Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 8  |  Issue : 4  |  Page : 499-504

The effect of nitroglycerin infusion versus hydralazine infusion as antihypertensive therapy in acute management of patients with severe pre-eclampsia


1 Department of Anesthesiology and Intensive Care, Ain-Shams University, Cairo, Egypt
2 Department of Obstetrics and Gynecology, Ain-Shams University, Cairo, Egypt

Date of Submission19-May-2014
Date of Acceptance09-Nov-2014
Date of Web Publication29-Dec-2015

Correspondence Address:
Rania M Ali
Department of Anesthesiology and Intensive Care, Ain-Shams University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7934.172670

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  Abstract 

Background
Severe pre-eclampsia (PE) is a potentially life-threatening multisystem disease that requires urgent management. Delivery of the fetus is the definitive treatment for PE. However, effective and safe control of severe hypertension is the most important aspect of critical care management. This study aimed to compare the effectiveness and safety profile of hydralazine infusion versus nitroglycerin infusion as antihypertensive therapy in the acute management of patients with severe PE.
Patients and methods
A total of 180 patients with severe PE admitted to Ain Shams Obstetric ICU to stabilize blood pressure before delivery were randomly assigned to one of two equal groups: group H and group N. Group H received hydralazine infusion (1 mg/ml) and group N received nitroglycerin infusion (1 mg/ml). The infusion rate (5 ml/h) was adjusted to maintain systolic blood pressure at 130-140 mmHg and diastolic blood pressure at 80-100 mmHg.
Results
As regards hemodynamic parameters, the time to achieve blood pressure control was significantly shorter in the N group compared with the H group. However, the number of cases of severe persistent hypertension and the number of attacks of hypotension were comparable between the two groups. Maternal side effects and fetal and neonatal complications were comparable between the two groups, except for maternal headache and tachycardia, which were significantly higher in the H group compared with the N group. Concerning the mode of delivery, the rate of cesarean section delivery was significantly higher than the rate of vaginal delivery in both groups. Meanwhile, the rate of cesarean section after induction of labor was significantly higher in the N group compared with the H group.
Conclusion
Nitroglycerin could be a good alternative option for the acute management of patients with severe PE. It is an effective antihypertensive with minimal side effects.

Keywords: hydralazine, nitroglycerin, severe pre-eclampsia


How to cite this article:
Ali RM, Salah D, Mansour DY. The effect of nitroglycerin infusion versus hydralazine infusion as antihypertensive therapy in acute management of patients with severe pre-eclampsia. Ain-Shams J Anaesthesiol 2015;8:499-504

How to cite this URL:
Ali RM, Salah D, Mansour DY. The effect of nitroglycerin infusion versus hydralazine infusion as antihypertensive therapy in acute management of patients with severe pre-eclampsia. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2019 Sep 20];8:499-504. Available from: http://www.asja.eg.net/text.asp?2015/8/4/499/172670


  Introduction Top


Pre-eclampsia (PE) is a multisystem disorder of endothelial cell dysfunction characterized by hypertension and proteinuria in the second half of pregnancy. PE complicates 2-8% of all pregnancies and is a significant cause of fetal and maternal morbidity and mortality [1] . Severe PE is a potentially life-threatening multisystem disease that requires urgent management [2] . Delivery of the fetus is the definitive treatment for PE. However, effective and safe control of severe hypertension is the most important aspect of critical care management, as the main cause of maternal death is poorly controlled hypertension. The challenge in using antihypertensive drugs in PE is to ensure maternal safety and at the same time not compromise the uteroplacental perfusion [3] .

Hydralazine is a peripheral vasodilator and one of the most commonly used intravenous drugs for women with severe hypertension in pregnancy, but it crosses the placenta, causes reflex tachycardia, and has unpredictable pharmacodynamics [4] . Nitroglycerin is a nitric oxide (NO) donor with a potent venodilator effect in low doses and an arteriolar dilator in high doses [5] . There are no sufficient data regarding the use of intravenous infusion of nitroglycerin as an antihypertensive agent in the management of patients with PE.

The aim of this study was to compare the effectiveness and safety profile of hydralazine infusion versus nitroglycerin infusion as antihypertensive therapy in the acute management of patients with severe PE.


  Patients and methods Top


This was a prospective study conducted at the ICU of the Obstetrics and Gynecology Hospital of Ain-Shams University over a period of 2 years from February 2012 until March 2014 as a randomized double-blinded controlled study on patients diagnosed with severe PE. The study was approved by the Ethical Research Committee at Ain-Shams University and all participants provided written informed consent.

Patients eligible for this study were aged between 20 and 40 years, at greater than 34 weeks of gestation, and were diagnosed as having uncomplicated severe PE on the basis of severe hypertension [systolic blood pressure (SBP) ≥160 mmHg or diastolic blood pressure (DBP) ≥110 mmHg; repeated measurement should be taken for confirmation no more than 15 min later] and presence of clinically significant proteinuria (0.3 g or more of protein in 24-h urine collection, or urinary protein/creatinine ratio of 30 or more) without imminence of eclampsia or target organ damage [6] . Exclusion criteria included patients with chronic hypertension or other chronic diseases, fetal compromise diagnosed before the start of the study, or any known allergy to one of the study drugs.

A total of 180 patients with severe PE admitted to the ICU to stabilize blood pressure (BP) before delivery were randomly assigned using computer-generated randomization by means of sealed, opaque, numbered envelopes to one of two groups (90 in each group): group H and group N. Group H received hydralazine infusion (apresoline prepared by mixing two ampoules of 20 mg each of hydralazine to a volume of 40 ml of sodium chloride 0.9% to obtain a concentration of 1 mg/ml); group N received nitroglycerin infusion (nitronal, drawn as it is from a bottle at a concentration of 1 mg/ml; thus, 1 mg/kg/min equals to 4.8 ml/h for an 80 kg patient).

Patients received full intensive care treatment for PE according to the standard protocol at the obstetric ICU of Ain-Shams University. Vital signs were monitored at admission and until patients were discharged from the ICU using ECG, pulse oximetry, and continuous invasive arterial BP monitoring through the radial artery, and with an indwelling catheter for urine output assessment. Assessment of fetal well-being was done before starting the study in the form of cardiotocography (CTG), modified biophysical profile, Doppler ultrasound on the umbilical artery, and growth scan. In addition, continuous fetal heart rate monitoring by means of CTG during the study time was established. All treatments were provided by physicians who were not involved in the study, including lactated Ringer solution at a rate of 75 ml/h, which was adjusted according to the fluid balance, magnesium sulfate (4 g intravenous loading dose over a period of 10 min and 1 g/h intravenous infusion until 24 h after delivery as seizure prophylaxis, its dose being adjusted according to renal function), and antihypertensive medications according to the assigned group. The starting infusion rate of the antihypertensive medication was 5 ml/h. The infusion rate was adjusted to maintain SBP at 130-140 mmHg and DBP at 80-100 mmHg with stepwise dosage increases as much as 1 ml/h every 10 min. The infusion rate was immediately reduced on any abrupt reduction in BP below the study endpoint and was discontinued when SBP fell below 120 mmHg or DBP below 80 mmHg, and a bolus of 150 ml lactated Ringer solution was given.

Severe persistent hypertension was considered when SBP was greater than 160 mmHg or DBP was greater than 110 mmHg after the administration of the maximum dose of allocated drug treatment, 20 ml/h. In such a case the patient was shifted to sodium nitroprusside infusion.

After stabilization of the patient and once the target BP was achieved, induction of labor was started with a 3 mg prostaglandin E 2 (PGE 2 ) vaginal tablet. It was to be repeated after 6 h if needed. In case oxytocin was to be used, it was administered at least 6 h after the last dose of PGE 2 .

If the patient was not eligible for induction of labor because of previous cesarean section (CS) delivery, transverse position of the fetus, or other standard obstetrical indications, CS was performed at once. CS was also performed in case of failed induction of labor (no uterine contractions or cervical changes after 6 mg of PGE 2 ), fetal compromise, arrest of progress of labor, and moderate or severe accidental hemorrhage.

The following data were recorded and included demographic characteristics, the time to achieve BP control (time from starting infusion until reaching the study endpoint), and number of sudden attacks of hypotension (BP values below the desired level). In addition, side effects of drugs such as tachycardia (heart rate >100 bpm), headache, nausea/vomiting, flushing, dizziness, and the mode of delivery (either vaginal or CS) were also recorded. Fetal outcome with respect to stillbirths (death in utero at delivery) and suspected fetal compromise by abnormal CTG [continuous or progressive fetal bradycardia <100 bpm, reduced fetal heart rate variability (<5 bpm) and lasting more than 90 min, atypical variable decelerations with over 50% of contractions or late decelerations, both for >30 min, single prolonged decelerations for more than 3 min, or sinusoidal pattern more than 10 min], 1-min Apgar score less than 7, and 5-min Apgar score less than 7 were also recorded.

Sample size determination

We calculated that we would need 85 patients in each group with 80% power for detecting a 15% reduction in SBP when the significance level was a = 0.05 with two-sided testing and previous experience showing normally distributed data and an SD of 8 mmHg. Therefore, we included 90 patients in each group.

Statistical analysis

Data were analyzed using the Statistical Program for Social Science (SPSS), version 18.0 (Chicago, Ill, USA). Data were tested for normality using the Kolmogorov-Smirnov test. Quantitative data were expressed as mean ± SD. Qualitative data were expressed as frequency and percentage.

The following tests were carried out:

  1. The independent-sample t-test to compare between two means.
  2. The c2 -test to compare proportions between two qualitative parameters.
Probability (P-value): P-values less than 0.05 were considered significant.


  Results Top


A total of 180 patients with severe PE admitted to the ICU to stabilize BP before delivery were randomly assigned to one of two groups (90 in each group): group H and group N. Group H received hydralazine infusion and group N received nitroglycerin infusion. Both groups were comparable with respect to demographic data [Table 1].
Table 1 Demographic data

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As regards hemodynamic parameters, the time to achieve BP control was significantly shorter in the N group compared with the H group. However, the number of cases of severe persistent hypertension and the number of attacks of hypotension were comparable between the two groups. Further, there was significant increase in the number of patients with tachycardia in the H group compared with the N group [Table 2].
Table 2 Hemodynamic parameters

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The maternal side effects were comparable between the two groups, except for headache, which was significantly higher in the H group compared with the N group. The fetal and neonatal complications were comparable between the two groups [Table 3].
Table 3 Maternal side effects and fetal and neonatal complications

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Concerning the mode of delivery, the rate of CS delivery was significantly higher than that of vaginal delivery in both groups. Although the rates of CS and vaginal delivery were comparable between the two groups, the rate of CS after induction of labor was significantly higher in the N group compared with the H group [Table 4].
Table 4 The mode of delivery

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  Discussion Top


The current study demonstrated that, although both hydralazine and nitroglycerin infusions are effective in acute control of hypertension in patients with severe PE before delivery, the therapeutic goal was reached faster with nitroglycerin and with greater safety profile than with hydralazine.

Prompt delivery for all women with severe PE who have reached a favorable gestational age (34 weeks) is recommended, as prolonging the pregnancy at this gestational age subjects the mother and fetus to significant risks with relatively small potential benefits. A decision to expedite delivery in the setting of severe PE does not mandate immediate cesarean delivery [7] . Cervical ripening agents may be used if the cervix is not favorable before induction. However, a prolonged induction is best avoided [8] .

The level of BP is the most important factor to be considered in the decision to treat hypertension during pregnancy to minimize the risk of hemorrhagic stroke, as cerebral autoregulation is impaired when the mean arterial pressure exceeds 145 mmHg [9] . The ideal drug for acute treatment of hypertension in patient with severe PE is one that lowers the pressure rapidly but can be titrated easily to avoid excessive reduction in BP. Drugs that abruptly lower maternal cardiac output are to be avoided in order not to cause a further decrease in the uterine blood flow. There is little evidence to favor any particular choice of antihypertensive agent for rapid treatment of severe hypertension in patients with severe PE, especially as all antihypertensive drugs cross the placenta [10] .

Hydralazine is a direct acting vasodilator. There is an initial latency period of 5-15 min followed by a progressive and often precipitous fall in BP that can last up to 12 h after intravenous administration. Although hydralazine's circulating half-life is only about 3 h, the half-time of its effect on BP is about 100 h. Because of hydralazine's prolonged and unpredictable antihypertensive effects and the inability to titrate the drug's hypotensive effect effectively, hydralazine was avoided in the management of hypertensive crises [11] . However, intravenous hydralazine has been used extensively in the setting of PE for the acute treatment of severe hypertension. Although a meta-analysis demonstrated a slightly increased rate of adverse events with hydralazine compared with labetalol, the evidence was not sufficient to make a definitive recommendation for one drug over the other [12] . Hydralazine has been widely used for many years in the setting of acute hypertension in pregnancy and is an acceptable antihypertensive drug in this setting [13],[14].

Endothelial dysfunction and reduced NO bioavailability are likely to play an important role in the maternal and fetal pathophysiology of PE [15] . Nitroglycerin, a NO donor, targets the underlying pathophysiological changes and reverses the endothelial dysfunction. There have been some reports demonstrating transdermal [16],[17] and intravenous [18],[19],[20],[21] use of nitroglycerin in patients with PE but of a smaller sample size and with a more heterogeneous enrollment criteria. The study by Cotton et al. demonstrated that combination of nitroglycerin and volume expansion in patients with severe pregnancy-induced hypertension is effective in reducing the mean arterial pressure as well as the pulmonary capillary wedge pressure while cardiac index and oxygen utilization were maintained [22] .

The results of the current study showed that the average time taken to achieve the desired BP level was shorter in the nitroglycerin group, and, although both groups were comparable regarding the number of attacks of hypotension and persistent hypertension, the nitroglycerin group showed less tachycardia, thus increasing the maternal safety margin. The lack of significant changes in heart rate seen in this study is consistent with previous studies on intravenous nitroglycerin [23],[24],[25],[26],[27],[28],[29],[30],[31],[32] . This can be explained by the venoarterial mechanism of action of nitroglycerin, as well as by the smaller baroreflex-induced heart rate response [18] . Other studies have documented either a decrease [33],[34] or an increase [35],[36] in heart rate with nitroglycerin. Also the continuous hydralazine infusion in theory had mostly provided a constant exposure to the drug to avoid sharp fluctuations in BP in comparison with the intermittent bolus therapy. Contrary to these advantages, it has been reported [37],[38] overshoot hypotension occurs with hydralazine infusion. They argued that with constant infusion, it is difficult to determine the cumulative dosage the patient had received.

The results of the current study showed that the maternal side effects were comparable between both groups, except for headache, which was significantly higher with hydralazine infusion. The fetal and neonatal outcomes were comparable between the two groups. This could be attributed to the smooth reduction in BP with the hydralazine and nitroglycerin infusion, and hence it was reflected in the uteroplacental blood flow. According to a systematic review by Magee et al. [12] , intravenous hydralazine is associated with more maternal and perinatal adverse effects than other drugs, particularly intravenous labetalol or oral or sublingual nifedipine.

Hydralazine exerts hazardous cardiovascular effects on the fetus, clinically and ultrasonographically [39],[40] . However, some studies have reported minimal effects [41],[42] . There is an evolving interest about the safety of nitroglycerin in a variety of antenatal and intrapartum indications [22],[43],[44],[45] . There have been no reported significant adverse fetal or maternal side effects associated with its administration [46],[47] .

Our study showed a high rate of CS delivery in both groups. Elective CS was reported as the most frequent mode of delivery in women with PE [48],[49] . However, nitroglycerin infusion was associated with a higher incidence of CS delivery especially after induction of labor in the current study. It could be attributed to its effective relaxation of the smooth muscle of the uterus [50] . Studies [51],[52] have shown that NO is an important factor in controlling the cervix during its transition from pregnancy to the beginning of labor, and in coordination with progestin regulates the uterine quiescence and cervical stiffness. Reduction in NO production in the uterus is related to the commencement of labor, whereas NO causes cervical ripening in the cervix. Therefore, NO donors can have therapeutic effects as tocolytic agents. To our knowledge, there is no study investigating the effect of nitroglycerin infusion on the progress of induction of labor. Hence, further investigation is needed.


  Conclusion Top


The choice of antihypertensive for the acute management of patients with severe PE should depend on the clinician's experience, familiarity with a particular drug, and what is known about adverse effects. Nitroglycerin could be a good alternative option. It is an effective antihypertensive with minimal side effects. However, more studies are necessary to confirm this conclusion and it is suggested to perform more randomized clinical trials on this significant issue.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


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  In this article
   Abstract
  Introduction
  Patients and methods
  Results
  Discussion
  Conclusion
   References
   Article Tables

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