Use of continuous infusion of nicardipine to control persistent postpartum hypertension: A retrospective study

To evaluate the effect of continuous infusion of nicardipine on the management of uncontrolled blood pressure (BP) during postpartum period. This retrospective study included 209 women diagnosed in hospital with hypertensive disorders during pregnancy and had uncontrolled BP after delivery between January 2018 to December 2020 Uncontrolled BP was defined as persistent elevation of systolic BP ≥ 160 mm Hg or diastolic BP ≥ 110 mm Hg. Patients were divided into 2 groups: nicardipine (N = 53; continuous nicardipine infusion and additional bolus of labetalol or hydralazine) and control (N = 156; consecutive bolus of labetalol or hydralazine). BP data were analyzed using the Mann–Whitney U and χ2 tests by dividing the time interval of 4 hours by the delivery time. The highest BP trends showed that the mean values of both systolic and diastolic BP immediately before delivery were higher in the nicardipine group than in the control. After 8 to 12 hours following delivery, both systolic and diastolic BP were lower in the nicardipine group than in the control. Subsequently, 16 to 20 hours after delivery, both systolic and diastolic BP were significantly lower in the nicardipine group than in the control (137/80 vs 141/84 mm Hg). Initially, the proportions of uncontrolled BP in the nicardipine group were higher than those in the control; however, it then became lower at all time intervals 8 hours after delivery. The proportions of patients who received additional antihypertensive agents and the median cumulative dosages were lower in the nicardipine group than in the control. Continuous infusion of nicardipine can help manage uncontrolled BP during the postpartum period.


Introduction
Hypertensive disorders of pregnancy remain one of the leading causes of maternal and perinatal mortality, with an incidence of nearly 10%. [1][2][3] Guidelines recommend controlling blood pressure (BP) with antihypertensive medication to prevent devastating complications such as intracranial hemorrhage, renal injury, and cardiopulmonary compromise when the persistent elevation of systolic BP ≥ 160 mm Hg or diastolic BP ≥ 110 mm Hg is present in pregnant women diagnosed with hypertensive disorders. [4][5][6][7] However, the target BP range to maintain sufficient perfusion to the uterus during pregnancy should not be lowered below a systolic BP of 140 to 150 mm Hg and a diastolic BP of 90 to 100 mm Hg. [8,9] While termination of pregnancy is the ultimate treatment for preeclampsia (PE) and other hypertensive disorders of pregnancy, BP does not normalize immediately after giving birth and may sometimes worsen for a certain period of time. [10][11][12] Therefore, close monitoring and control of BP is mandatory for reducing maternal complications even after delivery.
Nicardipine, a commonly used antihypertensive medication, is a potent vasodilator, which acts as a calcium channel blocker (CCB) on the vascular smooth muscle wall. [13][14][15] Nicardipine selectively responds to coronary and cerebral vessels over the systemic circulation, resulting in increased cerebral blood flow and oxygen delivery, with less inotropic effects on the myocardium. [16,17] Thus, nicardipine has been used widely for managing acute severe hypertension in patients with cerebrovascular accidents and postoperative BP control after cardiac or neurovascular surgery. [16,18] Previous studies on the efficacy of nicardipine in women with PE showed promising data that nicardipine may be equivalent or better than other antihypertensive agents in pregnancy, such as hydralazine and beta blockers, while ensuring maternal and fetal safety. [16,[18][19][20][21][22][23] Moreover, during the MKK and KRC contributed equally to this work. Medicine postpartum period, the target BP can be obtained by taking advantage of nicardipine without fear of causing side effects to the fetus. No studies have been conducted to determine whether the continuous infusion of nicardipine during the postpartum period is useful for the control of severe hypertension, compared to other conventional antihypertensive agents. This study aimed to assess the effectiveness of the continuous nicardipine infusion for the management of uncontrolled BP during the postpartum period.

Study design and population
A retrospective cohort study was performed on consecutive pregnant women who had been diagnosed with hypertensive disorders of pregnancy (chronic hypertension, gestational hypertension, PE, superimposed PE, and eclampsia) and had delivered after 24 weeks of gestation due to indications of maternal hypertensive diseases at Seoul National University Bundang Hospital from January 2018 to December 2020.
We used the definitions for each hypertensive disorder of pregnancy according to the guidelines of the American College of Obstetricians and Gynecologists. [2,24] When hypertension was diagnosed before pregnancy, the patient was classified as having chronic hypertension. Gestational hypertension was diagnosed when BP elevation was found after 20 weeks of gestation without proteinuria or other systemic findings. PE was defined as hypertension in association with one of the following: proteinuria or thrombocytopenia (cell counts < 100,000/mL), impaired liver function (2 folds elevation of liver enzymes), progressive renal insufficiency (serum creatinine > 1.1 mg/dL or twice the previous value), pulmonary edema, or new-onset cerebral symptoms or visual disturbance. Superimposed PE was defined as the development of PE in patients already diagnosed with chronic hypertension. If seizures were present in a woman with known PE or other hypertensive disorders, eclampsia was diagnosed.
Among the 309 patients, 209 (approximately 68%) presented with uncontrolled BP with systolic BP ≥ 160 mm Hg or diastolic BP ≥ 110 mm Hg on the day of delivery (Fig. 1). The study population was divided into 2 groups: patients who received a continuous infusion of nicardipine at the time of initial detection for high BP and those controlled by other antihypertensive medications intermittently administered for every moment of high BP measured. The patient assignment to continuous nicardipine group was implemented; When BP exceeded a severe range (160/110 mm Hg) at least 2 consecutive times during delivery, regardless of whether the patient had undergone vaginal delivery or cesarean section, or; When a patient diagnosed with PE showed at least 1 severe feature. In addition, all patients received magnesium sulfate infusion for seizure prophylaxis.
Maternal characteristics, all the measured BP data, other vital signs, the types and numbers of administered medications, and the cumulative doses were evaluated through electronic medical chart review. All BP data for 28 hours (from 4 hours before delivery to 24 hours after delivery) were analyzed at 4-hour intervals. The highest BP data and the proportion of uncontrolled BP defined as a systolic BP of ≥ 160 mm Hg or a diastolic BP of ≥ 110 mm Hg in each time interval were extracted from each patient. The symptoms considered as side effects (e.g., nausea, dizziness, palpitation, headache, or flushing sense) from medications including antihypertensive agents and others, including magnesium sulfate, were also checked. The study protocol was approved by the Institutional Review Board of the Seoul National University Bundang Hospital (No. B-1905-538-102).
At our institution, intravenous (IV) continuous nicardipine infusion was given with the fixed rate of 0.5 mcg/kg/minutes by infusion pump and was discontinued after approximately a day. Other agents used for postpartum BP control were IV bolus of labetalol (a well-known beta blocker) or hydralazine, and they were given instantaneously whenever BP was measured to exceed a systolic BP of > 160 mm Hg or a diastolic BP of > 110 mm Hg. When either labetalol or hydralazine was administered, BP was measured after 15 minutes of resting, and if BP did not subside to the target range, an additional dose or alternative medication was administered. Once the aforementioned BP thresholds were achieved and found to be consistently controlled, the measurement was repeated with longer intervals, such as every 30 minutes or after certain hours.
Patients with a BP between 140/90 mm Hg and 160/110 mm Hg during pregnancy were treated with oral anti-hypertensive medications to reach a target BP less than 140/90 mm Hg. Patients were monitored in the outpatient department unless severe hypertension developed. In the majority of cases, the prescribed first line anti-hypertensive agent was extended-release nifedipine. Patients were instructed to monitor their BP at home. During clinic visits, the initial prescribed dose (30 mg) of nifedipine was escalated up to 120 mg per day. A minority of patients were prescribed amlodipine (5-10 mg) first if this was preferred by the physician. Second line medication involved the addition of oral hydralazine (12.5 mg) to either nifedipine or amlodipine to achieve the target BP.

Statistical analysis
The Mann-Whitney U-test was used to compare continuous variables, while the χ 2 test was used for categorical variables. Statistical significance was set at P < .05. The data were analyzed using SPSS 25.0 (IBM, Armonk, NY). A modularized Python code that automatically performs the standardization process (version 3.6, Python Software Foundation) was used to analyze all the data extracted during hospitalization of the whole study population and to understand the trends of BP changes according to the timelines.

Patient characteristics
The study population consisted of 135 patients diagnosed with PE, 44 with gestational hypertension, 10 with chronic hypertension, 18 with superimposed PE, and 2 with eclampsia ( Fig. 1). Among them, approximately one-fourth of the patients (53/209) received continuous infusion of nicardipine immediately postpartum, while others did not.
The demographic and clinical characteristics of the study population are presented in Table 1. The mean gestational age at delivery was significantly earlier in the nicardipine group than in the control group (34.5 vs 35.1 weeks, P = .046). Other maternal characteristics did not differ between the 2 groups. The proportions of each type of hypertensive disorder of pregnancy were comparable; however, the rate of eclampsia was higher in the nicardipine group than in the control group (4% vs 0%, P = .015). The additional antihypertensive medications used were IV side shots of labetalol and hydralazine. The proportions of patients receiving labetalol and hydralazine for the control group were 14.1% (22/156) and 13.5% (21/156), respectively, and these numbers were higher than those administered additionally to nicardipine in the continuous nicardipine infusion group (9.4% [5/53] and 5.7% [3/53], respectively). The median total dosages of labetalol and hydralazine used in the control group were 20 mg (range 10-70 mg) and 10 mg (range 5-40 mg), respectively. In the nicardipine group, the dosages of labetalol and hydralazine additionally used with nicardipine were 10 mg (range 10-50 mg) and 8 mg (range 5-10 mg), respectively, which were much lower than those in the control group. Table 2 shows a comparison of the averages of highest BP checked in each time interval from 4 hours before delivery to 24 hours postpartum. The mean values of both systolic BP and diastolic BP immediately before delivery were higher in the nicardipine group than in the control group; however, the difference was statistically significant only for the analysis of diastolic BP (116 vs 111 mm Hg, P = .043). Up to 8 hours after delivery, there was no significant difference between the 2 groups. After 8 to 12 hours following delivery, the mean values Table 1 Demographic and clinical characteristics of the study population according to postpartum continuous nicardipine use.

Characteristics
Nicardipine of both systolic and diastolic BP were lower in the nicardipine group than in the control group. Subsequently, in the time interval of 16 to 20 hours following delivery, the averages of both systolic BP and diastolic BP were significantly lower in the nicardipine group than in the control group (137/80 vs 141/84 mm Hg, P = .031 for systolic BP, P = .035 for diastolic BP). The trends in BP control for the 2 groups are presented in Figure 2. Table 3 demonstrates subgroup analysis of the average highest BP in patients taking oral anti-hypertensive medication. A Table 2 Comparison of the highest blood pressure during postpartum 24 hours according to the use of continuous nicardipine infusion. Values are presented as mean ± standard deviation. BP = blood pressure. a P-value of comparison in systolic blood pressure between 2 groups. b P-value of comparison in diastolic blood pressure between 2 groups, bold values represent the statistically significant results.  Figure 3. The numbers of uncontrolled BP (defined as a systolic BP of > 160 mm Hg or a diastolic BP of > 110 mm Hg) detected for each group are shown in Figure 4. Before delivery, the nicardipine group showed higher proportions of uncontrolled BP detection than the control group (38% vs 32%, P = .032). The rates of uncontrolled BP detection during the postpartum period were lower in the nicardipine group than in the control group at all the time intervals from 8 hours following delivery, even though the difference did not reach statistical significance.

Discussion
According to the detection of BP for each 4-h-interval, the nicardipine group had both lower systolic BP and diastolic BP than the control group in the postpartum period, especially after 8 hours following delivery. The frequency of severely high BP detected in the postpartum period was lower in the nicardipine group than in the control group, and the trend graph demonstrated the possibility of a more stable antihypertensive effect of continuous nicardipine infusion than the control group, which followed the protocol using intermittent administration for each detection of uncontrolled high BP.
These results could be meaningful since the nicardipine group is assumed to have more severe patients or severe clinical features compared with the control group. In fact, the proportions of currently diagnosed hypertensive disorders and other maternal characteristics were not different; however, the gestational age at delivery was significantly earlier in the nicardipine group than the control group (34.5 vs 35.1 weeks, P = .046), implying that the clinical features of the nicardipine group could have been slightly more emergent than those of the control group. Moreover, the proportion of eclampsia was 4% in the nicardipine group and none in the control group. Although the features were more severe in patients who had received continuous nicardipine infusion, Figures 2 and 3 show that hypertension in the nicardipine group was controlled better than that of the control group with several short-acting shots of other agents.
If the effect to control hypertension is better or at least comparable to other antihypertensive agents, continuous infusion of nicardipine for the acute phase of severely high BP in the postpartum period helps in the management of hypertensive disorders in pregnancy. In clinical settings, close monitoring with repeated administration of short active agents and frequent measurements of vital signs thereafter for postpartum patients is a remarkable burden for medical facilities in terms of costs and labor of human resources. In this study, continuous infusion of CCB during the postpartum period in patients who had given birth and still presented with uncontrolled hypertension could be an alternative for intermittent use of antihypertensive agents at the sight of detection for high BP and could be used as a routine protocol for some indicated high-risk pregnancies, expecting to have a long time to recover from hypertension developed during pregnancy, even after delivery.
Severe hypertension that develops during the postpartum period is exacerbated by various iatrogenic conditions (e.g., volume retention, sympathomimetic activation, and vasoconstriction by ergonovine). [8,25] Acute and sudden onset of uncontrolled BP can lead to endothelial damage to multiple organs, cerebral edema sometimes accompanied by brain injury, and potentially maternal death. [8,20,[25][26][27] Thus, severe hypertension is an emergent condition for all pregnant women diagnosed with PE or other hypertensive disorders. Nevertheless, the postpartum state is likely to be neglected or is monitored less intensively than during pregnancy because termination of pregnancy is a wellknown treatment of choice. A previous study pointed out that one of the factors associated with delayed treatment for hypertensive emergencies was overnight severe hypertension occurring between 10 PM and 6 AM. [28] During the night, striking BP or symptoms of hypertension could be missed. Continuous infusion of nicardipine can prevent these risks and, thus, could be a complementary method to keep BP stable after delivery.
The antihypertensive mechanism of CCBs is far more suitable than other agents from the perspective of the pathophysiology of PE and other hypertensive disorders specified in pregnancy. In patients with PE, cardiac output is decreased, and intravascular volume expansion is restricted due to elevated systemic vascular resistance. This systematic change would impact decreased renal blood flow, lowered glomerular infiltration rate, and eventually oliguria. [9] Nicardipine has been proven to have advantages in increasing coronary blood flow and cardiac pumping activity. In addition, nicardipine improves glomerular infiltration rate by lowering renovascular resistance. [29] Therefore, nicardipine can act as an effective antihypertensive agent that can provide additional positive effects and manage severe hypertension, especially in women with PE with severe features.
In the subgroup analysis, continuous IV infusion of nicardipine showed a greater anti-hypertensive effect among patients with oral medications. One possible explanation the is pharmacokinetic interaction of CCB. In the study population, the major type of oral anti-hypertensive medication was CCB, in Table 3 Comparison of the highest blood pressure during the first 24 hours postpartum in patients with oral anti-hypertensive medication during pregnancy, according to the use of continuous nicardipine infusion. Values are presented as mean ± standard deviation. BP = blood pressure. a P-value of comparison in systolic blood pressure between 2 groups. b P-value of comparison in diastolic blood pressure between 2 groups. particular, extended-release nifedipine followed by amlodipine. Thus, it is plausible that enhanced pharmacological effects of the combination of dual CCB therapy would result in greater anti-hypertensive effect. [30] In fact, patients receiving oral medication were assumed to have more chronic hypertension compared to patients without oral medication. The rates of superimposed preeclampsia and chronic hypertension were higher in patients with oral medication compared with those without (P < .001, 31.3% vs 2.8% for superimposed preeclampsia; P < .001, 14.9% vs 2.1% for chronic hypertension). Thus, it could be presumed that the additive effect of nicardipine with either nifedipine or amlodipine was reflected in the significantly greater anti-hypertensive activity, particularly in patients with chronic hypertension. A few current guidelines recommend continuous IV infusion of nicardipine as a second-line alternative to refractory hypertension, which is not controlled by other initiating agents such as IV bolus of labetalol or hydralazine. [11,25,26] Nicardipine infusion is sometimes used for the antenatal period as well; however, CCBs are not commonly infused during pregnancy because they affect the muscular functions of the uterus and can lower the tone of the extremities or respiratory muscles. Oral CCB agents are used as tocolytics as well as antihypertensive agents during pregnancy.
Although few adverse maternal reactions have been reported for the use of nicardipine during pregnancy compared with that for the use of hydralazine, labetalol, or ketanserin, [19]