Pediatric Cardiology

, Volume 27, Issue 4, pp 402–407

A Prospective Evaluation of Nesiritide in the Treatment of Pediatric Heart Failure

Authors

  • J.L. Jefferies
    • Division of Pediatric CardiologyTexas Children’s Hospital
    • Section of Advanced Heart FailureTexas Heart Institute at St. Luke’s Episcopal Hospital, Baylor College of Medicine
  • S.W. Denfield
    • Division of Pediatric CardiologyTexas Children’s Hospital
  • J.F. Price
    • Division of Pediatric CardiologyTexas Children’s Hospital
  • W.J. Dreyer
    • Division of Pediatric CardiologyTexas Children’s Hospital
  • C.J. McMahon
    • Division of Pediatric CardiologyTexas Children’s Hospital
  • M.A. Grenier
    • Division of Pediatric CardiologyTexas Children’s Hospital
  • J.J. Kim
    • Division of Pediatric CardiologyTexas Children’s Hospital
  • V.V. Dimas
    • Division of Pediatric CardiologyTexas Children’s Hospital
  • S.K. Clunie
    • Division of Pediatric CardiologyTexas Children’s Hospital
  • B.S. Moffett
    • Division of PharmacyTexas Children’s Hospital
  • A.C. Chang
    • Division of Pediatric CardiologyTexas Children’s Hospital
  • T.I. Wann
    • Division of Pediatric CardiologyTexas Children’s Hospital
  • E.O. Smith
    • Division of NutritionTexas Children’s Hospital
    • Division of Pediatric CardiologyTexas Children’s Hospital
Article

DOI: 10.1007/s00246-005-1294-8

Cite this article as:
Jefferies, J., Denfield, S., Price, J. et al. Pediatr Cardiol (2006) 27: 402. doi:10.1007/s00246-005-1294-8

Abstract

This study sought to determine the potential of recombinant B-type natriuretic peptide (nesiritide) for the treatment of pediatric decompensated heart failure. Nesiritide is a widely used and effective treatment for decompensated heart failure (HF) in adults, but its safety and efficacy in pediatric patients is unclear. Outcomes of 55 separate nesiritide infusions of varying durations in 32 patients (13 males and 19 females; mean age, 8.01 years; range, 0.01–20.4) were evaluated prospectively. All patients received nesiritide in the intensive care unit. The starting dose (0.01 μg/kg/min) was titrated to a maximum of 0.03 μg/kg/min. All patients were monitored for clinical signs and symptoms, hemodynamics, urine output, electrolytes, oxygen requirements, and oral intake. Functional status was assessed by patients and/or their parents. All patients successfully underwent initiation and titration of nesiritide infusion. No hypotension or arrhythmias were noted during 478 cumulative days of therapy. Nesiritide was given safely with vasoactive medications. Mean urine output improved from 2.35 ± 1.71 cc/kg/hr on the day before nesiritide initiation (baseline) to 3.10 ± 1.94 cc/kg/hr on day 4 of treatment (p < 0.01). Serum creatinine decreased from 1.04 to 0.92 mg/dl (p = 0.096), mean central venous pressure from 13 to 7 mmHg (p = 0.018), and mean weight from 30.4 to 29.7 kg (p < 0.001) with therapy. Thirst, as subjectively assessed by patients old enough to respond, decreased with infusion in 31 of 42 cases (74%). Mean New York Heart Association functional class improved significantly (p < 0.001). Nesiritide infusion, alone or in combination, is a safe treatment for decompensated HF in pediatric patients. It is associated with decreased thirst and improved urine output and functional status, and it may be efficacious in the treatment of pediatric HF.

Key words

Heart failureNatriuretic peptidesPediatrics

Heart failure continues to be a significant cause of morbidity and mortality in the United States, Most of these cases occur in the adult population. Heart failure in the pediatric population is not well-defined, but data from the Pediatric Cardiomyopathy Registry suggest an annual incidence of 1.13 cases of cardiomyopathy per 100,000 [11]. The majority of children with dilated cardiomyopathy have heart failure. In adults, a large percentage of patients have ischemic cardiomyopathy. However, in children, ischemia is relatively rare. The etiology is more likely infection, inherited disease, or congenital disease. The Pediatric Cardiomyopathy Registry reports 27% of heart failure patients have a genetic diagnosis or syndrome and 5% of cases are secondary to myocarditis. Depending on the age of the patient, 25–75% of pediatric patients with heart failure have a diagnosis of congenital heart disease [2]. Current intravenous approaches to the management of decompensated heart failure include milrinone, epinephrine, dopamine, and dobutamine. However, a 5-year survival of 50% is still the expected outcome in pediatric heart failure patients.

B-type natriuretic peptide (BNP) is synthesized in the ventricular myocardium in response to volume overload. It is known to be a lusitropic agent and to result in arterial and venous dilatation, resulting in increased cardiac output without direct inotropic effects or reflex tachycardia [5, 22, 24]. BNP also results in suppression of the renin–angiotensin–aldosterone axis, as well as diuresis and natriureis [1, 3, 14, 23] The use of nesiritide (Natrecor, Scios, Fremont, CA, USA), a recombinant BNP, the management of adult patients with acutely decompensated heart failure is well described [5, 13, 15, 18]. However, the use of BNP for the management of heart failure in pediatric patients has not been well documented, although a small series of case reports have been published [8, 12].

The purposes of this pilot study were to (1) determine the safety of nesiritide infusion in children with regard to adverse events including hypotension and arrhythmias in the setting of cardiomyopathy and congenital heart disease, (2) determine the safety of nesiritide infusions given concomitantly with other vasoactive medications, and (3) determine the efficacy of nesiritide in the treatment of acutely decompensated heart failure in pediatric patients with congenital and acquired cardiac disease.

Materials and Methods

Study Design and Patient Recruitment

We performed a prospective cohort study in which all patients were evaluated before and after nesiritide infusion. All patients were treated at the Texas Children’s Hospital. Inclusion criteria included patients ranger than age 21 years having the diagnosis of decompensated heart failure. Exclusion criteria included the presence of a rhythm other than sinus rhythm and hypotension. All patients were evaluated by members of the Heart Failure Service from the Division of Pediatric Cardiology. Infusions were initiated and titrated in an intensive care setting in all patients.

Study Protocol

This study was approved by the institutional review board of the Baylor College of Medicine. For a subset of 20 patients, informed consent was obtained since nesiritide was not approved for inclusion in the Texas Children’s Hospital formulary at the time of their initial infusions. The remaining patients were not asked for informed consent because by the time of their initial infusions, nesiritide had been added to the Texas Children’s Hospital formulary for treatment of acutely decompensated heart failure.

Patients who met the inclusion criteria first underwent noninvasive assessment of blood pressure and heart rate and evaluation of serum electrolytes and serum BNP. In selected patients, appetite and thirst were assessed subjectively by the patient and documented before and after nesiritide therapy. In all cases, nesiritide was infused initially through a dedicated, peripheral intravenous line at a rate of 0.01 μg/kg/min. No patients received a bolus dose. The infusion dose was titrated upward in increments of 0.005 μg/kg/min at the discretion of the investigators and on the basis of clinical response and hemodynamics. The maximum nesiritide infusion dose was 0.03 μg/kg/min. During infusion, hemodynamics were monitored noninvasively, and urine output was documented. In selected patients requiring invasive monitoring, arterial blood pressure and central venous pressure were measured. Once the maximum dose was achieved, selected patients were continued on the infusion in a non-intensive care setting.

Discontinuation of the infusion was based on clinical compensation of heart failure and improvement in serum markers including BNP. Infusion was either discontinued immediately without downward titration or titrated downward by 0.01 μg/kg/min to a dose of 0.01 μg/kg/min and then discontinued. After infusion was discontinued, serum electrolyte levels were determined within 6 hours of completing the infusion. Serum BNP levels were determined 6 hours after discontinuing nesiritide therapy.

Statistical Analysis

Standard descriptive techniques were used to estimate incidence rates. A paired t-test was used to compare measures before and after nesiritide infusion. A p value of 0.05 was the criterion for statistical significance.

Results

A total of 55 separate infusions of nesiritide were given to 32 individual patients (13 males and 19 females). In all cases, nesiritide was infused continuously for at least 72 hours. Selected patients received more than 72 hours of therapy on the basis of their clinical status. The mean age of the patients was 8.01 years (range, 0.01–20.4). The underlying etiologies of heart failure present at the time of infusion varied, with congenital heart disease (14/55, 26%) and dilated cardiomyopathy (21/55, 38%) being most common (Table 1). No episodes of hypotension or arrhythmias were noted during nesiritide infusion. Selected patients (11/32) received more than one course of nesiritide therapy. These patients experienced good clinical response with the initial infusion but decompensated after discontinuation; thus, subsequent infusions of nesiritide were administered. A total of 478 infusion days were completed without adverse events.
Table 1

Baseline patient characteristics before nesiritide infusion (n = 55)a

Characteristic

No. (%)

Congenital disease

14 (26)

Dilated cardiomyopathy

21 (38)

Syndrome

7 (13)

Transplant

20 (36)

  Clinical evidence of rejection

9 (16)

  Coronary disease (transplant vasculopathy)

6 (11)

Pulmonary hypertension

29 (53)

Increased pulmonary artery disease (pulmonary artery pressure)

29 (53)

Renal disease

23 (42)

History of multiple cardiac surgeries

28 (51)

a Some patients received more than one infusion, and data reflect clinical status at each treatment.

Nesiritide was given concomitantly with furosemide during all infusions (100%), dopamine during 25 of 55 (45%), milrinone during 22 of 55 (40%), vasopressin during 5 of 55 (9%), epinephrine during 3 of 55 (5%), and ethacrynic acid during 42 of 55 (76%). Other drugs given concomitantly during nesiritide infusion were angiotensin-converting enzyme inhibitors in 36 of 55 cases (65%), beta-blockers in 26 of 55 (47%), spironolactone in 5 of 55 (9%), statins in 4 of 55 (7%), steroids in 28 of 55 (51%), and calcium channel blockers (amlodipine) in 14 of 55 (25%). These therapies were not typically uptitrated during nesiritide therapy. Intravenous immunoglobulin for treatment of presumptive myocarditis was given concomitantly during 8 of 55 infusions (15%), and immunosuppressive agents were given secondary to orthotopic heart transplantation during 23 of 55 (42%). Mechanical ventilation was performed during 15 of 55 infusions (27%).

During 13 of 55 infusions (24%), antibiotics were administered during at least part of the infusion period because there was a high index of suspicion of infection. Patients were being fed enterally during 39 of 55 infusions (71%) and parenterally during 16 of 55 (29%).

Patients capable of responding were asked to assess changes in appetite and thirst subjectively before and after nesiritide infusion. Thirty-one of 42 responding patients (74%) reported decreased thirst and 40 of 42 responding patients (95%) reported improved appetite with nesiritide therapy. Overall patient status and well-being, as assessed subjectively by both the patients and their parents, were also documented before and after nesiritide therapy. Forty of 46 patients (87%) and 47 of 55 parents (85%) reported a notable improvement in patient well-being with nesiritide therapy.

Serum BNP decreased significantly (p < 0.001) and serum creatinine and potassium decreased slightly (p = 0.096 and p = 0.091, respectively) after completion of nesiritide therapy. There was no significant change in serum sodium, chloride, bicarbonate, or blood urea nitrogen levels (Table 2).
Table 2

Changes in serum electrolyte, blood urea nitrogen, and creatinine levels with nesiritide therapy

Laboratory value

Before therapy (mean ± SD)

After therapy (mean ± SD)

p valuea

Sodium (mEq/L)

135.47 ± 5.74

135.93 ± 6.35

0.607

Potassium (mEq/L)

4.14 ± 0.77

3.93 ± 0.62

0.091

Chloride (mmol/L)

98.59 ± 6.80

95.65 ± 11.19

0.097

Bicarbonate (mmol/L)

24.76 ± 3.90

27.44 ± 10.37

0.079

Blood urea nitrogen (mg/dl)

38.44 ± 29.47

38.80 ± 26.21

0.897

Creatinine (mg/dl)

1.04 ± 0.67

0.92 ± 0.57

0.096

B-type natriuretic peptide (pg/ml)

1882.51 ± 1295.45

649.90 ± 571.90

< 0.001

a Wilcoxon signed-rank test.

No significant decreases in systolic or diastolic blood pressures were noted with therapy either during treatment or within 12 hours of its completion (p = 0.601 and p = 0.128, respectively). There was a decrease in heart rate immediately after completion of infusion, as well as 6 and 12 hours later (p < 0.001). A decrease in central venous pressure was noted (p = 0.018) as well as improvement in New York Heart Association class when assessment was possible (p < 0.001) (Table 3).
Table 3

Changes in functional parameters with nesiritide therapy

Parameter

Before therapy (mean ± SD)

After therapy (mean ± SD)

p value

Mean systolic blood pressure (mmHg)

94 ± 18

94 ± 15

0.601a

Mean diastolic blood pressure (mmHg)

56 ± 16

57 ± 14

0.128a

Mean heart rate (bpm)

113 ± 29

106 ± 28

< 0.001a

Mean central venous pressure (mmHg)

13 ± 2

7 ± 4

0.018a

Mean weight (kg)

30.4 ± 25.4

29.7 ± 24.6

< 0.001a

Mean urine output (cc/kg/hr)

2.35 ± 1.71

3.10 ± 1.95

<0.01

Gallop present (No.) (n = 55)

28 (51%)

16 (29%)

< 0.001a

Mean New York Heart Association class

3.5 ± 0.6

2.2 ± 1.0

< 0.001b

a Wilcoxon signed-rank test.

b McNemar test.

Mean urine output improved from 2.35 ± 1.71 cc/kg/hr at baseline to 3.10 ± 1.94 cc/kg/hr on day 4 of therapy (p < 0.01) (Table 3). Urine output on each of the initial 4 days of therapy was significantly greater than at baseline (p = 0.01) (Fig. 1).
https://static-content.springer.com/image/art%3A10.1007%2Fs00246-005-1294-8/MediaObjects/246_2005_1294_f1.jpg
Fig. 1

Urine output (mean ± SD) before and after initiation of nesiritide infusion (p = 0.01). Urine output increased significantly in the first 4 days of nesiritide therapy.

Discussion

The results of this pilot study indicate that nesiritide can be given safely to pediatric heart failure patients with or without congenital heart disease and that nesiritide may be efficacious in the treatment of pediatric heart failure. The results also indicate that nesiritide can be given to patients receiving other vasoactive medications safely, resulting in improved clinical response.

The management of heart failure continues to place a significant clinical and financial burden on the health care system. Guidelines have been developed for the management of decompensated heart failure in children [16]. However, these guidelines are limited secondary to a paucity of pediatric studies. The use of nesiritide, a recombinant form of BNP, is well documented and approved in the treatment of adults with heart failure. There are isolated reports of nesiritide therapy in children in the setting of heart failure but with very small numbers of patients evaluated [8, 12]. In this larger pediatric series, we safely used nesiritide in a broad range of pediatric patients with heart failure caused by congenital heart disease, cardiomyopathy, and orthotopic cardiac transplantation rejection without significant adverse events. Further studies are required to assess if there is a similar impact on the number of hospitalizations, hospital length of stay, and long-term outcomes as has been reported in the adult population [4, 6, 10].

In many adult studies, nesiritide has been administered as a continuous infusion following a bolus dose of 2 μg/kg. We elected not to use a bolus dose secondary to the possibility of hypotension. Many of our patients were on other afterload-reducing agents at the time of therapy initiation. Despite the lack of initial bolus therapy, the clinical response was good using an initial dose of 0.01 μg/kg/min and careful titration of the infusion to the maximum dose of 0.03 μg/kg/min. Although hypotension is a well-documented side effect of nesiritide therapy in adults, all of our pediatric patients had favorable hemodynamic parameters while on the infusion, with none developing hypotension. Remarkably, many children were on vasoactive medications such as milrinone at the time of nesiritide therapy, and despite the potential interacting effects of these agents, no untoward effects occurred. Although many reports document the use of nesiritide as a sole therapy in adults, there are data showing that the combination of nesiritide and milrinone may be useful in decompensated heart failure and may reduce pulmonary capillary wedge pressure [19]. Although our study was not designed to evaluate the potential additive effects of these therapies, we have at least documented their safe use in combination. The initiation and titration of therapy was performed in an intensive care setting in all patients. This approach was considered prudent for our study because limited data in pediatrics were available regarding adverse events. Because we have documented that no significant hypotension or arrhythmias occurred during the total course of therapy, it may be possible to consider administering nesiritide in a non-intensive care setting. However, more long-term, prospective data are needed for evaluation of adverse events.

The effect of nesiritide on serum electrolytes is noteworthy. There was no statistically significant change in serum sodium, potassium, or chloride (Table 2). However, the slight improvement in serum creatinine is an important finding that may portend long-term implications regarding morbidity and mortality in these patients. There appears to be an association between preservation of renal function in heart failure patients and long-term outcome [7, 9]. In addition, the improvement in creatinine that we observed is in direct contrast to the worsening of renal function observed in nesiritide-treated adult heart failure patients compared to controls [17, 21].

The finding of overall functional improvement as assessed by the patients and the parents is remarkable. However, we recognize that other therapies were often concomitantly administered and aided in the clinical compensation of heart failure. We also note that improvement in well-being was not assessed with a validated construct. Similar shortcomings are recognized in the assessment of thirst and appetite as well. However, the finding of improved appetite has potentially important implications because heart failure is an inherently catabolic process and any therapy that can improve overall nutrition, especially in the pediatric population, is likely to be important. It is possible that our finding of decreased thirst with therapy may have a potentially significant impact on the management of heart failure in both adults and children.

There are several limitations to our study. First, the study sample size is small. However, the study was designed to function as a pilot study of safety and efficacy. Despite the relatively small sample size, statistical significance was achieved in many parameters, including functional capacity and urine output. Second, the study was not blinded or randomized. This study, as stated previously, was designed as a pilot trial for preliminary data to guide a larger, prospective, controlled trial. Third, this is a short-term study; as such, no long-term follow-up data have been gathered with regard to functional class, hospitalization frequency and length, morbidity, or mortality. However, these end points were not predefined end points for our study. In addition, recently reported outcomes of nesiritide infusion in adults suggest that such treatment may actually increase mortality [20]. Fourth, in most patients, nesiritide was not the only heart failure therapy used. The documented clinical and serologic outcomes may not all be secondary to nesiritide infusion. However, clinical improvement and changes in surrogate markers of heart failure such as BNP did improve in many patients who were already receiving vasoactive medications and diuretics. The possible effects on the neurohormonal axis and synergism with other therapies will need to be addressed in future studies. Fifth, the pharmacokinetics of nesiritide in the pediatric population are unknown, although there is evidence that they are not significantly different from those in adults. However, this similarity may not extend to neonates and small children. This lack of clarity could influence dosing regimens in this population. Thus, further delineation of nesiritide’s pharmacokinetics is warranted.

Conclusions

Nesiritide can be used safely in pediatric patients to treat heart failure of wide-ranging etiologies either alone or in combination with other accepted heart failure regimens and may be efficacious in the treatment of pediatric heart failure. Further studies are warranted.

Copyright information

© Springer Science+Business Media, Inc. 2006