Clinical and Experimental Pharmacology and Physiology (2008) 35, 580585

doi: 10.1111/j.1440-1681.2007.04838.x

Original
Articles
Blackwell
Publishing
SM
Nitroglycerine
Verstegui
et
vs nifedipine
al. Asia in pre-eclampsia

EFFICACY OF NITROGLYCERINE INFUSION VERSUS SUBLINGUAL

NIFEDIPINE IN SEVERE PRE-ECLAMPSIA: A RANDOMIZED,
TRIPLE-BLIND, CONTROLLED TRIAL
S Manzur-Verstegui,* PB Mandeville, A Gordillo-Moscoso,* JF Hernndez-Sierra and
M Rodrguez-Martnez
*General Hospital No. 1, Mexican Social Security Institute, Department of Clinical Epidemiology and Department of
Physiology and Pharmacology, Faculty of Medicine, Autonomous University of San Luis Potos,
San Luis Potos, Mxico

SUMMARY
1. Information regarding the use of continuous i.v. administration of nitroglycerine as an antihypertensive agent in the
management of pre-eclampsia is scarce. In the present study, i.v.
nitroglycerine or sublingual nifedipine were administered to 32
women with severe pre-eclampsia who were being managed with
controlled plasma volume expansion and MgSO4 loading and
maintenance doses. Maternal blood pressure and heart rate
responses, fetal heart rate responses and perinatal fetal
maternal adverse effects were evaluated using classical parametric and non-parametric data analysis and data modelling by
mixed models.
2. An important hypotensive response was observed in both
groups, although this reponse was greater, faster and exhibited
less variability (more precision) in the nitroglycerine-treated
group. Heart rate also increased in both the nitroglycerine- and
nifedipine-treated groups (4.6 4.4 vs 8.6 5.3 b.p.m., respectively), although the increase in the nifedipine-treated group was
almost twofold that in the nitroglycerine-treated group. There
were no significant changes in fetal heart rate in response to
vasodilator therapy. The frequency of perinatal fetalmaternal
adverse effects was similar in both groups at 40% and the
adverse effects observed included flushing, headache, palpitations
and nausea.
3. In conclusion, i.v. infusion of nitroglycerine is an effective,
safe and alternative therapy for severe pre-eclampsia.
Key words: antihypertensive therapy, nifedipine, nitroglycerine,
severe pre-eclampsia.

INTRODUCTION
Pre-eclampsia is a multisystem disorder of vascular endothelial
function related to pregnancy that is characterized by persistent
Correspondence: Manuel Rodrguez-Martnez, Department of Physiology
and Pharmacology, Faculty of Medicine, Universidad Autnoma de San Luis
Potos, PO Box 1521-B, 78210 San Luis Potos, SLP Mxico. Email:
rodrigum@uaslp.mx
Received 14 May 2007; revision 12 August 2007; accepted 23 September
2007.
2007 The Authors
Journal compilation 2007 Blackwell Publishing Asia Pty Ltd

hypertension after the 20th gestational week and is usually associated

with proteinuria and oedema. Pre-eclampsia complicates 28% of
all pregnancies and is a significant cause of fetal and maternal morbidity
and mortality.1 It is considered a hypertensive urgency, the adequate
management of which can hinder progression to eclampsia, a hypertensive emergency where acute target organ damage already exists.2
When a patient is diagnosed with severe pre-eclampsia, two
important management goals must be pursued: (i) blood pressure
control; and (ii) the prevention of eclampsia.3 The placebo-controlled
Magpie trial confirmed the effectiveness of MgSO4 in the prevention
of eclampsia,4 although MgSO4 also has a small antihypertensive
effect.5 Alternatively, nifedipine, a dihydropyridine calcium channel
blocker with arterial vasodilator action that does not have adverse
fetal effects,6 is one of the recommended agents for the treatment
of hypertension in pregnancy.7,8
Three case reports have described the potential risk of sudden
maternal hypotension following the combined use of MgSO4 and
short-acting oral nifedipine as an antihypertensive (1020 mg) or as
a tocolytic (60 mg).911 Others have advised against the sublingual
use of nifedipine alone because of the potential for precipitous
maternal hypotension.3,12 Despite this, a recent retrospective study
has indicated that concomitant use of short-acting oral nifedipine
and MgSO4 does not seem to increase the risk of serious magnesiumrelated hypotensive effects.5 Moreover, it has been proposed that this
risk could be minimized by concurrent plasma volume expansion,
because pre-eclampsia is a volume-contracted state compared with
normal pregnancy.13
In contrast, nitroglycerine, a nitric oxide (NO) donor with low oral
bioavailability and a very short half-life, has potent venodilator
actions in low doses and affects arterial tone at high doses. Owing
to its effective tocolytic action, nitroglycerine has been used in
different obstetric emergency procedures15 and as a uterine relaxant
during fetal surgery.15 Nitroglycerine also has a low level of toxicity
and its most commonly reported adverse effect is headache. Even
so, information regarding the use of continuous i.v. administration
of nitroglycerine as an antihypertensive agent in the management of
pre-eclampsia is scarce.16,17
The present study hypothesized that, in women with severe
pre-eclampsia who are being managed with controlled extracellular
volume expansion and MgSO4 loading and maintenance doses, those
who received a continuous infusion of i.v. nitroglycerine would have
a faster and more precise reduction in their blood pressure levels than
those who received sublingual nifedipine and that this could be

581

Nitroglycerine vs nifedipine in pre-eclampsia

achieved with a fetalmaternal safety margin that was similar
between the two groups.

METHODS
A triple-blind, randomized, controlled clinical study was registered (Mexican
Social Security Institute (IMSS): 2003-474-05) and performed from March
2004 until March 2005 at the General Hospital No. 1, IMSS (San Luis Potos,
SLP Mxico) following CONSORT recommendations.18 The Hospital Ethics
Committee, in full accordance with International Ethical Guidelines for
Biomedical Research Involving Human Subjects (CIOMS/WHO), approved
the study. All women (1540 years of age) who presented with a pregnancy
of greater than 24 weeks, with or without labour and with singleton or
multiple fetuses, were evaluated obstetrically.
When the principal investigator (SMV) diagnosed patients with uncomplicated severe pre-eclampsia (without imminence of eclampsia or clinical
manifestations of target organ damage, as per the ACOG criteria19) and found
no history of chronic hypertension, antihypertensive therapy or life-threatening
fetal heart beat changes, as determined by cardiotachographic monitoring
(Corometrics Medical Systems, Walling Ford, CN, USA), the women were
invited to participate in the study. They were then informed about the nature,
scope and risks of the study and only those who gave written consent to
participate were included.
Selected women were hospitalized and routine blood and urine chemistry
tests were performed. With women in a seated position, blood pressure
and heart rate were measured using a fitted arm cuff (arm circumference
< 30 cm = regular cuff size; arm circumference > 30 cm = large cuff size)
and an automatic self-calibration monitor (Multiparameter Patient Monitor,
MEC 509 B; Mindray, Shenzhen, China), which had been validated previously
over the range 0300 mmHg against a mercury manometer and provided the
measurements of blood pressure (including mean) and heart rate. These
parameters, along with fetal heart rate, were recorded on a data-collection
sheet until the end of the trial.
An i.v. infusion of Ringers lactate solution was initiated (8 mL/kg per h)
in order to induce a small (< 1% of bodyweight) but controlled extracellular
volume expansion. One hour later, the infusion rate was reduced to 1 mL/kg
per h and a loading dose (4 g /250 mL D5W ) of MgSO4 (10%; Pisa, Guadalajara,
Mxico) was i.v. administered over 30 min. This loading dose was followed
by an i.v. infusion of 1 g/h MgSO4 (10 g /1000 mL D5W per 100 mL per h)
for up to 8 h post-partum. Subjects were monitored for recognized signs of
MgSO4 toxicity every 30 min after the loading dose and until the trial
finished. Women were excluded from the study if, during the MgSO4 loading
dose, they showed: (i) a decrease in systolic, diastolic or mean arterial
pressure > 10 mmHg; or (ii) any another sign of MgSO4 toxicity (i.e. sedation,
hypoventilation and hyporeflexia).
Thirty-two women were randomly assigned to either of the two treatment
groups: nitroglycerine or nifedipine. A statistician (PBM) generated the
balanced blocked randomization sequence (4 8) using the R V 2.01
program (http://www.R-project.org). The group to which each woman was
allocated was inscribed in opaque, sealed and progressively numbered
envelopes. An external collaborator assisted by opening the envelopes as each
women entered the study sequentially, preparing the appropriate active
substances and placebos and supplying, in a carefully blinded mode, the i.v.
and sublingual preparations (active and placebo) to the principal investigator
and external auxiliary nurse, respectively, who then administered the
preparations to the patients. The auxiliary nurses instructed women not to
swallow voluntarily for 20 min by asking them to keep their mouths open
and to refrain from discussing taste perceptions, if any.
In the nitroglycerine group, 5 mg/min nitroglycerine (25 mL/min) was
administered by continuous i.v. infusion with increases in dose of 5 mg/min
(25 mL/min) every 5 min until the therapeutic goal was reached, which was
a decrease in systolic blood pressure (SBP) to < 140 mmHg but not < 120 mmHg
and a decrease in diastolic blood pressure (DBP) to < 100 mmHg but not
< 80 mmHg within the first hour of treatment. The nitroglycerine (USP;
American Regent Laboratories, Shirley, NY, USA), was prepared by diluting
the 50 mg/10 mL ampoule in 240 mL D5W and was administered using
a Flow Gard 6201 single-channel pump (Baxter, Derrfield, IL, USA) and

a Lifeshield latex-free infusion set (Abbott, North Chicago, IL, USA). Simultaneously, a sublingual placebo preparation (100 mL normal saline) was
administered every 30 min. In the nifedipine group, the content (100 mL) of
a 10 mg capsule of nifedipine (Adalat; Bayer, Distrito Federal, Mexico, DF)
was drawn up into an insulin syringe and deposited sublingually, every
30 min as required. Simultaneously, a placebo i.v. infusion (D5W) was
administered (25 mL/min), with increases of 25 mL/min every 5 min until
the therapeutic goal had been reached. All the study participants, including
subjects, the principal investigator, the auxiliary nurses and the data analysts,
were blinded to the group allocations and the agents administered during
the trial.
Once the vasodilator therapy was initiated, maternal blood pressure and
maternal and fetal heart rates were measured every 5 min throughout the
following hour. If the therapeutic goal could not be reached in that time, the
trial was suspended and considered a treatment failure, in which case i.v.
hydralazine (hydralazine HCl; Americam Regent Laboratories) was used.20
Previously, a pilot study had been undertaken (by SMV and AGM) to
standardize blood pressure and heart rate measurements with the automatic
self-calibration monitor described above. In that preliminary study, two
measurements (0 and 10 min) were performed in 20 healthy pregnant
volunteers who had maintained a resting sitting position for 10 min. Calculated
blood pressure intraclass correlation coefficients (ICC) for intra- and
interobserver agreements21 were 0.96 and 1.0, respectively. The sample size
was calculated using blood pressure data from the pilot study and the equation
described by Diggle et al.:22
m = (2(za + zQ)2 s2 (1 r))/(n s2x d2)
where a is the probability of Type I error (= 0.05), d is the smallest clinical
diference that it is important to detect (5 mmHg), Q is the probability
type II error (= 1 power = 1 0.8 = 0.2), s2 is the non-explained variation
(20.53 mmHg), n = 13 measurements/patient, r is the serial correlation
coefficient (= 0.5194) and s2x is the variation within the xj (= 0.0972) for
m = 16 subjects per group.
Primary outcomes were the time-course of maternal blood pressure,
maternal heart rate and fetal heart rate. Secondary outcomes were the
perinatal variables, maternal adverse effects caused by vasodilator therapy
and mean arterial pressure (MAP) responses to 30 min MgSO4 loading dose
administration according to the final group allocations.

Statistical analysis
Statistical analysis was based on two randomly allocated groups (an intentionto-treat analysis), to a 95% confidence interval (CI) and using the R V 2.01
statistical program (http://www.R-project.org). All values reported are the
meanSD or proportions as percentages. Classical statistical tests were used
for two independent samples and paired samples after testing for normality
(ShapiroWilk) and homoscedasticity (Brown Forsythe).23 Classical statistical
tests were used for nominal and ordinal data.23 To identify important
explanatory variables of the response variables, the data from the 32 women
were assessed with mixed models24 and recalculated with linear models in
order to obtain r2 (group explained variation) and h2 (individually explained
variation), because such results are impossible to obtain from mixed models.

RESULTS
Figure 1 shows the flow of participants through each stage of the
trial. Baseline characteristics were comparable between the two
groups (Table 1). The effects of the MgSO4 loading dose were
analysed retrospectively according to the final group allocations.
Women finally allocated to the nitroglycerine group had a significantly
greater reduction in MAP (D) after the MgSO4 loading dose than
those who were finally allocated to the nifedipine group, although
absolute MAP values in both groups after the treatment were similar
(Table 2). The modelling of DMAP indicated that 15% of this variation

2007 The Authors

Journal compilation 2007 Blackwell Publishing Asia Pty Ltd

582

S Manzur-Verstegui et al.
Table 2 Retrospective analysis of mean arterial pressure before and 30 min
after MgSO4 loading dose, according to final allocation of women into the
two groups

Before
After
P value
(before vs after)
DMAP
(before after)

Nitroglycerine-treated
group (n = 16)

Nifedipine-treated
group (n = 16)

P value

131 3
125 4
< 0.0001

130 3
127 4
< 0.0001

0.618
0.252

5.8 2.0 (4.76.8)

3.7 2.3 (2.44.9)

0.009

Values are meanSD. For the difference in mean arterial pressure (DMAP)
values in parentheses indicate 95% confidence intervals.

Students t-test; paired t-test.

Table 3 Mean arterial pressure at 0 min and 60 min and changes in mean
arterial pressure over the 60 min in both groups

Fig. 1 Trial flow diagram showing the number of subjects actively followed
up at each trial step.

Table 1 Baseline characteristics of subjects according to treatment allocation

Nitroglycerine-treated
group (n = 16)
Age (years)
Weight (kg)
No. pregnancies
Gestation at entry
(weeks)
SBP (mmHg)
DBP (mmHg)
Pulse pressure
(mmHg)
MAP (mmHg)
Proteinuria
2+
3+
4+
In labour

Nifedipine-treated
group (n = 16)

P value

30.4 7.5
79.6 6.2
2.7 1.7
36.9 1.6

29.6 6.7
83.5 6.5
2.3 0.9
37.1 2.8

0.749
0.095
0.612
0.757

167 6
114 3
52 5

168 7
112 2
56 6

0.250
0.910
0.356

131 3

130 3

0.376
0.072

5 (31%)
11 (69%)
0 (0%)
6 (37.5%)

1 (6.25%)
14 (87.5%)
1 (6.25%)
5 (31%)

MAP (mmHg)
0 min
60 min
P value
(0 vs 60 min)
DMAP
(060 min)

Nitroglycerine-treated
group (n = 16)

Nifedipine-treated
group (n = 16)

P value

125 4
96 3
7.8e14

127 4
103 4
1.4e10

0.252
5.0e05

29 5 (26.531.3)

24 6 (21.027.4)

0.043

Values are meanSD. For the difference in mean arterial pressure (DMAP)
values in parentheses indicate 95% confidence intervals.

Students t-test; paired t-test.

treated group. Women finally allocated to the nitroglycerine and

nifedipine treatment groups showed a similar drop in SBP (from
167 6 to 159 7 mmHg (DMAP = 6.8 3.0 mmHg) and from
168 7 to 163 7 mmHg (DMAP = 5.6 2.5 mmHg), respectively)
after the MgSO4 loading dose, whereas DBP showed a significantly
(P = 0.0085, Students t-test) greater fall in women finally allocated
to the nitroglycerine treatment group (from 114 3 to 108 3 mmHg;
DMAP = 5.5 2.0 mmHg) than those finally allocated to the
nifedipine treatment group (from 112 2 to 109 4 mmHg;
DMAP = 2.8 3.1 mmHg).

1.000

Values are meanSD or the number of subjects with percentages given in

parentheses.

Students t-test; MannWhitney U-test; Fishers exact test.

Proteinuria was determined by reactive strips (Orbi-Test Combi 11;
Macame y Compaia, Distrito Federal, Mxico).
SBP, DBP, systolic and diasolic blood pressure, respectively; MAP, mean
arterial pressure.

could be negatively explained (b = 0.142) by bodyweight

(P = 0.0266). In this sense, it is important to note that subjects in
the nitroglycerine-treated group (P = 0.0946) tended to weigh
approximately 4 kg less (Table 1) than subjects in the nifedipine-

Primary outcomes
Within the nitroglycerine-treated group, 44% of patients received
5 mg/min, 44% received 10 mg/min and 12% received 15 or 20 mg/min
nitroglycerine, i.v. infusion; however, these doses were unrelated to
a subjects bodyweight. Conversely, within the nifedipine-treated
group none of the subjects required more than 10 mg nifedipine
to reach the therapeutic goal. The magnitude and time-course of
maternal hypotensive responses are indicated in Table 3 and Fig. 2,
respectively.
Mean arterial pressure showed a statistically significant decrease
just 5 min after initiation of the administration of nitroglycerine
(3.3 mmHg; P = 0.018, Wilcoxon signed-rank test) and 10 min after
the initiation of the administration of nifedipine (4.8 mmHg;

2007 The Authors

Journal compilation 2007 Blackwell Publishing Asia Pty Ltd

583

Nitroglycerine vs nifedipine in pre-eclampsia

Maternal heart rate was similar in both the nitroglycerine- and

nifedipine-treated groups before initiation of vasodilator therapy
(86 7 and 85 7 b.p.m., respectively). One hour later, heart rate
increased significantly (P < 0.001, paired t-test) in both groups,
although the increase was larger in the nifedipine-treated group than
the nitroglycerine-treated group (8.6 5.3 vs 4.6 4.4 b.p.m.,
respectively; P = 0.030, Students t-test). Fetal heart rate was similar
in both the nitroglycerine- and nifedipine-treated groups before the
intervention (138 2 and 140 1 b.p.m., respectively) and did not
change during vasodilator therapy.

Secondary outcomes

Fig. 2 Time-course of mean arterial pressure (MAP) in the nitroglycerine

(
)- and nifedipine ()-treated groups during vasodilator therapy; 95%
confidence intervals are included. Significant difference (P 0.02) with
respect to Time 0 (within groups) for all periods in which diamonds are joined
by continuous line (nitroglycerine-treated group) or dotted line (nifedipinetreated group). First and second analysis phases (see Results) are indicated.

P = 0.000002, paired t-test). One hour after the onset of vasodilator

therapy, there was an important fall in MAP in both groups, which
was significantly greater in the nitroglycerine-treated group than in
the nifedipine-treated group (DMAP 29 5 vs 24 6 mmHg,
respectively; P = 0.043). The time-course of MAP showed a quadratic
behaviour; hence, modelling of MAP was first performed from
530 min and later from 35 60 min (Fig. 2). In the first phase,
modelling indicated: (i) a clear time group interaction (P = 0.021);
(ii) that a small fraction of explained variation in MAP (approximately
15%) could also be related to maternal age (b = 0.078; P = 0.025),
number of pregnancies (b = 0.049; P = 0.028) and MAP after
administration of the MgSO4 loading dose (b = 0.9138; P < 0.0001);
and (iii) that the DMAP due to the MgSO4 loading dose did not influence the explained variation in MAP. In the second phase, modelling
indicated that only the variable group contributed to MAP variation
(b = 7.35; P < 0.0001). As shown in Fig. 2, the variability in MAP
(95% CI) during vasodilator therapy was almost twofold greater
in the nifedipine-treated group compared with the nitroglycerinetreated group; however, this variability was only statistically
significant from 30 min (P = 0.05, Brown Forsythe test) to 45 min
(P = 0.008, BrownForsythe test).
Systolic blood pressure fell similarly in both groups during
vasodilator therapy in both the nitroglycerine- and nifedipine-treated
groups (from 159 7 to 125 7 mmHg (DMAP = 34 10 mmHg)
and from 163 7 to 133 5 mmHg (DMAP = 30 8 mmHg),
respectively), whereas DBP showed a significantly greater fall in
the nitroglycerine-treated group (from 108 3 to 82 2 mmHg;
DMAP = 26 3 mmHg) compared with the nifedipine-treated
group (from 109 4 to 87 5 mmHg; DMAP = 22 7 mmHg;
P = 0.036, Welch two-sample test). The time-course and modelling
of DBP were similar to those shown for MAP.

In terms of perinatal variables (Table 4), the only significant difference

between the two groups was that 87.6% of babies in the nitroglycerinetreated group, compared with 56.2% in the nifedipine-treated
group received, an Apgar score 8 at the 1st min after birth. This
difference between the two groups essentially disappeared by 5 min.
The Neonatology Service reported that none of the newborns
had signs of MgSO4 toxicity. Similarly, there were no differences
in maternal adverse effects between the two groups during the
administration of vasodilator therapy (Table 5) and the most frequent
adverse effect was facial flushing. There were no cases of maternal
and/or fetal death.

DISCUSSION
Magnesium sulphate loading induced a small hypotensive response
(prior to that induced by vasodilators) that was more pronounced in
subjects who were finally allocated to the nitroglycerine treatment
group than in those who were finally allocated to the nifedipine
treatment group. The modelling of this hypotensive response
(D = before after) indicated that this difference could be related to
a relatively higher dose of MgSO4 in the nitroglycerine-treated
group, because women in this group tended to weigh approximately
4 kg less than those in the nifedipine-treated group. This also suggests
the need to review the efficacy of MgSO4 as an anticonvulsivant
(as well as its fetal effects) when a loading dose is administered
per kg bodyweight rather than a traditional fixed dose.4 Our analysis
also indicates that the MgSO4 loading dose-induced hypotensive
response did not affect the subsequent vasodilator effects of
nitroglycerine or nifedipine.
Nifedipine, a calcium channel blocker, was chosen because it is
one of the most widely used drugs in the management of pregnancy
induced hypertension in developing countries,25 such as Mexico.26
The route of administration of nifedipine used in the present study
ensured immediate contact of the total drug dose with the sublingual
mucosa, where it is primarily absorbed; however, it is not possible
to rule out partial absorption through the gastrointestinal tract due
to involuntary swallowing, so that the joint effect of both events on
absolute bioavailability is not known. It has been documented27 that
routes of administration of nifedipine that evade first-pass metabolism
in the gastrointestinal tract, such as use of the sublingual perforated
capsule, result in greater bioavailability and a faster and more stable
serum nifedipine concentration than methods that do not evade
first-pass metabolism (oral aspirated capsule content swallowed
and chewed capsule swallowed methods). Furthermore, sublingual
administration methods allow for a more gradual decrease in blood
pressure than oral swallowed methods, so that, clinically, they are

2007 The Authors

Journal compilation 2007 Blackwell Publishing Asia Pty Ltd

584

S Manzur-Verstegui et al.

Table 4 Perinatal variables in both groups

Nitroglycerine-treated
group (n = 16)

Nifedipine-treated
group (n = 16)

P value

4.7 2.0

4.3 2.0

0.575
1.000

Time to delivery after admission (h)

Mode of delivery
Vaginal
Caesarean
Indication for Caesarean
Cephalopelvic disproportion
Unfavourable cervix
Breech presentation
Twin parturition
Prematurity
Post-delivery bleeding
< 1000 mL
> 1000 mL
Birth weight (kg)
Gestational age by Capurro (weeks)
Apgar score at 1 min
<8
8
Apgar score at 5 min
<8
8
Total hospital days
Maternal
Newborn

5 (31%)
11 (68.8%)

4 (25%)
12 (75%)
1.000

4 (36.4%)
4 (36.4%)
1 (9.1%)
0 (0.0%)
2 (18.2%)

4 (33.3%)
5 (41.7%)
1 (8.3%)
1 (8.3%)
1 (8.3%)

15 (93.8%)
1 (6.3%)
2.8 0.6
36 2

13 (81.3%)
3 (18.8%)
2.9 0.7
36 3

2 (12.5%)
14 (87.5%)

7 (43.8%)
9 (56.3%)

1 (6.3%)
15 (93.8%)

0 (0.0%)
16 (100.0%)

3.0 0.8
3.0 0.8

2.9 0.6
2.9 0.6

0.599

0.779
0.843
0.033

0.043

0.540
1.000

Values are meanSD or the number of subjects with percentages given in parentheses.

Students t-test; Mann Whitney U-test; Fishers exact test.

Table 5 Adverse maternal effects that occurred during vasodilator therapy

Adverse effect

Flushing
Headache
Palpitations
Nausea
Total no. patients

Nitroglycerine-treated
group (n = 16)
4 (25.0%)
3 (18.8%)
3 (18.8%)
0 (0.0%)
16 (100.0%)

Nifedipine-treated
group (n = 16)
6 (37.5%)
2 (12.5%)
2 (12.5%)
1 (6.3%)
16 (100.0%)

P value

0.786

Data show the number of events with percentages given in parentheses.

Fishers exact test.

considered the most suitable to obtain a rapid onset of effect

following the administration of nifedipine.27 In addition, results here
indicate that, using the current delivery and administration methods
to administer nifedipine to women with severe pre-eclampsia who
were managed with controlled extracellular volume expansion and
MgSO4, excessive hypotension was not induced and no serious
side-effects occurred. The fact that the nifedipine-treated group
showed both greater MAP variability and a greater maternal heart rate
response than the nitroglycerine-treated group during vasodilatory
therapy suggests that, under the present study conditions, sublingual
nifedipine induces a greater variability in the arterial baroreflex
system through mechanisms that cannot be ascertained by the
present study.

Most subjects (88%) required 10 mg/min or less of continuous

i.v. nitroglycerine infusion to reach the therapeutic goal. Not only
did the hypotensive effect of nitroglycerine start sooner, but the
therapeutic goal was also reached faster and with greater precision
than with sublingual nifedipine. In addition, the fetalmaternal
safety margin for nitroglycerine infusion was similar to that observed
in the nifedipine-treated group. Thus, a continuous infusion of i.v.
nitroglycerine could be an alternative option for the management of
patients with severe pre-eclampsia who are intolerant to oral drug
administration or who require endotracheal intubation to induce
general anaesthesia.28 In addition, it has been reported recently that low
concentrations of nitroglycerine inhibit the hypoxia/reoxygenationinduced apoptosis observed in human chorionic villi from preeclamptic pregnancies.29 Contrary to these advantages, it has been
documented that high-dose (100300 mg/min, i.v.) nitroglycerine
induces intracranial hypertension30 and decreases cerebral perfusion
pressure;31 yet, we do not know whether the low dose (520 mg/min)
used in the present study produces such effects in women with severe
pre-eclampsia.
The slightly greater hypotensive response, although still within
the therapeutic goal range, seen with nitroglycerine compared with
nifedipine can be explained by the venoarterial mechanism of action
of nitroglycerine,16 as well as by the smaller baroreflex-induced heart
rate response. Time-courses of DBP and SBP suggest that the two
drugs decreased total peripheral resistance (TPR) and that if there
was an increased cardiac output, this was relatively minor with respect
to the reduction in TPR. The lack of effect of the vasodilator therapy
on the time-course of fetal heart rate suggests that the hypotensive

2007 The Authors

Journal compilation 2007 Blackwell Publishing Asia Pty Ltd

Nitroglycerine vs nifedipine in pre-eclampsia

response induced by these drugs did not affect placental blood
flow.
In conclusion, the findings of the present study demonstrate
that, in women with severe pre-eclampsia who are managed with
controlled extracellular volume expansion and MgSO4 loading and
maintenance doses, a continuous infusion of i.v. nitroglycerine
reduces blood pressure sooner, to a greater extent, faster and more
precisely than the use of sublingual nifedipine. The fetalmaternal
safety margin observed was similar between the two study groups.
To our knowledge, this is the first randomized, controlled study that
formally addresses this issue.

ACKNOWLEDGEMENTS
This research was supported by the Instituto Mexicano del Seguro
Social (IMSS) and the Universidad Autnoma de San Luis Potos
(UASLP). The authors thank Dr JL Romero-Santos (external
collaborator; General Hospital No.1, IMSS), Mrs Geraldine
MacDonald (independent English consultant; San Luis Potos,
Mxico) and the nursing personnel of the General Hospital No.1,
IMSS, for their excellent, professional assistance.

13.
14.

15.

16.

17.

18.

19.

20.

REFERENCES
1.

World Health Organization. WHO international collaborative study of

hypertensive disorders of pregnancy. Geographic variation in the
incidence of hypertension in pregnancy. Am. J. Obstet. Gynecol. 1988;
158: 803.
2. Varon J, Marik PE. The diagnosis and management of hypertensive crises.
Chest 2000; 118: 224 7.
3. Frias AE, Belfort MA. Post-Magpie. How should we be managing
severe preeclampsia? Curr. Opin. Obstet. Gynecol. 2003; 15: 48995.
4. The Magpie Trial Collaborative Group. Do women with preeclampsia,
and their babies, benefit from magnesium sulphate? The Magpie Trial:
A randomized placebo-controlled trial. Lancet 2002; 359: 187790.
5. Magee LA, Miremadi S, Li J et al. Therapy with both magnesium sulfate
and nifedipine does not increase the risk of serious magnesium-related
maternal side effects in women with pre-eclampsia. Am. J. Obstet.
Gynecol. 2005; 193: 153 63.
6. Jayawardana J, Lekamge N. A comparison of nifedipine with methyldopa
in pregnancy induced hypertension. Ceylon Med. J. 1994; 39: 8790.
7. Rey E, LeLorier J, Burgess E, Lange IR, Leduc L. Report of the Canadian
Hypertension Society Consensus Conference: 2. Pharmacologic
treatment of hypertensive disorders in pregnancy. Can. Med. Assoc. J.
1997; 157: 124554.
8. Brown MA, Hague WM, Higgins J et al. The detection, investigation
and management of hypertension in pregnancy: Executive summary.
Aust. N.Z. J. Obstet. Gynecol. 2000; 40: 133 8.
9. Waisman GD, Mayorga LM, Camera MI, Vignolo CA, Martinotti A.
Magnesium plus nifedipine: Potentiation of hypotensive effect in
preeclampsia? Am. J. Obstet. Gynecol. 1988; 159: 308 9.
10. Snyder SW, Cardwell MS. Neuromuscular blockade with magnesium
sulfate and nifedipine. Am. J. Obstet. Gynecol. 1989; 161: 356.
11. Ben-Ami M, Giladi Y, Shalev E. The combination of magnesium
sulphate and nifedipine: A cause of neuromuscular blockade. Br. J.
Obstet. Gynecol. 1994; 101: 2623.
12. Impey L. Severe hypotension and fetal distress following sublingual
administration of nifedipine to a patient with severe pregnancy induced

21.
22.
23.

24.
25.

26.

27.

28.

29.

30.

31.

585

hypertension at 33 weeks. Br. J. Obstet Gynaecol. 1993; 100: 959

61.
Kirshon B, Moise Jr KJ, Cotton DB et al. Role of volume expansion
in severe pre-eclampsia. Surg. Gynecol. Obstet. 1988; 167: 36771.
Riley ET, Flanagan B, Cohen SE, Chitkara U. Intravenous nitroglycerin:
A potent uterine relaxant for emergency obstetric procedures. Review
of the literature and report of three cases. Int. J. Obstet. Anesth. 1996;
5: 2648.
Clark KD, Viscomi CM, Lowel J, Chien EK. Nitroglycerin for relaxation
to establish a fetal airway (EXIT procedure). Obstet. Gynecol. 2004;
103: 111315.
Cotton DB, Jones MM, Longmire S, Dorman KF, Tessem J, Joyce TH.
Role of intravenous nitroglycerin in the treatment of severe pregnancyinduced hypertension complicated by pulmonary edema. Am. J. Obstet
Gynecol. 1986; 154: 913.
Cetin A, Yurtcu N, Juvenal T, Imir AG, Duran B, Cetil M. The effect
of glyceryl trinitrate on hypertension in women with severe preeclampsia,
HELLP syndrome and eclampsia. Hypertens. Pregnancy 2004; 23: 37
46.
Altman DG, Schulz KF, Moher D et al. The revised CONSORT
statement for reporting randomized trials. Explanation and elaboration.
Ann. Int. Med. 2001; 134: 66394.
American College of Obstetricians and Gynecologists. Diagnosis and
management of preeclampsia and eclampsia. ACOG Prac. Bull. 2002;
33: 114.
Paterson-Brown S, Robson SC. Hydralazine boluses for the treatment
of severe hypertension in preeclampsia. Br. J. Obstet. Gynecol. 1994;
101: 40913.
McGraw K, Wong SP. Forming inferences about some intraclass
correlation coefficients. Psychol. Methods 1996; 1: 3046.
Diggle PJ, Heagerty PJ, Liang KY, Zeger SL. Analysis of Longitudinal
Data, 2nd edn. Oxford University Press, New York 2002; 26 30.
Heiberger RM, Holland B. Statistical Analysis and Data Display. An
Intermediate Course with Examples in S-plus, R and SAS. Springer
Text in Statistics. Springer Science + Business Media Inc., New York.
2004.
Pinheiro JC, Bates DM. Mixed-Effects Models in S and S-Plus Statistics
and Computing. Springer-Verlag, New York. 2000.
Jagasothy R, Paranthaman S. Sublingual nifedipine compared with
intravenous hydralazine in the acute treatment of severe hypertension
in pregnancy: Potential for use in rural practice. J. Obstet. Gynaecol.
Res. 1996; 22: 214.
Ministry of Health. Technical Guidelines for Prevention, Diagnosis and
Management of Preeclampsia/Eclampsia in Mexican Health Sector.
Ministry of Health, Mxico. 2002 (in Spanish).
Kubota R, Komiyama T, Shimada H. Evaluation of the method for
nifedipine administration for a rapid onset of clinical effect: A clinical
study in normal volunteers. Yakugaku Zasshi 2001; 121: 355 64.
Longmire S, Leduc L, Jones MM, Hawkins JL, Joyce TH, Cotton DB.
The hemodynamic effects of intubation during nitroglycerin infusion
in severe preeclampsia. Am. J. Obstet. Gynecol. 1991; 154: 551 6.
Belkacemi L, Bainbridge SA, Dickinson MA, Smith GN, Graham CH.
Glyceryl trinitrate inhibits hypoxia/reoxygenation-induced apoptosis in
the syncytiotrophoblast of the human placenta: Therapeutic implications
for preeclampsia. Am. J. Pathol. 2007; 170: 90920.
Dohi S, Matsumoto M, Takahashi T. The effects of nitroglycerin on
cerebrospinal fluid pressure in awake and anesthetized humans.
Anesthesiology 1981; 54: 51114.
Weyland A, Grune F, Buhre W, Kazmaier S, Stephan H, Sonntag H.
The effect of nitroglycerin on cerebrovascular circulation, cerebrovascular
CO2-reactivity and blood flow rate in basal cerebral arteries. Anaesthesist
1996; 45: 103744.

2007 The Authors

Journal compilation 2007 Blackwell Publishing Asia Pty Ltd