Safety and Efficacy of Nesiritide in Pediatric Heart Failure

Division of Pediatric Cardiology, Texas Children's Hospital, Houston, Texas 77030, USA.
Journal of cardiac failure (Impact Factor: 3.05). 09/2007; 13(7):541-8. DOI: 10.1016/j.cardfail.2007.04.005
Source: PubMed


We hypothesized that recombinant B-type natriuretic peptide (BNP) (nesiritide) could improve urine output and neurohormonal markers of heart failure without worsening renal function in pediatric patients.
We analyzed our experience involving 140 nesiritide infusions in 63 consecutive children. Serum levels of BNP and electrolytes were measured before and after therapy. Dosing was begun at 0.01 without a bolus and titrated to a maximum of 0.03, in increments. Blood pressure, heart rate, and heart rhythm were monitored. In a substudy, 20 patients with decompensated cardiomyopathy-related heart failure received 72 hours of nesiritide with prospective assessment of aldosterone, norepinephrine, plasma renin, and endothelin-1 levels before and after therapy. The heart rate decreased significantly (P = .001). Urine output increased significantly on Days 1 and 3 (P < or = .001 and .004, respectively). The mean serum creatinine level decreased from 1.135 to 1.007 mg/dL (P < or = .001). In the substudy, aldosterone levels decreased from 37.5 +/- 57.1 to 20.5 +/- 41.9 ng/dL (P = .005). Plasma renin, norepinephrine, and endothelin-1 levels decreased nonsignificantly. Two infusions were discontinued because of hypotension.
Nesiritide safely treated decompensated heart failure in children. Increased urine output reflected improving renal function. Improved neurohormonal markers were seen after 72 hours of therapy, and complications were uncommon.

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    • "Pharmacologic therapies for pediatric cardiovascular patients require careful scrutiny of the parameters that reflect their developmental changes in drug metabolism, excretion, and distribution (Chang and Towbin, 2006) (Moffett and Chang, 2006). Neurohormonal regulation in heart failure is closely monitored when using angiotensin receptor blockers (ARBs), aldosterone antagonists, betablockers , natriuretic peptides (Jefferies et al., 2007), vasopressin antagonists, tumor necrosis factor inhibitors, and neutral endopeptidase inhibitors (Chang and Towbin, 2006). Current treatments of acute decompensated heart failure include calcium sensitizing agents to replace traditional inotropic therapies. "
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    ABSTRACT: Up to now, the occult phase of the cardiomyopathy in Doberman Pinschers, with a cumulative prevalence of 63 % in Europe (WESS et al., 2009b), can only be diagnosed by specialized and cost-intensive methods, such as the 24-h-ECG (Holter) and the echocardiogram. Electrocardiographic and echocardiographic changes usually appear at an age, in which the dogs were already used for breeding. Considering the genetic health of the Doberman Pinscher breed, it is of great importance to diagnose the genetically determined cardiomyopathy before it can be passed on to the offspring. The aim of this study Analysis of NTpro-BNP in Dilated Cardiomyopathy of the Doberman Pinscher was to evaluate NTpro-BNP in the Doberman Pinscher population, in healthy animals as well as in various stages of cardiomyopathy, to define reference values and to validate the use of NTpro-BNP as a diagnostic tool. Therefore, 250 healthy and 108 dogs with cardiomyopathy were studied between 2004 and 2008, in total 480 examinations. NTpro-BNP measurements were performed in plasma samples, using the ELISA VETSIGNTM Canine CardioSCREEN Ntpro-BNP, Guildhay Ltd., UK. NTpro-BNP concentrations increased in correlation with the severity of disease. There was a statistically significant difference between the healthy control group (mean 315.7 pmol/l) and the occult and decompensated groups as well as the whole dog population with cardiomyopathy. To differentiate healthy dogs from dogs with cardiomyopathy, a cut-off value of 413.8 pmol/l was established that provided an area under the receiver operator curve of 0.820, with a sensitivity and specifity of 72.4 % and 80.2 %, respectively. There was no significant influence of age, weight or sex on the NTpro-BNP concentration. Sensitivity reached 90.0 % for predicting abnormal echocardiographic changes. Interestingly, there was a statistically significant increase of NTpro-BNP in the occult group with exclusively VPCs even before echocardiographic changes were present. The “still normal” group, consisting of examinations of dogs that appeared to be healthy without any measurable signs at that time, but which later on developed cardiomyopathy, is highly interesting. Although the mean NTpro-BNP level (499.7 pmol/l) was higher than the mean NTpro-BNP concentration in the occult group with exclusively VPCs, no statistically significant difference was achieved in comparision to the healthy control group using Bonferroni’s equitation. The small number of only 17 dogs in this group might be a reason for the lack of statistical significance. One limitation of this study is the fact that not all dogs, especially those in the healthy control group, could be followed up to the end of their lives. Therefore, it might be possible that “still healthy” dogs with genetically determined cardiomyopathy are included in the healthy control group. As a consequence, the reference value could be falsely high. Long-term studies will be needed to validate the reference value in a group of definitively genetically healthy animals. The tendency to higher NTpro-BNP values in the still normal group also should be studied in a larger population in order to evaluate the potential of NTpro-BNP as an early marker of cardiomyopathy in Doberman Pinschers. NTpro-BNP cannot replace the Holter ECG and echocardiographic measurements in the diagnosis of occult cardiomyopathy at present. But if the time-consuming and cost-intensive methods that require a high specialization are not available, NTpro-BNP levels could indicate the necessity of referring the patient to a cardiologist. Because of the high sensitivity of 90 % for predicting abnormal echocardiographic changes, it might be possible that the measurement of NTpro-BNP eventually could replace the echocardiographic examination, but not the Holter-ECG. Bis heute kann das okkulte Stadium der Kardiomyopathie beim Dobermann, die im europäischen Raum eine kumulative Prävalenz von 63 % aufweist (WESS et al., 2009b), in seinen verschiedenen Ausprägungen nur durch aufwändige und kostenintensive Methoden, wie dem 24-Stunden-EKG und der Echokardiographie, diagnostiziert werden. Die elektrokardiographischen und echokardiographischen Veränderungen treten im Allgemeinen allerdings erst in einem Alter auf, in dem die Hunde bereits im Zuchteinsatz waren. Im Hinblick auf die genetische Gesundheit des Dobermanns ist es von großer Bedeutung, die genetisch determinierte Kardiomyopathie bereits zu diagnostizieren, bevor sie weiter vererbt wird. Ziel der vorliegenden Arbeit Untersuchungen zu NTpro-BNP bei der dilatativen Kardiomyopathie des Dobermanns war es zum einen, erstmalig NTpro-BNP beim gesunden Dobermann und in verschiedenen Stadien der Kardiomyopathie zu evaluieren und Referenzwerte zu erstellen, zum anderen, die Eignung von NTpro-BNP als (Früh-)Diagnostikum zu validieren. Dazu wurden 480 Untersuchungen an 250 gesunden und 108 erkrankten Hunden zwischen 2004 und 2008 analysiert. NTpro-BNP wurde im Plasma mittels dem ELISA VETSIGNTM Canine CardioSCREEN Ntpro-BNP, Guildhay Ltd., UK, bestimmt. Die Konzentration von NTpro-BNP stieg mit zunehmender Schwere der Erkrankung an. Die gesunde Kontrollgruppe mit einer mittleren NTpro-BNP-Konzentration von 315,7 pmol/l unterschied sich statistisch signifikant von den okkulten Gruppen und der dekompensierten Gruppe sowie der erkrankten Gesamtgruppe. Bei einem Cut-off von 413,8 pmol/l erreichte die Area Under the Curve (AUC) der ROC-Analyse 0,820, Sensitivität und Spezifität betrugen 72,4 % und 80,2 % zur Unterscheidung von gesunden und an Kardiomyopathie erkrankten Hunden. Alter, Gewicht und Geschlecht hatten keinen Einfluss auf die NTpro-BNP-Konzentration. Echokardiographische Veränderungen können mit einer hohen Sensitivität (90 %) vorausgesagt werden. Besondere Beachtung verdient die Tatsache, dass NTpro-BNP bereits im okkulten Stadium mit ausschließlich ventrikulären Extrasystolen statistisch signifikant erhöht war. Von besonderem Interesse ist die „noch normale Gruppe“, in die diejenigen Untersuchungen von Hunden eingegangen sind, die zu diesem Zeitpunkt vollkommen unauffällig waren, im Verlauf von Kontrolluntersuchungen aber diagnostizierbare Veränderungen im Sinne einer Kardiomyopathie entwickelten. Obwohl der Mittelwert der noch normalen Gruppe mit 499,7 pmol/l über dem der Gruppe im okkulten Stadium mit ausschließlich ventrikulären Extrasystolen lag, erreichte er im Mehrfachvergleich nach Bonferroni dennoch keine statistische Signifikanz gegenüber der gesunden Gruppe. Dies könnte an der relativ geringen Anzahl von nur 17 Patienten in diesem Stadium liegen. Dass nicht alle Hunde der gesunden Gruppe bis zu ihrem Lebensende verfolgt werden konnten, stellt eine Limitation dieser Studie dar. Dadurch könnten in der Kontrollgruppe „noch gesunde“, aber genetisch determiniert kranke Hunde eingeschlossen worden sein. Dies hätte eventuell einen falsch hohen Referenzwert zur Folge. Es wird die Aufgabe von weiteren Langzeitstudien sein, den in vorliegender Untersuchung ermittelten Referenzwert anhand einer definitiv aus genetisch gesunden Tieren bestehenden Kontrollgruppe zu validieren. Auch die Tendenz zu erhöhten NTpro-BNP-Werten bereits im subklinischen Stadium der Erkrankung sollte anhand einer größeren Patientenpopulation weiter verfolgt werden um zu evaluieren, ob sich NTpro-BNP eventuell als Biomarker zur Frühdiagnostik der Kardiomyopathie beim Dobermann einsetzen lässt. Die Messung von NTpro-BNP kann die etablierten Methoden zur Diagnose der okkulten Kardiomyopathie beim Dobermann derzeit nicht ersetzen. Wenn die aufwändigen, eine hohe Spezialisierung erfordernden kardiologischen Diagnostika wie 24-Stunden-EKG und Echokardiographie nicht zur Verfügung stehen, könnte die Bestimmung von NTpro-BNP jedoch einen Hinweis bezüglich der Dringlichkeit einer weiteren diagnostischen Aufarbeitung durch einen Kardiologen liefern. Aufgrund der hohen Sensitivität von 90 % zur Vorhersage von echokardiographischen Veränderungen könnte die NTpro-BNP-Messung zukünftig eventuell die echokardiographische Untersuchung ersetzen, nicht jedoch das 24-Stunden-EKG.
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