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Clinical and Experimental Pharmacology and Physiology (2008) 35, 580–585 doi: 10.1111/j.1440-1681.2007.04838.x

BlackwellPublishingAsiaOriginal Articles Nitroglycerinevsnifedipinein pre-eclampsiaSMVer á steguietal.

EFFICACY OF NITROGLYCERINE INFUSION VERSUS SUBLINGUAL

NIFEDIPINE IN SEVERE PRE-ECLAMPSIA: A RANDOMIZED,

TRIPLE-BLIND, CONTROLLED TRIAL

S Manzur-Verástegui,* PB Mandeville,† A Gordillo-Moscoso,*† JF Hernández-Sierra† and

M Rodríguez-Martínez†‡

*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 Potosí,

San Luis Potosí, México

SUMMARY

1. Information regarding the use of continuous i.v. administra-

tion 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 32women 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 paramet-

ric 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., respec-

tively), although the increase in the nifedipine-treated group wasalmost 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 fetal–maternal

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

hypertension after the 20th gestational week and is usually associated

with proteinuria and oedema. Pre-eclampsia complicates 2–8% 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 hyper-

tensive 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 (10–20 mg) or as

a tocolytic (60 mg).

9–11

Others have advised against the sublingualuse 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 magnesium-

related 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 procedures

15

and as a uterine relaxantduring 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

Correspondence: Manuel Rodríguez-Martínez, Department of Physiology

and Pharmacology, Faculty of Medicine, Universidad Autónoma de San Luis

Potosí, PO Box 1521-B, 78210 San Luis Potosí, SLP México. Email:

[email protected]

Received 14 May 2007; revision 12 August 2007; accepted 23 September

2007.

© 2007 The Authors

Journal compilation © 2007 Blackwell Publishing Asia Pty Ltd



Nitroglycerine vs nifedipine in pre-eclampsia 581

© 2007 The AuthorsJournal compilation © 2007 Blackwell Publishing Asia Pty Ltd

achieved with a fetal–maternal 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 Potosí,

SLP México) 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 (15–40 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 un-

complicated severe pre-eclampsia (without imminence of eclampsia or clinical

manifestations of target organ damage, as per the ACOG criteria 19) 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 pressureand 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 0–300 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 Ringer’s 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,

México) 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). Simul-

taneously, 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 d

2)

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 x j (= 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 intention-

to-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

mean±SD or proportions as percentages. Classical statistical tests were used

for two independent samples and paired samples after testing for normality

(Shapiro–Wilk) 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 r 2 (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 ofDMAP indicated that 15% of this variation

http://www.r-project.org/






582 S Manzur-Verástegui et al.


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-

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, Student’s 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).

Primary outcomes

Within the nitroglycerine-treated group, 44% of patients received 5mg/min, 44% received 10mg/min and 12% received 15 or 20mg/min

nitroglycerine, i.v. infusion; however, these doses were unrelated to

a subject’s 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;

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

Nitroglycerine-treated

group (n = 16)

Nifedipine-treated

group (n = 16)

P value

Before 131 ± 3 130 ± 3 0.618†

After 125 ± 4 127 ± 4 0.252†

P value(before vs after) < 0.0001

‡

< 0.0001

‡

DMAP

(before – after)

–5.8 ± 2.0 (4.7–6.8) –3.7 ± 2.3 (2.4–4.9) 0.009†

Values are mean±SD. For the difference in mean arterial pressure (DMAP)

values in parentheses indicate 95% confidence intervals.†Student’s 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


group (n = 16)

Nifedipine-treated

group (n = 16)

P value

MAP (mmHg)

0 min 125 ± 4 127 ± 4 0.252†

60 min 96 ± 3 103 ± 4 5.0e –05†

P value

(0 vs 60 min)

7.8e –14‡ 1.4e –10‡

DMAP

(0– 60 min)

–29 ± 5 (26.5–31.3) –24 ± 6 (21.0–27.4) 0.043†

Values are mean±SD. For the difference in mean arterial pressure (DMAP)

values in parentheses indicate 95% confidence intervals.†Student’s t -test; ‡ paired t -test.

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


group (n = 16)

Nifedipine-treated

group (n = 16)

P value

Age (years) 30.4 ± 7.5 29.6 ± 6.7 0.749†

Weight (kg) 79.6 ± 6.2 83.5 ± 6.5 0.095†

No. pregnancies 2.7 ± 1.7 2.3 ± 0.9 0.612‡

Gestation at entry(weeks)

36.9 ± 1.6 37.1 ± 2.8 0.757†

SBP (mmHg) 167 ± 6 168 ± 7 0.250‡

DBP (mmHg) 114 ± 3 112 ± 2 0.910‡

Pulse pressure

(mmHg)

52 ± 5 56 ± 6 0.356‡

MAP (mmHg) 131 ± 3 130 ± 3 0.376‡

Proteinuria 0.072§

2+ 5 (31%) 1 (6.25%)

3+ 11 (69%) 14 (87.5%)

4+ 0 (0%) 1 (6.25%)

In labour 6 (37.5%) 5 (31%) 1.000§

Values are mean±SD or the number of subjects with percentages given in

parentheses.†Student’s t -test; ‡Mann–Whitney U -test; §Fisher’s exact test.

Proteinuria was determined by reactive strips (Orbi-Test Combi 11;

Macame y Compañia, Distrito Federal, México).

SBP, DBP, systolic and diasolic blood pressure, respectively; MAP, mean

arterial pressure.





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

5–30 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 theDMAP due to the MgSO4 loading dose did not influ-

ence 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 nitroglycerine-

treated group; however, this variability was only statistically

significant from 30 min ( P=

0.05, Brown–Forsythe test) to 45 min( P = 0.008, Brown–Forsythe 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.

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, Student’s 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

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

between the two groups was that 87.6% of babies in the nitroglycerine-

treated 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 approximately4 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 possibleto 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 documented 27 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

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 (nifedipine-

treated group). First and second analysis phases (see Results) are indicated.



584 S Manzur-Verástegui et al.


considered the most suitable to obtain a rapid onset of effect

following the administration of nifedipine.

27

In addition, results hereindicate 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 precisionthan with sublingual nifedipine. In addition, the fetal–maternal

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/reoxygenation-

induced apoptosis observed in human chorionic villi from pre-

eclamptic pregnancies.29 Contrary to these advantages, it has been

documented that high-dose (100–300 mg/min, i.v.) nitroglycerine

induces intracranial hypertension30 and decreases cerebral perfusion

pressure;

31

yet, we do not know whether the low dose (5–20 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

Table 5 Adverse maternal effects that occurred during vasodilator therapy

Adverse effect Nitroglycerine-treated

group (n = 16)

Nifedipine-treated

group (n = 16)

P value

Flushing 4 (25.0%) 6 (37.5%)

Headache 3 (18.8%) 2 (12.5%)

Palpitations 3 (18.8%) 2 (12.5%)

Nausea 0 (0.0%) 1 (6.3%)

Total no. patients 16 (100.0%) 16 (100.0%) 0.786†

Data show the number of events with percentages given in parentheses.†Fisher’s exact test.

Table 4 Perinatal variables in both groups


group (n = 16)

Nifedipine-treated

group (n = 16)

P value

Time to delivery after admission (h) 4.7 ± 2.0 4.3 ± 2.0 0.575†

Mode of delivery 1.000§

Vaginal 5 (31%) 4 (25%)

Caesarean 11 (68.8%) 12 (75%)

Indication for Caesarean 1.000

§

Cephalopelvic disproportion 4 (36.4%) 4 (33.3%)

Unfavourable cervix 4 (36.4%) 5 (41.7%)

Breech presentation 1 (9.1%) 1 (8.3%)

Twin parturition 0 (0.0%) 1 (8.3%)

Prematurity 2 (18.2%) 1 (8.3%)

Post-delivery bleeding 0.599§

< 1000 mL 15 (93.8%) 13 (81.3%)

> 1000 mL 1 (6.3%) 3 (18.8%)

Birth weight (kg) 2.8 ± 0.6 2.9 ± 0.7 0.779†

Gestational age by Capurro (weeks) 36 ± 2 36 ± 3 0.843†

Apgar score at 1 min 0.033§

< 8 2 (12.5%) 7 (43.8%)

≥ 8 14 (87.5%) 9 (56.3%)

Apgar score at 5 min 0.043§

< 8 1 (6.3%) 0 (0.0%)≥ 8 15 (93.8%) 16 (100.0%)

Total hospital days

Maternal 3.0 ± 0.8 2.9 ± 0.6 0.540‡

Newborn 3.0 ± 0.8 2.9 ± 0.6 1.000§

Values are mean±SD or the number of subjects with percentages given in parentheses.†Student’s t -test; ‡Mann–Whitney U -test; §Fisher’s exact test.





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 fetal–maternal

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 Autónoma de San Luis Potosí

(UASLP). The authors thank Dr JL Romero-Santos (external

collaborator; General Hospital No.1, IMSS), Mrs Geraldine

MacDonald (independent English consultant; San Luis Potosí,

México) and the nursing personnel of the General Hospital No.1,

IMSS, for their excellent, professional assistance.

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