Isradipine for Treatment of Acute Hypertension in Hospitalized Children and Adolescents

Authors

  • Yosuke Miyashita MD, MPH,

    1. From the Division of Nephrology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA ; 1Group Health Research Institute, Seattle, WA ; 2Departments of Health Services & Pediatrics, Maternal Child Health Program & Adolescent Medicine Section ; 3 and Division of Nephrology, Pediatric Hypertension Program,4 Seattle Children’s Hospital, University of Washington, Seattle, WA
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  • 1 Do Peterson MS,

    1. From the Division of Nephrology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA ; 1Group Health Research Institute, Seattle, WA ; 2Departments of Health Services & Pediatrics, Maternal Child Health Program & Adolescent Medicine Section ; 3 and Division of Nephrology, Pediatric Hypertension Program,4 Seattle Children’s Hospital, University of Washington, Seattle, WA
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  • 2 Jane M. Rees PhD, MS, RD,

    1. From the Division of Nephrology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA ; 1Group Health Research Institute, Seattle, WA ; 2Departments of Health Services & Pediatrics, Maternal Child Health Program & Adolescent Medicine Section ; 3 and Division of Nephrology, Pediatric Hypertension Program,4 Seattle Children’s Hospital, University of Washington, Seattle, WA
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  • and 3 Joseph T. Flynn MD, MS 4

    1. From the Division of Nephrology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA ; 1Group Health Research Institute, Seattle, WA ; 2Departments of Health Services & Pediatrics, Maternal Child Health Program & Adolescent Medicine Section ; 3 and Division of Nephrology, Pediatric Hypertension Program,4 Seattle Children’s Hospital, University of Washington, Seattle, WA
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Yosuke Miyashita, University of Pittsburgh, Children’s Hospital of Pittsburgh of UPMC, Division of Nephrology, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224
E-mail: yosuke.miyashita@chp.edu

Abstract

J Clin Hypertens (Greenwich).

Severe acute hypertension in pediatric patients requires prompt and controlled blood pressure (BP) reduction to prevent end-organ damage. The authors aimed to examine the efficacy and safety of isradipine, an orally administered second-generation dihydropyridine calcium channel blocker, for treatment of acute hypertension in hospitalized pediatric patients. A retrospective analysis of 391 doses of isradipine administered to 282 patients (58% boys) with acute hypertension and median age of 12.8 years (range, 0.1–21.9) was performed. Primary diagnoses included renal disease (n=154), malignancy (45), nonrenal transplant (37), neurologic disease (21), and other (25). The decrease in systolic BP was 16.3%±11.6% (mean ± SD) and diastolic BP was 24.2%±17.2%. BPs were significantly lower in all age groups and in all diagnosis categories following isradipine administration. The decrease in BP was the highest in children younger than 2 years. The mean increase in pulse after a dose was 7±17 beats per minute. Forty adverse events were reported in 33 patients, with emesis and nausea being the most common; 5 of these events were hypotension. The authors conclude that isradipine effectively reduces BP in a wide variety of hospitalized children and adolescents with acute hypertension. A lower initial dose of 0.05 mg/kg may be appropriate in children younger than 2 years. J Clin Hypertens (Greenwich). 2010;12:850–855.

Severe acute hypertension in children, if left untreated, can lead to end-organ damage, most frequently affecting the central nervous system.1 While this provides impetus for prompt treatment, therapy must also be restrained, as current expert recommendations are to reduce mean arterial pressure (MAP) by no more than 25% in the first 8 to 12 hours of therapy to reduce the risk of end-organ ischemia from overly aggressive blood pressure (BP) reduction.2

For many years, short-acting (SA) nifedipine has been recommended for management of acute hypertension in pediatrics.1,3,4 However, this agent is considered contraindicated in adults with acute hypertension because of the risk for sudden and severe reduction in BP that can lead to ischemic events.5 The pediatric literature on SA nifedipine has been more controversial. While its efficacy has been supported by several case series,6–8 there are also a number of reports of adverse events after use of SA nifedipine in children, including sudden severe reduction in BP,6–8 change in neurological status,7 cerebral ischemia,9 and ventricular arrhythmia.10 Additionally, administration of SA nifedipine to infants and small children is difficult because of the high concentration of drug in the liquid within the capsule.11 For these reasons, some experts have recommended that alternative agents be used.12,13

Isradipine is a second-generation dihydropyridine calcium channel blocker with initial BP response occurring in approximately 1 hour, peak serum concentration in 1 to 3 hours, and peak response in 2 to 3 hours.11,14,15 It is one of a number of agents recommended for acute hypertension in children.2 A stable extemporaneous suspension can be formulated using powder from the capsule, allowing accurate dosing in infants and young children.16 There are several published pediatric case series of long-term isradipine use in hypertensive children17–19 and one report of its use in adults with acute hypertension,20 but none examining its efficacy in pediatric acute hypertension. The objective of this study therefore was to describe the efficacy of isradipine for acute hypertension in hospitalized children and adolescents.

Methods

Study Design

This was a single-center retrospective observational study of all isradipine doses administered at Seattle Children’s Hospital between January 1, 2006, and December 31, 2007. Inclusion criteria included patients receiving isradipine in the emergency department or inpatient units for treatment of acute BP elevations as determined by the treating clinicians and patients who had BP recordings available in the medical records. We limited our analysis to first doses administered to ensure that the BP change reflected response to a single dose of isradipine. Exclusion criteria included no documented BP recording prior to isradipine dose, no documented BP recording within 6 hours after a dose, and isradipine given for reasons other than acute hypertension (eg, patients receiving long-term isradipine).

We reviewed medical records for patients’ age, sex, weight, primary diagnosis, BP, and pulse rate just prior to isradipine dose, the lowest BP and concurrent pulse rate within 6 hours of the dose, the timing of the lowest BP, use of concurrent long- and short-term antihypertensive medication, and documentation of events and new symptoms within 6 hours of the dose in nursing records. The institutional review board at Seattle Children’s Hospital approved data collection for this study.

Statistical Analysis

The primary statistical analysis was descriptive statistics on percent change in systolic BP (SBP), diastolic BP (DBP), and pulse rate after isradipine, and paired t tests for change in SBP, DBP, and pulse rate. For SBP and DBP, the null hypotheses were percent change in BP=0 with α=0.025 (Bonferroni correction) and pulse change=0 with α=0.05. We additionally performed multiple linear regression as a secondary analysis to determine whether any patient characteristics were associated with differences in BP change. The baseline linear regression model had post-isradipine MAP as the dependent variable and dose (mg), patient’s weight (kg), and pre-isradipine MAP as the independent variables. Other patient characteristics such as age, sex, diagnosis, isradipine formulation (capsule vs suspension), use of long-term BP medication(s), and use of other concurrent short-term BP medication(s) were entered into the models to determine whether these characteristics were associated with differences in MAP change. MAP was calculated as: MAP=DBP+[(SBP−DBP)/3]. We chose MAP as the dependent variable for the regression since expert recommendations for goal BP reduction in short-term hypertension therapy is given for change in MAP. Finally, the rank-sum test was used to determine whether there was an association between dose size and occurrences of MAP decrease >25%, between dose size and adverse events, and between MAP decrease >25% and adverse events.

More than 100 of these doses included in the full dataset were in patients who had received isradipine during more than one hospitalization. Given this, we re-analyzed the data and excluded repeated admissions by the same patients. These results (data not shown) were nearly identical to those including all doses; therefore, we are reporting the results of the full dataset analysis only.

Results

Patients

During the study period, 2111 doses of isradipine were administered at Seattle Children’s Hospital. A total of 391 doses met the above inclusion and exclusion criteria and were included in this analysis (Figure). Patient median age was 12.8 years (range, 0.1–21.9 years). Table I describes the demographic and clinical characteristics of the study population. There was a wide range in age groups, with 2- to 12-year-olds and 12- to 17-year-olds being the most frequent, at 32% and 43%, respectively. Renal patients, including those who received dialysis and renal transplants, made up the largest diagnosis group, with 154 patients (55%). They were followed by 45 patients (16%) with malignancy, 37 patients (13%) with nonrenal transplants, 21 patients (7%) with neurological diseases, and 25 patients (9%) with other diagnoses.

Figure Figure.

 Diagram of inclusion and exclusion criteria for isradipine doses given at Seattle Children's Hospital during the study period.

Table I.   Patient Characteristics (N=391)
CharacteristicNo. (%)
Sex 
 Male225 (58)
 Female166 (42)
Age, y 
 0–234 (9)
 2–12127 (32)
 12–17167 (43)
 ≥1763 (16)
Dose, mg/kg 
 0–0.554 (14)
 0.05–0.1234 (60)
 ≥0.1103 (26)
Formulation 
 Capsule247 (63)
 Suspension144 (37)
Long-term blood pressure medications 
 No192 (49)
 Yes199 (51)
Short-term blood pressure medications 
 No273 (70)
 Yes118 (30)

A total of 247 doses were given as whole capsules and 144 were given as compounded suspension. In addition, 199 doses (51%) were given concurrently with at least one long-term BP medication, while 118 doses (30%) were given concurrently with at least one other short-term BP medication, arbitrarily defined as either 12 hours prior to or 6 hours after the dose of isradipine.

Effect on BP

Overall, both SBP and DBP decreased significantly; SBP decreased by 16.3%±11.6% (mean ± SD) (range, −14.3 to 51.9; P<.0001) and DBP decreased by 24.2%±17.2% (range, −34.7 to 74.2; P<.0001). The median time of lowest BP recorded after a dose of isradipine was 2.5 hours (2.7±1.5 hours). Using multiple linear regression, having a diagnosis of renal disease (P<.001) or neurologic disease (P=.03) was associated with a smaller decrease in MAP, while having a diagnosis of nonrenal organ transplant (P=.009) or malignancy (P=.002) was associated with a greater decrease in MAP. Other patient characteristics were not significantly associated with different degrees of MAP changes.

Table II shows the MAP percent decreases stratified by patient weight–adjusted dose size (mg/kg), age, and diagnosis. MAP decreased substantially across all dose ranges with possibly a slight trend for greater MAP decreases in the higher-dose categories. The two youngest age groups, 0- to 2-years-old and 2- to 12-years old, had the greatest mean MAP percentage decrease. While there were statistically significant differences in MAP change between diagnosis groups, the clinical responses were of similar magnitude.

Table II.   Stratified Analysis of Decrease in MAP and Increase in Pulse by Weight Adjusted by Dose, Age, and Diagnosis
  Decrease in MAP, %Increase in Pulse, %
 No. (%)Mean ± SDMean ± SDP Value
  1. Abbreviations: MAP, mean arterial pressure; SD, standard deviation.

Dose, mg/kg
 ≤0.0554 (14)16.3±10.53±16.24
 0.05–0.10234 (60)20.9±13.57±16<.0001
 ≥0.10103 (26)23.3±14.28±18<.0001
Age, y
 0–234 (9)22.4±13.42±18.48
 2–12127 (32)23.3±14.16±17.0001
 12–17167 (43)19.3±13.39±17<.0001
 ≥1763 (16)19.7±11.94±12.014
Diagnosis
 Renal232 (59)19.2±12.66±15<.0001
 Malignancy56 (14)24.6±14.19±17.0001
 Nonrenal transplant54 (14)25.4±14.310±19.0002
 Neurologic22 (6)15.6±11.0−3±14.33
 Others27 (7)22.7±15.23±21.39

Because there were a substantial number of patients in the data sample who received long-term BP medication(s) and/or concurrent short-term BP medication(s), there may have been a confounding association between isradipine and BP reduction, although multiple linear regression analysis indicated that this was not the case. A separate stratified analysis indicated that similar BP reduction was seen in all settings. The SBP reduction and DBP reduction in patients receiving isradipine only (n=141) was 16.0%±10.9% (P<.0001) and 24.9%±17.4% (P<.0001), respectively. The SBP reduction and DBP reduction in patients receiving isradipine and short-term BP medication(s) (n=51) was 19.8%±13.9% (P<.0001) and 27.4%±17.6% (P<.0001), respectively. The SBP reduction and DBP reduction in patients receiving isradipine and long-term BP medication(s) (n=132) was 14.9%±11.0% (P<.0001) and 21.8%±17.4% (P<.0001), respectively. Finally, the SBP reduction and DBP reduction in patients receiving isradipine and both short- and long-term BP medication(s) (n=67) was 17.2%±11.5% (P<.0001) and 24.8%±15.8% (P<.0001), respectively.

Adverse Effects

The increase in pulse rate was 7±17 beats per minute. When stratified by weight-adjusted dose, age, and diagnosis, the pulse rate increases were approximately in the same range, as indicated in Table II.

There were a total of 40 adverse events documented by nursing staff after 33 doses of isradipine: 8 events each of emesis and headache, 5 events of nausea, 4 events of hypotension requiring intervention, 3 events each of flushing/feeling hot and dizziness/lightheadedness, 2 events of palpitations, and 1 event each of hypotension (received no intervention), abdominal pain, preventricular contraction, chest pain, irritability, confusion, and itchiness.

A total of 5 doses were documented to have caused hypotension with 4 of the 5 patients receiving intervention by clinicians. All 4 patients received normal saline boluses and 1 patient was briefly treated (for 67 minutes) with a dopamine infusion. Table III provides further information about these patients. They received isradipine doses between 0.06 and 0.11 mg/kg. One of the 5 patients had also received 10 mg of intravenous hydralazine approximately 1 hour prior to isradipine. Interestingly, all 5 of these patients were concurrently receiving azole antifungals, either fluconazole or voriconazole.

Table III.   Characteristics and Medical Intervention Performed on Patients Documented to Have Severe Hypotension After Isradipine Administrationa
Age, yDiagnosisDose, mg (mg/kg)FormulationChange in Pulse RateOther BP MedicationsIntervention
  1. Abbreviations: BP, blood pressure; NS, normal saline. aAll patients received either fluconazole or voriconazole.

18Malignancy10 (0.11)Capsule16Hydralazine 10 mgNS bolus
15Malignancy2.5 (0.06)Capsule48NoneNS bolus and dopamine drip
15Nonrenal transplant4.8 (0.1)Suspension4NoneNS bolus
11Malignancy3.5 (0.1)Suspension24NoneNS bolus
14Renal5 (0.07)Capsule20EnalaprilNone

We conducted a further analysis of isradipine doses that resulted in a decrease in MAP >25% (Table IV). There was a statistically significant difference in dose size between doses that resulted in MAP decrease >25% vs those that resulted in MAP decrease <25%: 0.09 mg/kg vs 0.08 mg/kg. When stratified by age groups, the two youngest groups had the most frequent MAP decrease >25% (47% of 0- to 2-year-olds, 43% of 2- to 12-year-olds). Finally, there was no significant association found between adverse events and dose size (P=.21, Mann-Whitney) or between adverse events and MAP decrease >25% (P=.12, Mann-Whitney).

Table IV.   Dose Difference in MAP Decrease >25% vs <25% and Frequency of MAP Decrease >25% Stratified by Age
MAP decreaseMedian dose, SD (mg/kg)P Value (Mann-Whitney)
  1. Abbreviations: MAP, mean arterial pressure; SD, standard deviation.

 <25%0.08 (0.031).008
 >25%0.09 (0.028) 
Age categories, y
  0–247% 
 2–1243% 
 12–1729% 
 ≥1727% 

Discussion

The choice of agent for therapy of acute hypertension is mainly determined by the clinical condition and treatment goal for each individual patient, and there are a number of possible agents, both oral and intravenous, available.2,21 Because of concerns about adverse events related to SA nifedipine, Seattle Children’s Hospital adopted isradipine for first-line oral therapy for acute hypertension in the early 2000s. In this study, the first to describe the use of isradipine treatment of acute hypertension in children and adolescents in the hospital setting, we demonstrate that isradipine effectively lowered BP in a wide variety of hypertensive patients. Clinical characteristics such as patients’ sex, age, use of long- and short-term antihypertensive medication, and isradipine formulation did not appear to influence the efficacy of the medication.

As indicated by the wide range of SBP and DBP decreases, the BP response to individual isradipine doses was quite variable. A greater percentage of MAP decreases and most frequent MAP decrease >25% were observed in the youngest age group, younger than 2 years. In addition, since younger patients have lower baseline BPs, the same percentage of MAP reduction will most likely result in more clinically significant BP reduction in younger patients. Therefore, a lower starting dose of 0.05 mg/kg may be appropriate for this age group. There was a statistically significant difference in dose size between doses that resulted in MAP decrease >25% vs those that resulted in MAP decrease <25%: 0.09 vs 0.08 mg/kg. However, this 0.01-mg/kg dose difference is most likely clinically insignificant. Interestingly, there was no significant association between dose size and occurrence of adverse events or between MAP decrease >25% and occurrences of adverse events.

Adverse events were documented in approximately 8% of isradipine doses analyzed. Whether there was a direct causal relationship between many of these events and isradipine administration is uncertain since these were hospitalized patients, many of whom had concurrent medical problems. However, hypotension certainly can be linked to use of isradipine. The most intriguing common patient characteristic was that all 5 of the patients who were noted to be hypotensive were concurrently receiving azole antifungals agents. Isradipine is a substrate of cytochrome P450 CYP3A3/4, which is inhibited by azole antifungals. It is likely that altered calcium channel blocker metabolism producing an exaggerated clinical response might be expected in patients receiving azole antifungals. Therefore, choosing an alternative antihypertensive medication may be warranted for patients receiving azole antifungals.

Limitations of the Study

There are a number of limitations to this study, the first of which is its single-center retrospective observational design without an active treatment or placebo group against which to compare the efficacy of isradipine. Second, we used the lowest recorded BP measurement to represent efficacy of the medication, following similar methods used in earlier studies of SA nifedipine.6–8 However, this may not be completely representative of the efficacy of the medication given the wide fluctuation of BPs that may have occurred in the several hours following administration of isradipine. Third, documented adverse events using nursing records may not be truly reflective of actual events related to isradipine. As mentioned before, this data sample was from hospitalized children and adolescents and many of the documented events may have been related to other factors and not isradipine. Conversely, the documented events may have been incomplete. Lastly, given the design of this study, all potential confounders are likely unaccounted. We collected many patient characteristics that could theoretically influence efficacy of isradipine including age, sex, diagnosis, formulation, and use of other long- and short-term antihypertensive medication. Using multiple linear regression, only underlying diagnosis had a statistically significant effect on BP change, but we cannot be sure that there were not additional patient factors that might have influenced the BP response to isradipine.

Conclusions

Isradipine was an effective agent for treatment of hospitalized children and adolescents with acute hypertension and had an acceptable rate of adverse effects. Given larger-than-desired degrees of BP reduction, an initial dose of no more than 0.05 mg/kg should be used in children younger than 2 years, and an alternative non–calcium channel blocker antihypertensive agent should be considered for patients concurrently receiving azole antifungals.

Acknowledgments and disclosures:  Statistical consultation was supported by a University of Washington House Staff Association Research Grant. Yosuke Miyashita, MD, MPH, was supported by the University of Washington Pediatric Nephrology Research Training Grant T32 DK007662. Joseph Flynn, MD, MS, is a consultant to Pfizer, Inc, and Novartis Pharmaceuticals. The other authors have no actual or perceived conflicts of interest to disclose.

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