Nicardipine Versus Nifedipine for Postpartum Hypertensive Emergencies in Severe Preeclampsia

Summary

This protocol aims to evaluate the efficacy and safety of nicardipine and nifedipine in patients with severe preeclampsia-induced postpartum hypertensive emergencies.

Abstract

Severe preeclampsia (sPE)-induced postpartum hypertensive emergencies (PHEs) pose a threat to maternal safety, requiring rapid and stable blood pressure (BP) control. This protocol describes an observational, non-randomized controlled cohort study designed to evaluate the efficacy and safety of two calcium channel blockers-nicardipine (NIC) and nifedipine (NIF)-in patients with sPE-induced PHEs. Key procedural steps include: retrospective enrollment of 131 eligible patients (67 in the NIC group, 64 in the NIF group) admitted between April 2024 and May 2025; propensity score matching to balance baseline characteristics (e.g., age, gestational age, baseline BP); standardized routine sPE management plus targeted antihypertensive treatment (NIC via continuous intravenous infusion, NIF via oral immediate-release tablets); and systematic monitoring of predefined endpoints (BP control metrics, hemodynamic parameters, biological markers including brain natriuretic peptide [BNP] and D-dimer, adverse events, and short-term maternal outcomes). Statistical analyses will use SPSS 32.0, with appropriate tests for between-group comparisons and covariance analysis to adjust for confounding. This protocol is intended to provide a standardized workflow for comparing the two agents in real-world clinical settings, to inform individualized PHE management-particularly regarding drug selection based on clinical context (e.g., venous access availability, monitoring resources)-and to support evidence-based decision-making for postpartum hypertensive crisis care.

Introduction

Severe preeclampsia (sPE) is a serious complication peculiar to pregnancy, characterized by hypertension, proteinuria, and multiple organ dysfunction. For these patients, the postpartum period remains a "high-risk window" for both maternal safety¹. Among sPE patients, around 30% to 50% experience persistent hypertension within 24 h post-delivery, with 10%-15% possibly progressing to hypertensive emergencies (systolic blood pressure [SBP] ≥160 mmHg and/or diastolic blood pressure [DBP] ≥ 110 mmHg)². If not controlled in time, it may induce serious events such as eclampsia recurrence, cerebral hemorrhage, acute heart failure, or placental abruption, elevating the risk of maternal death and long-term cardiovascular disease³. Therefore, the rapid and stable antihypertensive treatment of postpartum hypertensive emergencies (PHEs) is the key to improving prognoses.

At present, calcium channel blockers (CCBs) are recommended by domestic and foreign guidelines as the first-line drugs for pregnancy and postpartum hypertension because of their definite antihypertensive effects and minimal influences on uteroplacental blood flow⁴. Nifedipine (NIF), as a classic dihydropyridine CCB, was once a common choice for postpartum hypertension emergencies due to its rapid onset and ease of oral administration⁵. However, its short half-life and tendency to cause reflex tachycardia and significant fluctuations in blood pressure (BP) may increase myocardial oxygen consumption and compromise perfusion of vital organs⁶. Nicardipine (NIC), as a new dihydropyridine CCB, exerts its effect by selectively dilating peripheral arteries and inhibiting calcium influx in vascular smooth muscle. It possesses pharmacological advantages such as rapid onset (taking effect within 5 min as an intravenous formulation), stable BP curve (with a trough-to-peak ratio [T/P]), and minimal impact on heart rate. It has been proven to be safer for controlling BP fluctuations in non-pregnant hypertensive emergencies⁷. However, for the specific pathophysiological condition of sPE (which involves generalized small-vessel vasospasm, endothelial damage, and increased volume load), there are few targeted comparative studies on the efficacy and safety profiles of the two drugs in PHEs.

Current clinical practice is mostly based on experience or extrapolation from non-specific studies. Some small-sample observational studies suggest that NIC may reduce adverse reactions such as increased heart rate and headache, but the sample sizes are insufficient, and the "sPE" population was not strictly defined⁸. Moreover, although clinical guidelines indicate that the selection of CCBs should be individualized, they do not clearly specify the preferred recommendation levels for the two drugs⁹. Furthermore, postpartum patients have differences in drug metabolism compared to those during pregnancy due to uterine contractions, redistribution of blood volume, and the need for breastfeeding. Current studies have not adequately evaluated the impact of drugs on short-term maternal outcomes (such as postpartum hemorrhage and postpartum infection), leading to confusion in clinical decision-making. Therefore, this study focuses on patients with severe postpartum preeclampsia-induced hypertensive emergencies, comparing the differences between NIC and NIF, and observing their impacts on short-term maternal outcomes. NIC can be considered an optimal solution if it achieves stable BP reduction while minimizing adverse reactions. If the efficacy of the two drugs is equivalent, it is necessary to weigh pharmacoeconomic considerations and patient preferences. The findings of this study could advance the scientific and individualized management of PHEs, reduce the risk of maternal complications, and improve long-term maternal outcomes, with significant clinical translational value. The primary outcome was the time to target blood pressure (SBP < 160 mmHg and DBP < 110 mmHg) in the two groups. Secondary outcomes included the rate of 2 h blood pressure control, blood pressure fluctuation, hemodynamic changes, incidence of adverse events, and short-term maternal outcomes.

Protocol

Ethics and quality control

The hospital ethics committee approved this study. Written informed consent was waived due to the study's retrospective nature. The data were entered into the electronic medical record system by designated personnel, and double-checking was conducted to ensure accuracy; drugs were used strictly according to instructions, and adverse reactions were promptly reported.

Research design

This study is a non-randomized controlled cohort study, focusing on patients with sPE-induced PHEs to compare the efficacy and safety of NIC and NIF (Figure 1). The sample size was estimated based on the primary outcome measure, 'time to the BP goal.' Referring to previous studies¹⁰, the expected average time to the BP goal in the NIF group was 85 ± 10 min. Assuming that the NIC group could shorten this time by 30% (i.e., 60 ± 10 min), with a two-sided α = 0.05 and power 1 - β = 0.8, calculation using the formula for the two independent sample t-test indicated a minimal requirement of 55 cases per group. Considering a 15% dropout rate, 131 cases were ultimately included (67 cases in the NIC group and 64 cases in the NIF group). This design was chosen because PHE requires rapid antihypertensive intervention, and randomization may delay treatment and violate clinical ethics. The retrospective cohort design can reflect the real clinical medication scenario and enhance the external applicability of the results.

Research participants and grouping

The research participants were selected from the patients with sPE and PHEs who were admitted from April 2024 to May 2025. Inclusion criteria: (1) Diagnosis of moderate-to-sPE according to the criteria (SBP ≥ 160 mmHg and/or DBP ≥ 110 mmHg after 20 weeks of pregnancy, accompanied by proteinuria ≥2 g/24 h or random urine protein (+++), or combined with thrombocytopenia, liver function impairment, pulmonary edema, or other organ involvement)¹¹; (2) New-onset or persistent hypertensive emergency (SBP ≥ 160 mmHg and/or DBP ≥110 mmHg) within 24 h after delivery (from childbirth to 24 h); (3) Age 18-45 years, with singleton pregnancy. Exclusion criteria: (1) Severe heart, liver, renal failure (e.g., ejection fraction < 40%, serum creatinine > 265 µmol/L), or heart failure; (2) Allergies to NIC or NIF; (3) Active peptic ulcers or bleeding tendency; (4) Breastfeeding contraindications; (5) Other serious complications (pulmonary embolism, and acute stroke, etc.). Based on actual clinical medication, the patients were divided into the NIC group (n = 67) and the NIF group (n = 64). Through propensity score matching (PSM), matching variables included age, gestational age, postpartum time, baseline SBP/DBP, comorbidities (such as diabetes, chronic hypertension), proteinuria level, and baseline values of liver and kidney function. 1:1 nearest neighbor matching was used, and the caliper width was set at 0.25 standard deviations. Group assignment was determined by the attending physician according to the clinical practice and was based on the availability of venous access, the urgency of elevated blood pressure, the patient's coexisting conditions (e.g., arrhythmia), and gastrointestinal status.

Treatment methods

All patients received routine postpartum management of sPE (including sedation, magnesium sulfate for anticonvulsant therapy, and correction of hypoalbuminemia), and were given targeted antihypertensive treatment. The dosage, route of administration (intravenous infusion), and course of treatment of magnesium sulfate in the two groups all followed a unified clinical pathway to achieve standardized treatment. NIC group: Normal saline was used to dilute to obtain NIC hydrochloride solution (concentration 0.1-0.2 mg/mL). The initial dose was 0.5 µg/kg/min. After the blood pressure was reduced to the target value, the infusion speed was adjusted while the blood pressure was monitored and the maximum dose was 15 mg/h. NIF group: NIF tablets (specification: 10 mg/tablet) were taken orally, 10 mg/time, blood pressure was remeasured after 20 min of medication. If the target BP was not reached, an additional 20 mg was given. Blood pressure was measured again after 20 min, and another 20 mg was taken if the blood pressure did not reach the standard.

For both groups, the dosage was maintained once BP reached the target level. If any serious adverse reactions occurred (such as hypotension [SBP < 90 mmHg] or reflex tachycardia [HR > 120 beats/min]), the medication was discontinued and symptomatic treatment was provided. Nifedipine is an immediate-release dosage form that meets the clinical needs of rapid onset and on-demand dose escalation. During the observation period, the use of antihypertensive drugs other than the study drug was prohibited. If the drug was stopped after serious adverse reactions, only symptomatic and supportive treatment was given, and no other antihypertensive drugs were added.

Endpoints

(1)  The time to the BP goal (from the first administration to SBP<160 mmHg and DBP<110 mmHg) was recorded (excluding a single accidental reading), and the proportion of patients achieving the goal within 2 h after administration was counted. This target BP refers to the domestic and foreign guidelines for the management of hypertensive disorders complicating pregnancy, which aim to rapidly reduce the risk of severe hypertension while avoiding hypoperfusion of vital organs caused by excessive hypotension. (2) The maximum DBP and SBP decreases (ΔSBP, ΔDBP) within 30 min after treatment, and the T/P (the ratio of minimum effective concentration to peak concentration) was recorded. (3) Venous blood samples were collected from all patients before administration and 2 h post administration. D-dimer (D-D) was detected by an automatic coagulation function analyzer. Brain natriuretic peptide (BNP) was detected by an electrochemiluminescence immunoassay analyzer. BNP is released by the ventricular muscle in response to increased volume load or pressure load. Patients with postpartum sPE are prone to increased cardiac load due to vasospasm and volume remodeling. BNP can reflect cardiac function sensitively and is a commonly used marker of cardiac load in clinical practice. (4) Changes in central venous pressure (CVP), systemic vascular resistance (SVR), and stroke volume (SV) before and after administration were tracked. (5) Adverse reactions during the treatment process were reported. The 24 h postpartum hemorrhage and serum creatinine were also documented. CVP was monitored through an invasive central venous catheter. SVR and SV were measured using a noninvasive hemodynamic monitor based on bioreactance, calibrated with standard body surface area before monitoring, and the data were recorded every 15 min and averaged for analysis.

Statistical methods

Measurement data, expressed by mean±standard deviation, were compared between groups with the independent sample t-test or Mann-Whitney U test. The number of cases (%) was used to describe counting data, whose between-group comparisons were made by χ2 tests or Fisher's exact tests. After PSM matching, covariance analysis was used to control baseline confounding factors. P < 0.05 was the significance level.

Results

Comparison of clinical baseline data

In the baseline data, no statistically significant differences were observed between the two patient groups (P > 0.05). The SMDs were all controlled within 0.2, confirming low selection bias and group comparability (Table 1).

Comparison of BP goal achievement

The time to the BP goal in NIF and NIC groups was (152.87 ± 53.10) min and (119.22 ± 45.95)...

Discussion

This study compared the efficacy and safety of NIC vs. NIF in patients with sPE-induced PHEs. The results indicated that NIC was significantly better than NIF in BP lowering speed, goal achievement rate, and BP stability: its time to the BP goal was shortened, the 2 h goal achievement rate was improved, and ΔSBP and ΔDBP fluctuations were smaller. In addition, patients receiving NIC had fewer adverse reactions and better preservation of renal function. Although the two groups were similar in short-term maternal...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Automatic coagulation function analyzer -	Infitek Co., Ltd., Shandong, China	BCA-A-4-20	It is a fully automated optical coagulation analyzer designed for high-precision measurement of routine and special coagulation markers, including D-dimer.
Bioreactance hemodynamic monitor (NICOM)	Cheetah Medical		Used to measure SVR and SV
Central venous catheter	Arrow		Used for CVP monitoring
Electrochemiluminescence immunoassay analyzer	Nanjing RealMind Biotech Co., Ltd., Nanjing, China	MCL60	It is a fully automated electrochemiluminescence analyzer capable of high-sensitivity measurement of cardiac biomarkers such as BNP.