For those using drugs to treat infants and children, the integration of developmental pharmacology is crucial to appropriate clinical practice. Changes in metabolic capacity, distribution sites, and ...organ function all affect the way in which medications are handled in the very young. This review examines the developmental changes that profoundly affect the responses of children to medications and related therapies.
Infants and children are far different from adults in terms of societal, psychosocial, behavioral, and medical perspectives. More than 100 years ago Dr. Abraham Jacobi, the father of American pediatrics, recognized the importance of and need for age-appropriate pharmacotherapy when he wrote, “Pediatrics does not deal with miniature men and women, with reduced doses and the same class of disease in smaller bodies, but . . . has its own independent range and horizon.”
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As our knowledge of normal growth and development has increased in the past several decades, so has our recognition that developmental changes profoundly affect the responses . . .
Well-functioning vascular access is essential for the provision of adequate CRRT. However, few data exist to describe the effect of catheter size or location on CRRT performance in the pediatric ...population.
Data for vascular access site, size, and location, as well as type of anticoagulant used and patient demographic data were gathered from the ppCRRT registry. Kaplan-Meier curves were generated and then analyzed by log-rank test or Cox Proportional Hazards model.
Access diameter was found to significantly affect circuit survival. None of the 5 French catheters lasted longer than 20 hours. Seven and 9 French, but not 8 French, catheters fared worse than larger diameter catheters (p=0.002). Circuits associated with internal jugular access survived longer than subclavian or femoral access associated circuits (p<0.05). Circuit survival was also found to be favorably associated with the CVVHD modality (p<0.001).
Functional CRRT circuit survival in children is favored by larger catheter diameter, internal jugular vein insertion site and CVVHD. For patients requiring catheter diameters less than 10 French, CRRT circuit survival might be optimized if internal jugular vein insertion is feasible. Conversely, when a vascular access site other than the internal jugular vein is most prudent, consideration should be given to using the largest diameter catheter appropriate for the size of the child. The CVVHD modality was associated with longer circuit survival, but the mechanism by which this occurs is unclear.
Objective: To describe the clinical and laboratory features of obesity associated proteinuria and focal segmental glomerulosclerosis. Study design: The patients were seen over a 12-year period at two ...large children’s hospitals. Renal biopsies, performed for the diagnosis of unexplained heavy proteinuria and prepared for light, immunofluorescent, and electron microscopy, were read independently by two pediatric pathologists. Blood pressure, body mass index, serum levels of creatinine, albumin, and cholesterol, and 24-hour urinary protein were measured. Results: Seven African American adolescents were identified with obesity-associated proteinuria, which was characterized by severe obesity (120 ± 30 kg), markedly elevated body mass index (46 ± 11), mild hypertension (134/74 ± 10/18 mm Hg), slightly low to normal serum albumin levels (3.6 ± 0.2 g/dL), moderately elevated serum cholesterol levels (196 ± 60 mg/dL), and elevated 24-hour protein excretion (3.1 ± 1.3 g/dL). Calculated creatinine clearance was normal in 6 patients and decreased in one. Typical renal histologic features included glomerular hypertrophy, focal segmental glomerulosclerosis, increased mesangial matrix and cellularity, relative preservation of foot process morphology, and absence of evidence of inflammatory or immune-mediated pathogenesis. One patient showed a dramatic reduction in proteinuria in response to weight reduction. Three patients who were given angiotensin-converting enzyme inhibitors had reduced urinary protein losses from 2.9 g to 0.7 g per day. One patient developed end-stage renal disease. Conclusion: Obese adolescents should be monitored for proteinuria, which has distinct clinical and pathologic features and may be associated with significant renal sequelae. Such proteinuria may respond to weight reduction and/or treatment with angiotensin-converting enzyme inhibitors. (J Pediatr 2001;138:481-5)
Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics ...of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to <6 years; 34 patients, 6 to <12 years; 33 patients, 12 to 18 years). Patients received MMF 600 mg/m2 b.i.d. concomitantly with cyclosporine and corticosteroids with or without antilymphocyte antibody induction. One year after transplantation, patient and graft survival (including death) were 98% and 93%, respectively. Twenty-five patients (25%) experienced a biopsy-proven (Banff grade borderline or higher) or presumptive acute rejection within the first 6 months post-transplantation. Analysis of pharmacokinetic parameters for mycophenolic acid (MPA) and mycophenolic acid glucuronide showed no clinically significant differences among the age groups. The dosing regimen of MMF 600 mg/m2 b.i.d. achieved the targeted early post-transplantation MPA 12-h area under concentration-time curve (AUC0-12) of 27.2 microg h per ml. Adverse events had similar frequencies among the age groups (with the exception of diarrhea, leukopenia, sepsis, and anemia, which were more frequent in the <6 years age group) and led to withdrawal of MMF in about 10% of patients. Administration of MMF 600 mg/m2 b.i.d. is effective in prevention of acute rejection, provides predictable pharmacokinetics, and is associated with an acceptable safety profile in pediatric renal transplant recipients.
Inadequate compliance with prescribed medication regimens in children is complex and poorly understood. We measured the extent and pattern of noncompliance with cyclosporine in our adolescent renal ...transplant population and attempted to determine factors associated with poor compliance. After informed consent, each patient was provided cyclosporine capsules in a medication bottle equipped with an electronic monitoring device (MEMS-4) in the lid. Of the 24 patients eligible, 19 patients (8 female, 11 male) completed the study. Four (21%) patients took less than 80% of the prescribed cyclosporine doses. Five (26%) patients took drug holidays involving > or = consecutive doses. There was a trend towards improved compliance with the evening dose (88.5% vs. 93.4%, P = 0.09) and a downward trend in compliance over the course of the study (P = 0.17). None of the variables tested were found to be associated with noncompliance. Experienced physicians and nurses were able to identify 2 of the 4 individuals who were identified by MEMS as noncompliant. Additionally, 2 of the 4 noncompliance patients demonstrated low cyclosporine trough levels (< 50 ng/ml). Noncompliance with cyclosporine regimens occurs commonly in adolescent renal transplant recipients. Unexpectedly low cyclosporine levels are strongly suggestive of noncompliance, whereas other variables, including prediction by physicians and nurses intimately involved in the care, were not reflective of noncompliance.
Pediatric patients with multi-organ dysfunction syndrome receiving continuous renal replacement therapy.
Critical illness leading to multi-organ dysfunction syndrome (MODS) and associated acute renal ...failure (ARF) is less common in children compared to adult patients. As a result, many issues plague the pediatric ARF outcome literature, including a relative lack of prospective study, a lack of modality stratification in subject populations and inconsistent controls for patient illness severity in outcome analysis.
We now report data from the first multicenter study to assess the outcome of pediatric patients with MODS receiving continuous renal replacement therapy (CRRT). One hundred twenty of 157 Registry patients (63 male/57 female) experienced MODS during their course.
One hundred sixteen patients had complete data available for analysis. The most common causes leading to CRRT were sepsis (N = 47; 39.2%) and cardiogenic shock (N = 24; 20%). Overall survival was 51.7%. Pediatric Risk of Mortality (PRISM 2) score, central venous pressure (CVP), and% fluid overload (%FO) at CRRT initiation were significantly lower for survivors versus nonsurvivors. Multivariate analysis controlling for severity of illness using PRISM 2 at CRRT initiation revealed that%FO was still significantly lower for survivors versus nonsurvivors (P < 0.05) even for patients receiving both mechanical ventilation and vasoactive pressors. We speculate that increased fluid administration from PICU admission to CRRT initiation is an independent risk factor for mortality in pediatric patients with MODS receiving CRRT.
We suggest that after initial resuscitative efforts, an increased emphasis should be placed on early initiation of CRRT and inotropic agent use over fluid administration to maintain acceptable blood pressure.
Renal biopsy is crucial for the diagnosis, management, and monitoring of many kidney diseases. Although percutaneous renal biopsy is considered a routine safe procedure in children, the optimal ...length of in-hospital observation following the procedure is not yet known. We prospectively studied two comparable groups of children to compare the success and safety of performing native renal biopsy as an outpatient procedure versus keeping the children hospitalized post biopsy. Doppler ultrasonography of the biopsied kidney was performed approximately 2 weeks after the procedure. For 40 children the biopsy was performed on a same-day basis (study group) and another 15 children were kept for overnight observation (control group). All biopsies yielded adequate tissue for histopathological diagnosis. There was no difference between the two groups in the amount of reported pain and analgesics used after the procedure. Only 1 child in the study group was readmitted 5 days after the biopsy for 48 h, but no major complications were detected. The incidence of post-biopsy intra- or perirenal hematoma detection by sonography was not statistically different between the two groups (39% study group, 43% control group). Follow-up imaging studies were performed on 10 of the 20 children who had an early post-biopsy hematoma and all were completely normal. Patients and their families appreciated being discharged home the same day. In addition, total charges for hospitalization were significantly less for the study group than the control group. We conclude that in selected patients, same-day discharge after renal biopsy may be performed safely without an increased risk of complications.
Currently available extracorporeal circuits in the US often require blood priming to prevent hypotension/anemia in smaller pediatric patients. The PRISMA M10 circuit, available in other countries has ...not received extensive study and has not been cleared for use in the US. We performed an FDA mandated study of the M10 circuit in the US for use in critically ill pediatric patients with acute kidney injury <15 kg in size. FDA guidelines allowed for maximal blood pump flow of 20 ml/min. Fifteen pts (9 M, 6 F, mean size 5.8+/-2.8 kg, range 2.6-12.5 kg, age 4 d - 13 mo, mean creatinine =1.2+/-0.7 mg/dL) were studied at 4 ppCRRT centers. Sixty-one filters (range 1-4 circuits per pt) were used (mean circuit life 28.6+/-22.5 h, range 1 to 74.5 h, 55%>24 h). No blood leaks occurred. All circuits achieved Qb 20 ml/min. Forty-two out of 61 filters clotted and mean circuit life was lower for these filters than those changed for other reasons (23+/-17 vs. 41+/-28 h, <0.005). Circuits using larger access demonstrated significantly longer survival. We conclude that the M10 filter can serve well for CRRT in small pediatric patients. Further study is needed to determine in higher blood flow rates would decrease clotting rates and increase filter life span and ultrafiltration rates.
Many issues plague the pediatric ARF outcome literature, which include data only from single center sources, a relative lack of prospective study, mixture within studies of renal replacement therapy ...modality without stratification and inconsistent use of methods to control for patient illness severity in outcome analysis. Since January 2001, the Prospective Pediatric CRRT (ppCRRT) Registry Group has been collecting data from multiple United States pediatric centers to obtain demographic data regarding pediatric patients who receive CRRT, assess the effect of different CRRT prescriptions on circuit function and evaluate the impact of clinical variables on patient outcome. The aim of the current paper is to describe the ppCRRT Registry design, review the decision process and rationale for the options chosen for the ppCRRT format and discuss the analysis plan and future projects envisioned for the ppCRRT Registry.
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