We found that prophylactic ondansetron did not influ-
ence the incidence of maternal hypotension following
spinal anaesthesia for elective caesarean delivery. How-
ever, we demonstrated a significant dose-dependent
11 13 15 20 25 30 35 40 45 End trend in ephedrine dosing with dose of ondansetron.
Time (min) As a result we studied the change in arterial pressure
Ondansetron 4 mg Ondansetron 8 mg in three successive steps to estimate the impact of
ondansetron on maternal haemodynamics. First, we
compared SBP, MAP and DBP values between groups,
finding statistically significant but clinically irrelevant
differences in SBP at 15 min. Secondly, we analysed
the variation of SBP from baseline, with significant dif-
ferences between placebo and ondansetron 8 mg groups
of 6 mmHg at 9 and 11 min, and 9 mmHg at 13 and
35 min. Finally, to assess the impact of these results
we also compared the variation of MAP from baseline,
observing that there were only differences with minimal
clinical relevance at 9 min.
The results of this study contrast with those from
Owczuk et al.4 and Sahoo et al.5 Possible reasons in-
clude the specific population, sample size, study design
and anaesthetic technique. Our study, which compared
four groups, had more patients (n = 128) than the other
two studies although the number in each group (n = 32)
was similar. Owczuk4 studied a general surgical popula-
tion while Sahoo5 studied obstetric patients undergoing
caesarean delivery. Our study included three doses of
ondansetron (2, 4, 8 mg vs. placebo) while Owczuk4
compared ondansetron 8 mg (n = 35) with placebo
(n = 36) and Sahoo5 compared ondansetron 4 mg
(n = 24) with placebo (n = 24). We included three differ-
ent doses of ondansetron, as no data were available

Table 3 Requirements of ephedrine and phenylephrine

Placebo Ondansetron 2 mg Ondansetron 4 mg Ondansetron 8 mg P value
(n = 32) (n = 32) (n = 32) (n = 32)
Ephedrine 12 (37.5%) 11 (34.3%) 6 (18.7%) 5 (15.6%) 0.11
Phenylephrine 1 (3.1%) 2 (15.6%) 1 (3.1%) 1 (3.1%) 0.89
Data are number (%). Significant dose-dependent trend in ephedrine dosing with dose of ondansetron (P = 0.02).

Table 4 Adverse effects

Placebo Ondansetron 2 mg Ondansetron 4 mg Ondansetron 8 mg P value
(n = 32) (n = 32) (n = 32) (n = 32)
Electrocardiogram changes 0 0 0 0 1
Nausea 7 (21.8%) 5 (15.6%) 6 (18.7%) 2 (6.2%) 0.34
Vomiting 1 (3.1%) 0 3 (9.3%) 1 (3.1%) 0.27
Pruritus 1 (3.1%) 1 (3.1%) 1 (3.1%) 1 (3.1%) 1
Skin flushing 4 (12.5%) 7 (21.8%) 2 (6.2%) 3 (9.3%) 0.26
Discomfort 6 (18.7%) 5 (15.6%) 3 (9.3%) 1 (3.1%) 0.22
Data are number (%).

Please cite this article in press as: Ortiz-Gómez JR et al. The effect of intravenous ondansetron on maternal haemodynamics during elective
caesarean delivery under spinal anaesthesia: a double-blind, randomised, placebo-controlled trial. Int J Obstet Anesth (2014), http://
dx.doi.org/10.1016/j.ijoa.2014.01.005
J.R. Ortiz-Gómez et al.
regarding the minimum effective dose that would atten-
uate hypotension without side effects.
We consider anaesthetic technique the most impor-
tant factor that might account for the difference between
the studies. Each of the three studies used a different
dose of hyperbaric bupivacaine: Owczuk4 used 20 mg;
Sahoo5 used 10 mg and we personalised each dose
resulting in a mean dose of 9.7 ± 0.4 mg in the placebo
group and 9.6 ± 0.3 mg in each of the ondansetron
groups. The mean doses are slightly smaller than the
10 mg used by Sahoo5 but individualising each dose
may avoid over- or under-dosing in women at the upper
or lower extremes of height.
Our methodology differed from that of the other two
studies on the administration of intrathecal fentanyl
20 lg. This makes a direct comparison with the findings
of Sahoo5 difficult as the mechanism of action of ondan-
setron may be central and therefore affected by intrathe-
cal opioids. We included intrathecal fentanyl because an
overall goal of this study was to improve the anaesthetic
management of women undergoing caesarean delivery.
Despite achieving a T4 block with spinal anaesthesia,
some women experience visceral discomfort, particularly
if the uterus is exteriorised. Intrathecal fentanyl has been
reported to improve the quality of spinal anaesthesia,16
with a dose of 10–25 lg used commonly.17,18 In a study
of healthy parturients, intrathecal fentanyl 20 lg was
superior to intravenous ondansetron 4 mg for preven-
tion of perioperative nausea, but not vomiting, during
spinal anaesthesia for caesarean delivery. The investiga-
tors attributed these findings to a possible reduction in
visceral stimulation.19
Differences in the design of the three studies should
be noted. The first is the definition of hypotension.
Owczuk4 did not supply a definition while Sahoo5 used
a SBP <90 mmHg or DBP <60 mmHg. We used the cri-
teria outlined in the Cochrane Review of hypotension in
obstetrics.2 Another difference is that Sahoo5 adminis-
tered intravenous fentanyl if the patient felt pain and
tramadol or promethazine to treat adverse effects. These
medications could modify blood pressure either directly
or indirectly, possibly through a central mechanism. We
did not use other supplemental analgesia and if required,
those women were to be eliminated from the study. Fi-
nally, we used low doses of oxytocin (1 U) after umbili-
cal cord clamping, followed by an infusion of 2.5 U/h,
to avoid side effects which could affect haemodynam-
ics.20 Sahoo did not report the dose of oxytocin.5
Maayan-Metzger et al.21 reported that nearly one-
half of mothers had a 30% or greater decrease in their
mean arterial pressure during neuraxial anaesthesia for
caesarean delivery. This hypotension is well tolerated
by healthy women with term infants.21 However, in wo-
men with comorbidities or at-risk fetuses, hypotension
may prove detrimental. Ondansetron is widely used in
the prophylaxis and treatment of postoperative nausea
Please cite this article in press as: Ortiz-Gómez JR et al. The effect of intravenous ondansetron on maternal haemodynamics during elective
caesarean delivery under spinal anaesthesia: a double-blind, randomised, placebo-controlled trial. Int J Obstet Anesth (2014), http://
dx.doi.org/10.1016/j.ijoa.2014.01.005
5
and vomiting. The main adverse effects are diarrhoea
(16%), fever (8%) and headache (17%), although more
important adverse effects have been reported such as
electrocardiographic changes, proarrhythmic activity,
coronary vasospasm and acute myocardial ischae-
mia.22–26 Thus, it is important to compare the risk-ben-
efit balance between a possible improvement in the
incidence of hypotension versus the potential side
effects. It should be highlighted that the incidence of
adverse effects in the study could be influenced by one
patient if she reported an adverse effect that lasted for
several minutes: for example, the incidence of pruritus
(2.5%) resulted from only four patients (one patient in
each group who reported pruritus at between nine and
13 time points). The same also applied to skin flushing
or discomfort.
In conclusion, our study showed that prophylactic
ondansetron had very little, if any, effect on the inci-
dence of hypotension in healthy parturients undergoing
spinal anaesthesia with bupivacaine and fentanyl for
elective caesarean delivery. Since these results differ
from those reported by other studies, we believe that
further research is needed.
Disclosure
The authors received no external funding for this study
and have no conflicts of interest to declare.
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Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/
10.1016/j.ijoa.2014.01.005.