Beth A. Vogt

The Pharmacokinetics of Enalapril in Children and Infants with Hypertension

Forty children with hypertension between the age of 2 months and 15 years received 0.07 to 0.14 mg/kg of enalapril as a single daily dose. Enalapril was administered orally as a novel extemporaneous suspension in children younger than 6 years of age and as tablets in older children. First‐dose and steady‐state pharmacokinetics were estimated in children ages 1 to 24 months, 25 months to < 6 years, 6 to < 12 years, and 12 to < 16 years. Maximum serum concentrations for enalapril occurred approximately 1 hour after administration. Serum concentrations of enalaprilat, the active metabolite of enalapril, peaked between 4 and 6 hours after the first dose and 3 and 4 hours after multiple doses. The area under the concentration versus time curve (AUC), adjusted for body surface area, did not differ between age groups. Based on comparison of first‐dose and steady‐state AUCs, the accumulation of enalaprilat in children ranged from 1.13‐ to 1.45‐ fold. For children ages 2 to 15 years, mean urinary recovery of total enalaprilat ranged from 58.3% in children ages 6 to < 12 years to 71.4% in children ages 12 to < 16 years. Urinary recovery for children ages 2 to < 6 years was 66.8%. The mean percentage conversion of enalapril to enalaprilat ranged from 64.7% for children ages 1 to 24 months to 74.6% for children ages 6 to < 12 years. The median effective half‐life for accumulation ranged from 14.6 hours in children ages 12 to < 16 years to 16.3 hours in children ages 6 to < 12 years. There were two serious adverse events, neither of which was attributed to enalapril or resulted in discontinuation of the study drug. The extemporaneous suspension used in this study was tolerated well. The pharmacokinetics of enalapril and enalaprilat in hypertensive children ages 2 months to 15 years with normal renal function appears to be similar to that previously observed in healthy adults.

Hypertension in children and adolescents: definition, pathophysiology, risk factors, and long-term sequelae

Abstract Background: Awareness of hypertension as an adult public health issue has increased dramatically during the past 3 decades, leading to substantial decreases in morbidity and mortality related to stroke and coronary artery disease. Awareness of blood pressure issues in the pediatric population also has increased, leading to conceptual changes in the diagnosis and treatment of childhood hypertension. The current focus has shifted to early identification of mild to moderate hypertension in asymptomatic, otherwise healthy children and adolescents. Objective: The purpose of this article was to define hypertension in the pediatric population and describe the secondary causes of childhood hypertension, risk factors and potential pathophysiology of essential hypertension in childhood, and the long-term sequelae for individuals with hypertension identified during childhood. Methods: Information regarding pediatric hypertension was identified through a MEDLINE ® search of the literature from 1985 to 2000. Results: Definitions of pediatric hypertension have been carefully refined over the past 30 years, and normative data are available for children and adolescents, based on age, sex, and height. Childhood hypertension may be identified during evaluation of an acutely ill child, but is increasingly identified during routine blood pressure screening, particularly in adolescents. Although, historically, most pediatric hypertension was believed to be secondary in origin (related to an identifiable underlying disorder), recent data suggest that almost 90% of hypertensive adolescents have essential hypertension. The proposed factors that may be involved in the pathophysiology of essential hypertension include familial and genetic influences, race, and salt sensitivity. Although an essential hypertension gene has not yet been identified, several monogenic forms of hypertension have been described, which may account for a minority of individuals with presumed essential hypertension. In addition, a number of candidate genes that may be involved in the complex genetic susceptibility to hypertension have been described. There is growing evidence concerning adverse long-term consequences of hypertension identified in childhood and adolescence, including increased incidence of cardiovascular and coronary heart disease. Conclusions: Based on the generally accepted concept that essential hypertension begins in childhood, early optimization of blood pressure control in childhood may reduce an individuals lifetime risk of cardiovascular morbidity and mortality. In addition, aggressive treatment of cardiovascular risk factors during childhood and adolescence may have a major impact on the prevalence of adult cardiovascular disease.

Outcome differences between young children and adolescents undergoing kidney transplantation.

BACKGROUND/PURPOSE Although graft loss remains the biggest challenge for all pediatric kidney transplant (KT) recipients, unique challenges exist within different age groups. We aim to evaluate the different characteristics and graft survival outcomes of young children and adolescents undergoing KT. METHODS Children who underwent isolated KT between 2000 and 2013 at our institution were included in this retrospective analysis. Patient characteristics and outcomes were compared using students t-test, chi-square test, Kaplan-Meier curve and Cox proportional hazards model. RESULTS Of 73 children who underwent KT, 31 were <12 (young children), and 42 were ≥ 12 years old (adolescents). Overall patient survival was 100%. The younger group had superior 5-year (100% vs. 75.5%) and 10-year (94.4% vs. 43.8%) graft survival (p=0.008). Factors predictive of poor graft survival on multivariate analysis were older age at transplantation (HR 1.2, CI 1-1.4, p=0.047), female gender (HR 9.0, CI 1.9-43, p=0.006), and acute rejection episodes (HR 13, CI 2-90, p=0.008). The most common causes of graft loss were acute and chronic rejection episodes and immunosuppression nonadherence. CONCLUSION Adolescents undergoing KT have inferior graft survival compared to younger children. In adjusted modeling, children with older age, female gender, and acute rejection episodes have inferior graft survival.

Famotidine disposition in children and adolescents with chronic renal insufficiency.

The pharmacokinetics of intravenous famotidine (0.5 mg/kg, maximum 20 mg) were evaluated in 18 pediatric patients (ages 1–18 years) with stable, chronic renal insufficiency. Subjects were stratified by calculated creatinine clearance (Clcr) into mild (Clcr ≥ 50 to < 90 mL/min/1.73 m2), moderate (Clcr ≥ 25 to < 50 mL/min/1.73 m2), and severe (Clcr ≤ 10 mL/min/1.73 m2) renal insufficiency groups. Significant differences between the mild, moderate, and severe groups were found for elimination rate (Kel), apparent elimination half‐life (t1/2), area under the curve (AUC), and total plasma clearance (Clp) (p < 0.01). Famotidine renal clearance (Clr) was found to be significantly different between the mild and severe groups (p < 0.05). A linear relationship was observed between Clcr and Clp (p < 0.0001; R2 = 0.70). No significant differences in nonrenal clearance (Clnr) were found between groups; however, Clnr as a percentage of Clp was significantly different in the severe group (92.9% ± 7.3% Clnr) compared to the combined mild and moderate groups (21.9% ± 45.6% Clnr) (p < 0.05). It was concluded that the pharmacokinetics of famotidine are significantly altered in children with chronic renal insufficiency; accordingly, dosing should be based on glomerular filtration rate (i.e., Clcr).

Complications of peritoneal dialysis in children with Eagle-Barrett syndrome

Abstract.Eagle Barrett syndrome (EBS) is characterized by the triad of abdominal muscle deficiency, urinary tract abnormalities, and cryptorchidism. Approximately 25% of patients with EBS progress to end-stage renal disease. It is speculated that the abdominal muscular defects in EBS pose technical problems in achieving successful peritoneal dialysis (PD). In this retrospective analysis, we reviewed the medical records of EBS and non-EBS PD patients cared for at Rainbow Babies and Childrens Hospital from 1985 to 2002; 5 EBS and 9 non-EBS patients were analyzed. PD duration, total complication rates, and catheter usage rates in the two groups were not significantly different. The two most frequent complications were peritonitis and catheter mechanical malfunction during 103 patient-months in EBS patients and 296 patient-months in non-EBS patients. Peritonitis occurred 1 episode every 20.6 patient-months and 14.8 patient-months in EBS and non-EBS patients, respectively. The time from PD initiation to onset of any complication, including first peritonitis, was not significantly different in the two groups. Although the age at PD initiation was significantly different between the groups, there was no correlation between age at onset of PD and complication rates or time to first complication. Despite their abdominal muscle defects, EBS patients do not have more-frequent PD complications.

The role of continuous renal replacement therapy in the management of acute kidney injury associated with sinusoidal obstruction syndrome following hematopoietic cell transplantation

Maintaining fluid balance, pre‐ and post‐MA‐HCT is essential and usually requires frequent administration of diuretics. Hepatic sinusoidal obstructive syndrome is potentially life‐threatening, especially when associated with AKI and MOF. This study describes six patients who developed AKI‐associated SOS and diuretic‐resistant FO who subsequently underwent CRRT using standardized management guidelines for fluid balance post‐HCT. Retrospective chart review was done for HCT patients between September 2011 and October 2013 at a tertiary care childrens hospital. Thirty‐four patients underwent MA‐HCT in the study period. Six patients had SOS complicated by diuretic‐resistant FO and underwent CRRT. Defibrotide was used in three patients. Median time on CRRT was 10.5 days. Sixty‐six percent (N = 4 of 6) of patients had full resolution of SOS symptoms with a mortality rate of 34% (N = 2 of 6). Among patients who had full recovery of SOS symptoms, one patient developed AKI, end‐stage renal diseases and underwent kidney transplantation 34‐months post‐HCT. Thus, of six included patients, two died and one developed ESRD with only 50% (N = 3 of 6) good outcome. Use of a standardized, evidence‐based fluid balance protocol and early initiation of CRRT for HCT‐related AKI/SOS was associated with good outcomes.