Safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia: Rationale and methods of a phase II randomized trial.

Bronchopulmonary dysplasia (BPD) is a disease of chronic respiratory insufficiency stemming from premature birth and iatrogenic lung injury leading to alveolar simplification, impaired alveolar-capillary development, interstitial fibrosis, and often pulmonary hypertension. BPD is the most common pulmonary sequela of prematurity and is often fatal; however, there remains no FDA-approved therapies to treat or prevent BPD. Sildenafil is increasingly used off-label in premature infants despite scant safety and efficacy data. Sildenafil reduces lung injury and preserves normal vasculature in preclinical models, and improves outcomes in children with pulmonary hypertension, and thus is a promising candidate for BPD. Following phase I studies, we developed the phase II SIL02 trial to describe the safety, pharmacokinetics and preliminary effectiveness of intravenous and enteral sildenafil in premature infants at risk for BPD. SIL02 is a randomized, double-blind, placebo-controlled, 3-cohort, sequential dose-escalating trial of enteral or intravenous (IV) sildenafil dosed every 8 h for up to 34 days. The target IV doses were 0.125, 0.5 and 1 mg/kg/dose in cohorts 1, 2 and 3, respectively; while the enteral doses will be double the IV doses. Eligible infants must be < 29 weeks' gestation at birth and requiring respiratory support at 7-28 days' postnatal age. Adverse events and preliminary effectiveness will be compared by treatment group. Using the final population PK model, empirical Bayesian estimates will be generated for each patient. Preliminary effectiveness will be measured by the incidence of moderate to severe BPD or death at 36 weeks and change in the BPD risk estimation.

Safety of sildenafil in extremely premature infants: a phase I trial.

OBJECTIVE: To characterize the safety of sildenafil in premature infants. STUDY DESIGN: A phase I, open-label trial of sildenafil in premature infants receiving sildenafil per usual clinical care (cohort 1) or receiving a single IV dose of sildenafil (cohort 2). Safety was evaluated based on adverse events (AEs), transaminase levels, and mean arterial pressure monitoring. RESULTS: Twenty-four infants in cohort 1 (n = 25) received enteral sildenafil. In cohort 2, infants received a single IV sildenafil dose of 0.25 mg/kg (n = 7) or 0.125 mg/kg (n = 2). In cohort 2, there was one serious AE related to study drug involving hypotension associated with a faster infusion rate than specified by the protocol. There were no AEs related to elevated transaminases. CONCLUSION: Sildenafil was well tolerated by the study population. Drug administration times and flush rates require careful attention to prevent infusion-related hypotension associated with faster infusions of IV sildenafil in premature infants. CLINICAL TRIAL: ClinicalTrials.gov Identifier: NCT01670136.

Physiologically-Based Pharmacokinetic Modeling Characterizes the CYP3A-Mediated Drug-Drug Interaction Between Fluconazole and Sildenafil in Infants.

Physiologically-based pharmacokinetic (PBPK) modeling can potentially predict pediatric drug-drug interactions (DDIs) when clinical DDI data are limited. In infants for whom treatment of pulmonary hypertension and prevention or treatment of invasive candidiasis are indicated, sildenafil with fluconazole may be given concurrently. To account for developmental changes in cytochrome P450 (CYP) 3A, we determined and incorporated fluconazole inhibition constants (KI ) for CYP3A4, CYP3A5, and CYP3A7 into a PBPK model developed for sildenafil and its active metabolite, N-desmethylsildenafil. Pharmacokinetic (PK) data in preterm infants receiving sildenafil with and without fluconazole were used for model development and evaluation. The simulated PK parameters were comparable to observed values. Following fluconazole co-administration, differences in the fold change for simulated steady-state area under the plasma concentration vs. time curve from 0 to 24 hours (AUCss,0-24 ) were observed between virtual adults and infants (2.11-fold vs. 2.82-fold change). When given in combination with treatment doses of fluconazole (12 mg/kg i.v. daily), reducing the sildenafil dose by ~ 60% resulted in a geometric mean ratio of 1.01 for simulated AUCss,0-24 relative to virtual infants receiving sildenafil alone. This study highlights the feasibility of PBPK modeling to predict DDIs in infants and the need to include CYP3A7 parameters.

Reassessing Rabbit Antithymocyte Globulin Induction in Kidney Transplantation (RETHINK): An Analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry.

BACKGROUND: There is no consensus on rabbit antithymocyte globulin (rATG) dose used for induction immunosuppression in pediatric kidney transplants. We aimed to identify whether a lower rATG dose provides safe and effective immunosuppression compared with a higher dose. METHODS: We retrospectively analyzed all first-time kidney transplant recipients (aged <21 y) in the North American Pediatric Renal Trials and Collaborative Studies registry since 1998 on mycophenolate mofetil- and tacrolimus-based immunosuppression with rATG induction. An a priori cutoff of 7.5 mg/kg cumulative rATG dose was used to identify low (<7.5 mg/kg) and high (≥7.5 mg/kg) exposure groups. Primary outcome was time to first-acute rejection episode. Secondary outcomes included graft function, patient survival, hospitalizations due to infections, and time to first-posttransplant lymphoproliferative disorder episode. RESULTS: Four hundred fifty-five patients met inclusion criteria (59% male, 49% whites, 26% blacks, 38% living donor source). Median cumulative rATG dose was 6.8 mg/kg with a median of 5 doses and a median 1.5 mg/kg/dose introduced at a median of postoperative 0 days. Sixty-four percent received <7.5 mg/kg total rATG. There was no difference in age at transplant, gender, race, end-stage renal disease causes, or HLA mismatch among groups. Time to first-acute rejection was similar (P = 0.07). There was no significant difference in graft or patient survival or time to posttransplant lymphoproliferative disorder. Hospitalization for infection rates was similar. CONCLUSIONS: These data demonstrate a wide variation in cumulative rATG induction dose. A smaller rATG dose <7.5 mg/kg may provide effective and safe immunosuppression compared with a higher dose.

Effects of changes in adult erythropoietin dosing guidelines on erythropoietin dosing practices, anemia, and blood transfusion in children on hemodialysis: findings from North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS).

BACKGROUND: While adult hemodialysis (HD) patients have increased morbidity with higher target hemoglobin levels, similar findings have not been demonstrated in pediatric patients. We evaluated changes in transfusions, anemia frequency, and erythropoietin (epo) dosing among pediatric HD patients before, during, and after implementation of federal dialysis payment policies regarding epo dosing for adult HD patients. METHODS: This is a retrospective cohort study of pediatric HD patients enrolled in NAPRTCS. We evaluated need for transfusion, anemia, median hemoglobin, and median epo dose 6 months after starting HD in 3 eras: baseline (2003-2007), implementation (2008-2011), and post implementation (2012-2016). We used multivariate logistic regression models to evaluate potential differences in transfusion across the eras. RESULTS: Six months after dialysis initiation, 12.6% of patients required transfusion pre-implementation, 17.9% during implementation, and 15.5% post implementation. Anemia occurred in 17.4% of patients pre, 23.5% during, and 23.8% post implementation, with median hemoglobin levels of 11.9 g/dL pre, 11 g/dL during, and 11 g/dL post implementation. Epo use was high across all 3 eras, but epo dosing decreased during and post implementation, despite more anemia during these periods. Odds of transfusion in implementation era compared with pre-implementation was 1.75 (95% CI 1.11-2.77) and odds of transfusion in post implementation era compared with pre was 1.19 (95% CI 0.71-1.98), controlling for age, race, gender, and prior transplant status. CONCLUSIONS: During and following implementation of adult epo dosing guidelines, transfusion and anemia frequency increased in pediatric HD patients. Ideal target hemoglobin levels for pediatric dialysis patients warrant further study.

Kidney transplant practice patterns and outcome benchmarks over 30 years: The 2018 report of the NAPRTCS.

The NAPRTCS has collected clinical information on children undergoing renal transplantation since 1987 and now includes information on 12 920 renal transplants in 11 870 patients. Since the first data analysis in 1989, NAPRTCS reports have documented marked improvements in patient and allograft outcomes after pediatric renal transplantation in addition to identifying factors associated with both favorable and poor outcomes. The registry has served to document and influence practice patterns, clinical outcomes, and changing trends in renal transplantation and also provides historical perspective. This report highlights current practices in an era of major changes in DD kidney allocation and continuing steroid minimization. This report presents outcomes of the patients in the NAPRTCS transplant registry up to end of 2017. In particular, an increase in the cumulative incidence of late first AR has occurred in the most recent cohort, while all prior cohorts had a lower cumulative incidence of late first AR.

Population pharmacokinetics of sildenafil in extremely premature infants.

AIMS: To characterize the population pharmacokinetics (PK) of sildenafil and its active metabolite, N-desmethyl sildenafil (DMS), in premature infants. METHODS: We performed a multicentre, open-label trial to characterize the PK of sildenafil in infants ≤28 weeks gestation and < 365 postnatal days (cohort 1) or < 32 weeks gestation and 3-42 postnatal days (cohort 2). In cohort 1, we obtained PK samples from infants receiving sildenafil as ordered per the local standard of care (intravenous [IV] or enteral). In cohort 2, we administered a single IV dose of sildenafil and performed PK sampling. We performed a population PK analysis and dose-exposure simulations using the software NONMEM®. RESULTS: We enrolled 34 infants (cohort 1 n = 25; cohort 2 n = 9) and collected 109 plasma PK samples. Sildenafil was given enterally (0.42-2.09 mg/kg) in 24 infants in cohort 1 and via IV (0.125 or 0.25 mg/kg) in all infants in cohort 2. A 2-compartment PK model for sildenafil and 1-compartment model for DMS, with presystemic conversion of sildenafil to DMS, characterized the data well. Coadministration of fluconazole (n = 4), a CYP3A inhibitor, resulted in an estimated 59% decrease in sildenafil clearance. IV doses of 0.125, 0.5 and 1 mg/kg every 8 hours (in the absence of fluconazole) resulted in steady-state maximum sildenafil concentrations that were generally within the range of those reported to inhibit phosphodiesterase type 5 activity in vitro. CONCLUSIONS: We successfully characterized the PK of sildenafil and DMS in premature infants and applied the model to inform dosing for a follow-up, phase II study.

Risk factors associated with allograft failure in pediatric kidney transplant recipients with focal segmental glomerulosclerosis.

BACKGROUND: With improved outcomes for children transplanted with FSGS since previous NAPRTCS registry reports, this study re-evaluates the association of living donation, immunosuppression, and DGF on graft survival. SETTING: Patients transplanted between 2002 and 2016, comparing FSGS diagnosis vs other glomerular diseases. METHODS: Primary outcomes were allograft survival and FSGS recurrent-free graft survival. Potential risk factors were obtained at the time of transplant and up to 30 days post-transplantation. Analysis considered a priori that DGF may be a proxy for severe FSGS recurrence. Multivariable survival models for outcome were tested for sensitivity without/with DGF to determine features independent of recurrence. RESULTS: From the larger cohort of 3010 patients, 5-year graft survival in children with FSGS (n = 455) was worse (74.3%) compared with other glomerular diseases (87.1%, n = 690) (HR 1.45, P = 0.033). Modeling all glomerular diseases, survival risk was associated with deceased donor (HR 1.83, P = 0.002), re-transplantation (HR 1.58, P = 0.013), and recipient age (HR 1.06/y, P = 0.002). The living donor advantage was not confirmed in a FSGS model (HR 1.51 for deceased, P = 0.12). DGF was highly associated with graft failure (HR 4.39, P < 0.001) and independent of re-transplant history but not FSGS diagnosis. Induction agents or primary immunosuppression choices were not associated with survival. CONCLUSION: Graft survival rates have improved since the previous report. Living donor did not predict graft failure, but there remains no survival advantage. DGF was the primary independent predictor for graft loss secondary to FSGS recurrence, consistent with DGF being a proxy for severe recurrent disease.

Lithium for the Maintenance Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Discontinuation Study.

OBJECTIVE: This study examined the role of lithium in the maintenance treatment of pediatric patients with bipolar I disorder (BP-I). METHOD: Participants aged 7 to 17 years who presented with a manic or mixed episode received 24 weeks of lithium treatment in one of two multiphase studies, the Collaborative Lithium Trials (CoLT 1 and CoLT 2). Responders were randomized to continue lithium or to be cross-titrated to placebo for up to 28 weeks. The primary outcome measure was relative risk of study discontinuation for any reason. RESULTS: A Cox regression analysis found that those who continued treatment with lithium (n = 17) had a lower hazard ratio compared to those who received placebo (n = 14) (p = .015)]. The vast majority of discontinuations were due to mood symptom exacerbations, with most of these occurring in the placebo-treated group. Discontinuation for other reasons occurred at similarly low rates across both group. Most adverse events were mild to moderate in severity, and only one study participant was discontinued from the trial owing to a serious adverse event (aggression). There was no statistically significant difference with respect to weight gain in participants receiving lithium compared to those receiving placebo. CONCLUSION: This randomized, double-blind, placebo-controlled Discontinuation Trial builds support for the role of lithium as a maintenance treatment in pediatric patients with bipolar disorder and for the safety and tolerability of 28 weeks of maintenance lithium treatment. CLINICAL TRIAL REGISTRATION INFORMATION: Lithium for the Treatment of Pediatric Mania; https://clinicaltrials.gov/; NCT00442039 (CoLT 1). Safety and Efficacy Study of Lithium for the Treatment of Pediatric Mania; https://clinicaltrials.gov/; NCT01166425 (CoLT 2).

Population Pharmacokinetics and Exploratory Exposure-Response Relationships of Diazepam in Children Treated for Status Epilepticus.

Diazepam is labeled for status epilepticus (SE) in children, but there are limited data characterizing its disposition in pediatric patients. We developed a population pharmacokinetic (PK) model of i.v. diazepam in children with SE. We evaluated relationships between PK parameters and both safety and efficacy, and simulated exposures using dosing regimens from the product label and clinical practice. The model was developed using prospective data from a pediatric clinical trial comparing diazepam to lorazepam for treatment of SE. Altogether, 87 patients aged ≥ 3 months to < 18 years contributed 162 diazepam concentrations. Diazepam PKs were well characterized by a two-compartment model scaled by body size. No significant or clinically important relationships were observed between diazepam PKs and safety or efficacy. Simulations demonstrated that, compared with label dosing, the study dose (0.2 mg/kg i.v., maximum 8 mg) resulted in greater frequency in rapidly achieving the target therapeutic range of 200-600 ng/mL.

Clinical outcomes and survival in pediatric patients initiating chronic dialysis: a report of the NAPRTCS registry.

BACKGROUND: The 2011 annual report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) registry comprises data on 6482 dialysis patients over the past 20 years of the registry. METHODS: The study compared clinical parameters and patient survival in the first 10 years of the registry (1992-2001) with the last decade of the registry (2002-2011). RESULTS: There was a significant increase in hemodialysis as the initiating dialysis modality in the most recent cohort (42% vs. 36%, p < 0.001). Patients in the later cohort were less likely to have a hemoglobin <10 g/dl [odds ratio (OR) 0.68; confidence interval (CI) 0.58-0.81; p < 0.001] and height z-score <2 standard deviations (SD) below average (OR 0.68, CI 0.59-0.78, p < 0.0001). They were also more likely to have a parathyroid hormone (PTH) level two times above the upper limits of normal (OR 1.39, CI 1.21-1.60, p < 0.0001). Although hypertension was common regardless of era, patients in the 2002-2011 group were less likely to have blood pressure >90th percentile (OR 1.39, CI 1.21-1.60, p < 0.0001), and a significant improvement in survival at 36 months after dialysis initiation was observed in the 2002-2011 cohort compared with the 1992-2001 cohort (95% vs. 90%, respectively). Cardiopulmonary causes were the most common cause of death in both cohorts. Young age, growth deficit, and black race were poor predictors of survival. CONCLUSIONS: The survival of pediatric patients on chronic dialysis has improved over two decades of dialysis registry data, specifically for children <1year.

Pharmacokinetics of Clindamycin in Obese and Nonobese Children.

Although obesity is prevalent among children in the United States, pharmacokinetic (PK) data for obese children are limited. Clindamycin is a commonly used antibiotic that may require dose adjustment in obese children due to its lipophilic properties. We performed a clindamycin population PK analysis using data from three separate trials. A total of 420 samples from 220 children, 76 of whom had a body mass index greater than or equal to the 95th percentile for age, were included in the analysis. Compared to other metrics, total body weight (TBW) was the most robust measure of body size. The final model included TBW and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (liters/hour) = 13.8 × (TBW/70)0.75 × [PMA2.83/(39.52.83+PMA2.83)]; volume of distribution (V) was associated with TBW, albumin (ALB), and alpha-1 acid glycoprotein (AAG): V (liters) = 63.6 × (TBW/70) × (ALB/3.3)-0.83 × (AAG/2.4)-0.25 After accounting for differences in TBW, obesity status did not explain additional interindividual variability in model parameters. Our findings support TBW-based dosing for obese and nonobese children.

Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study.

BACKGROUND: Lithium is a benchmark treatment for bipolar disorder in adults. Definitive studies of lithium in pediatric bipolar I disorder (BP-I) are lacking. METHODS: This multicenter, randomized, double-blind, placebo-controlled study of pediatric participants (ages 7-17 years) with BP-I/manic or mixed episodes compared lithium (n = 53) versus placebo (n = 28) for up to 8 weeks. The a priori primary efficacy measure was change from baseline to the end of study (week 8/ET) in the Young Mania Rating Scale (YMRS) score, based on last-observation-carried-forward analysis. RESULTS: The change in YMRS score was significantly larger in lithium-treated participants (5.51 [95% confidence interval: 0.51 to 10.50]) after adjustment for baseline YMRS score, age group, weight group, gender, and study site (P = .03). Overall Clinical Global Impression-Improvement scores favored lithium (n = 25; 47% very much/much improved) compared with placebo (n = 6; 21% very much/much improved) at week 8/ET (P = .03). A statistically significant increase in thyrotropin concentration was seen with lithium (3.0 ± 3.1 mIU/L) compared with placebo (-0.1 ± 0.9 mIU/L; P < .001). There was no statistically significant between-group difference with respect to weight gain. CONCLUSIONS: Lithium was superior to placebo in reducing manic symptoms in pediatric patients treated for BP-I in this clinical trial. Lithium was generally well tolerated in this patient population and was not associated with weight gain, distinguishing it from other agents commonly used to treat youth with bipolar disorder.

Outcome of Patients Initiating Chronic Peritoneal Dialysis During the First Year of Life.

BACKGROUND AND OBJECTIVE: Among children with end-stage renal disease (ESRD), those who abstract initiated chronic dialysis during the first year of life historically were less likely to survive or receive a kidney transplant compared with those who initiated dialysis later in childhood.We hypothesized that recently treated infants have experienced improved outcomes. METHODS: We queried the North American Pediatric Renal Trials and Collaborative Studies database, obtaining information on 628 children who initiated maintenance peritoneal dialysis for treatment of ESRD at ,1 year of age. We further subcategorized these children by age(neonates, #31 days and infants, 32­365 days) and date of dialysis initiation (past,1992­1999, and recent, 2000­2012). RESULTS: Survival while on dialysis and overall survival were significantly better among neonates and infants in the recent cohort. Overall survival at 3 years after dialysis initiation was 78.6%and 84.6% among the recently treated neonates and infants, respectively. Neonates and infants in the recent cohort also were more likely to terminate dialysis for transplantation, and graft survival was improved among recently transplanted infants (3-year graft survival 92.1%). CONCLUSIONS: Among children who initiate chronic peritoneal dialysis for treatment of ESRD in the first year of life, survival has improved in recent years. Graft survival also has improved for the subset of these patients who received a kidney transplant.

Design of the standardizing care to improve outcomes in pediatric end stage renal disease collaborative.

The Standardizing Care to Improve Outcomes in Pediatric End Stage Renal Disease (SCOPE) Collaborative is a North American multi-center quality transformation effort whose primary aim is to minimize exit-site infection and peritonitis rates among pediatric chronic peritoneal dialysis patients. The project, developed by the quality improvement faculty and staff at the Children's Hospital Association's Quality Transformation Network (QTN) and content experts in pediatric nephrology and pediatric infectious diseases, is modeled after the QTN's highly successful Pediatric Intensive Care Unit and Hematology-Oncology central line-associated blood-stream infection (CLABSI) Collaboratives. Like the Association's other QTN efforts, the SCOPE Collaborative is part of a broader effort to assist pediatric nephrology teams in learning about and using quality improvement methods to develop and implement evidence-based practices. In addition, the design of this project allows for targeted research that builds on high-quality, ongoing data collection. Finally, the project, while focused on reducing peritoneal dialysis catheter-associated infections, will also serve as a model for future pediatric nephrology projects that could further improve the quality of care provided to children with end stage renal disease.

Longitudinal study of cognitive and academic outcomes after pediatric liver transplantation.

OBJECTIVE: To determine the evolution of cognitive and academic deficits and risk factors in children after liver transplantation. STUDY DESIGN: Patients ≥2 years after liver transplantation were recruited through Studies of Pediatric Liver Transplantation. Participants age 5-6 years at Time 1 completed the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition, Wide Range Achievement Test, 4th edition, and Behavior Rating Inventory of Executive Function (BRIEF). Participants were retested at age 7-9 years, Time 2 (T2), by use of the Wechsler Intelligence Scales for Children, 4th edition, Wide Range Achievement Test, 4th edition, and BRIEF. Medical and demographic variables significant at P ≤ .10 in univariate analysis were fitted to repeated measures modeling predicting Full Scale IQ (FSIQ). RESULTS: Of 144 patients tested at time 1, 93 (65%) completed T2; returning patients did not differ on medical or demographic variables. At T2, more participants than expected had below-average FSIQ, Verbal Comprehension, Working Memory, and Math Computation, as well as increased executive deficits on teacher BRIEF. Processing Speed approached significance. At T2, 29% (14% expected) had FSIQ = 71-85, and 7% (2% expected) had FSIQ ≤70 (P = .0001). A total of 42% received special education. Paired comparisons revealed that, over time, cognitive and math deficits persisted; only reading improved. Modeling identified household status (P < .002), parent education (P < .01), weight z-score at liver transplantation (P < .03), and transfusion volume during liver transplantation (P < .0001) as predictors of FSIQ. CONCLUSIONS: More young liver transplantation recipients than expected are at increased risk for lasting cognitive and academic deficits. Pretransplant markers of nutritional status and operative complications predicted intellectual outcome.

Solid tumors following kidney transplantation in children.

Kidney transplant recipients have an increased risk of cancer. Data on non-LPD malignancies (solid tumors) in pediatric renal transplant recipients are limited. We performed a cohort study using the NAPRTCS transplant registry to describe the incidence of non-LPD malignancy compared with the general pediatric population. The observed incidence rate of non-LPD malignancy in the NAPRTCS transplant registry was 72.1 per 100,000 person-years (SIR 6.7; 95% CI, 5.3, 8.5); a 6.7-fold increased risk compared with the general pediatric population (10.7 cases per 100,000 person-years). Non-LPD malignancy was diagnosed in 35 subjects at a median of 726 days post-transplant. The most common type of malignancy was renal cell carcinoma. The increased risk of non-LPD malignancy was seen in all patients regardless of age, gender, race, etiology of end-stage kidney disease, and transplant era. The specific type of immunosuppression was not identified as a risk factor. In this first large-scale study of North American pediatric renal transplant recipients, we observed a 6.7-fold increased risk of non-LPD malignancy compared with the general pediatric population. Further examination of this unique patient population may provide greater insight into the impact of transplant and immunosuppression on malignancy risk.

Factors predicting health-related quality of life in pediatric liver transplant recipients in the functional outcomes group.

Data from 997 pediatric LT recipients were used to model demographic and medical variables as predictors of lower levels of HRQOL. Data were collected through SPLIT FOG project. Patients were between 2 and 18 yr of age and survived LT by at least 12 months. Parents and children (age ≥ 8 yr) completed PedsQL™ 4.0 Generic Core and CF Scales at one time point. Demographic and medical variables were obtained from SPLIT. HRQOL scores were categorized as "poor" based on lower 25% of scores for each measure. Logistic regression models were generated. Single-parent households (OR 1.94, CI 1.13-3.33, p = 0.017), anti-seizure medications (OR 3.99, CI 1.26-12.70, p = 0.019), and number of days hospitalized (OR 1.03, CI 1.01-1.06, p = 0.0067) were associated with lower self-reported HRQOL. Parent data identified increasing age at transplant, age 5-12 yr at survey, hospitalization >21 days at LT, re-operations, diabetes, and growth failure at LT as additional predictors of generic HRQOL. Male gender, single-parent households, higher bilirubin levels at LT, and use of anti-seizure medication predicted lower cognitive function scores. HRQOL following pediatric LT is related to medical and demographic variables.

Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples from premature infants.

BACKGROUND: Limited pharmacokinetic (PK) data of metronidazole in premature infants have led to various dosing recommendations. Surrogate efficacy targets for metronidazole are ill-defined and therefore aimed to exceed minimum inhibitory concentration of organisms responsible for intra-abdominal infections. METHODS: We evaluated the PK of metronidazole using plasma and dried blood spot samples from infants ≤32 weeks gestational age in an open-label, PK, multicenter (N = 3) study using population PK modeling (NONMEM). Monte Carlo simulations (N = 1000 virtual subjects) were used to evaluate the surrogate efficacy target. Metabolic ratios of parent and metabolite were calculated. RESULTS: Twenty-four premature infants (111 plasma and 51 dried blood spot samples) were enrolled: median (range) gestational age at birth 25 (23-31) weeks, postnatal age 27 (1-82) days, postmenstrual age 31 (24-39) weeks and weight 740 (431-1466) g. Population clearance (L/h/kg) was 0.038 × (postmenstrual age/30) and volume of distribution (L/kg) of 0.93. PK parameter estimates and precision were similar between plasma and dried blood spot samples. Metabolic ratios correlated with clearance. CONCLUSION: Simulations suggested the majority of infants in the neonatal intensive care unit (>80%) would meet the surrogate efficacy target using postmenstrual age-based dosing.

Pediatric kidney transplant practice patterns and outcome benchmarks, 1987-2010: a report of the North American Pediatric Renal Trials and Collaborative Studies.

The NAPRTCS transplant registry has collected clinical information on children undergoing kidney transplantation since 1987 and now includes information on 11 603 kidney transplants in 10 632 patients. Since the first data analysis in 1989, NAPRTCS reports have documented marked improvements in outcome after kidney transplantation in addition to identifying factors associated with both favorable and poor outcomes. Patient demographics have changed over the course of the registry with a decrease in the percentage of white recipients from a high of 72% in 1987 to less than 43% in 2007. The percentage of living donors decreased to its lowest point in 2007 at 37%. Acute rejection rates continue to decline with improvements in short- and long-term graft survival. Recently, NAPRTCS data have been used as a source of benchmark data for pediatric kidney transplant centers.