Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole.

Pharmacokinetic models rarely undergo external validation in vulnerable populations such as critically ill infants, thereby limiting the accuracy, efficacy, and safety of model-informed dosing in real-world settings. Here, we describe an opportunistic approach using dried blood spots (DBS) to evaluate a population pharmacokinetic model of metronidazole in critically ill preterm infants of gestational age (GA) ≤31 weeks from the Metronidazole Pharmacokinetics in Premature Infants (PTN_METRO, NCT01222585) study. First, we used linear correlation to compare 42 paired DBS and plasma metronidazole concentrations from 21 preterm infants [mean (SD): post natal age 28.0 (21.7) days, GA 26.3 (2.4) weeks]. Using the resulting predictive equation, we estimated plasma metronidazole concentrations (ePlasma) from 399 DBS collected from 122 preterm and term infants [mean (SD): post natal age 16.7 (15.8) days, GA 31.4 (5.1) weeks] from the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections (SCAMP, NCT01994993) trial. When evaluating the PTN_METRO model using ePlasma from the SCAMP trial, we found that the model generally predicted ePlasma well in preterm infants with GA ≤31 weeks. When including ePlasma from term and preterm infants with GA >31 weeks, the model was optimized using a sigmoidal Emax maturation function of postmenstrual age on clearance and estimated the exponent of weight on volume of distribution. The optimized model supports existing dosing guidelines and adds new data to support a 6-hour dosing interval for infants with postmenstrual age >40 weeks. Using an opportunistic DBS to externally validate and optimize a metronidazole population pharmacokinetic model was feasible and useful in this vulnerable population.

Framework of the strengths and challenges of clinically integrated trials: An expert panel report.

The limitations of the explanatory clinical trial framework include the high expense of implementing explanatory trials, restrictive entry criteria for participants, and redundant logistical processes. These limitations can result in slow evidence generation that is not responsive to population health needs, yielding evidence that is not generalizable. Clinically integrated trials, which integrate clinical research into routine care, represent a potential solution to this challenge and an opportunity to support learning health systems. The operational and design features of clinically integrated trials include a focused scope, simplicity in design and requirements, the leveraging of existing data structures, and patient participation in the entire trial process. These features are designed to minimize barriers to participation and trial execution and reduce additional research burdens for participants and clinicians alike. Broad adoption and scalability of clinically integrated trials are dependent, in part, on continuing regulatory, healthcare system, and payer support. This analysis presents a framework of the strengths and challenges of clinically integrated trials and is based on a multidisciplinary expert "Think Tank" panel discussion that included representatives from patient populations, academia, non-profit funding agencies, the U.S. Food and Drug Administration, and industry.

Drug development for major chronic health conditions-aligning with growing public health needs: Proceedings from a multistakeholder think tank.

The global pharmaceutical industry portfolio is skewed towards cancer and rare diseases due to more predictable development pathways and financial incentives. In contrast, drug development for major chronic health conditions that are responsible for a large part of mortality and disability worldwide is stalled. To examine the processes of novel drug development for common chronic health conditions, a multistakeholder Think Tank meeting, including thought leaders from academia, clinical practice, non-profit healthcare organizations, the pharmaceutical industry, the Food and Drug Administration (FDA), payors as well as investors, was convened in July 2022. Herein, we summarize the proceedings of this meeting, including an overview of the current state of drug development for chronic health conditions and key barriers that were identified. Six major action items were formulated to accelerate drug development for chronic diseases, with a focus on improving the efficiency of clinical trials and rapid implementation of evidence into clinical practice.

A reappraisal of risk factors for hypertension after pediatric acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalized children and increases the risk of chronic kidney disease (CKD) and hypertension, but little is known about the patient level risk factors for pediatric hypertension after AKI. The aims of this study are to evaluate the prevalence and risk factors for new onset hypertension in hospitalized children with AKI and to better understand the role of acute kidney disease (AKD) in the development of hypertension. METHODS: This study was an observational cohort of all children ≤ 18 years old admitted to a single tertiary care children's hospital from 2015 to 2019 with a diagnosis of AKI. Hypertension was defined as blood pressure > 95th percentile for sex, age, height, diagnosis of hypertension on the problem list, or prescription of antihypertensive medication for > 90 days after AKI. RESULTS: A total of 410 children were included in the cohort. Of these, 78 (19%) developed hypertension > 90 days after AKI. A multivariable logistic regression model identified AKD, need for kidney replacement therapy, congenital heart disease, and non-kidney solid organ transplantation as risk factors for hypertension after AKI. CONCLUSIONS: Incident hypertension after 3 months is common among hospitalized children with AKI, and AKD, need for dialysis, congenital heart disease, and non-kidney solid organ transplant are significant risk factors for hypertension after AKI. Monitoring for hypertension development in these high-risk children is critical to mitigate long-term adverse kidney and cardiovascular outcomes.

Phase I study of liver depot gene therapy in late-onset Pompe disease.

Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for enzyme replacement therapy (ERT) by creating a liver depot for acid α-glucosidase (GAA) production. We report initial safety and bioactivity of the first dose (1.6 × 1012 vector genomes/kg) cohort (n = 3) in a 52-week open-label, single-dose, dose-escalation study (NCT03533673) in patients with late-onset Pompe disease (LOPD). Subjects discontinued biweekly ERT after week 26 based on the detection of elevated serum GAA activity and the absence of clinically significant declines per protocol. Prednisone (60 mg/day) was administered as immunoprophylaxis through week 4, followed by an 11-week taper. All subjects demonstrated sustained serum GAA activities from 101% to 235% of baseline trough activity 2 weeks following the preceding ERT dose. There were no treatment-related serious adverse events. No subject had anti-capsid T cell responses that decreased transgene expression. Muscle biopsy at week 24 revealed unchanged muscle glycogen content in two of three subjects. At week 52, muscle GAA activity for the cohort was significantly increased (p < 0.05). Overall, these initial data support the safety and bioactivity of AAV8-LSPhGAA, the safety of withdrawing ERT, successful immunoprophylaxis, and justify continued clinical development of AAV8-LSPhGAA therapy in Pompe disease.

Correlating Severity of Pulmonary Hypertension by Echocardiogram with Mortality in Premature Infants with Bronchopulmonary Dysplasia.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth. Infants with BPD are at increased risk for pulmonary hypertension (PH). Cardiac catheterization is the gold standard for diagnosing PH, but cardiac catheterization is challenging to perform in small, sick, premature infants. The utility of echocardiography for diagnosing PH and predicting outcomes in extremely premature infants has not been clearly defined. Therefore, we sought to use predefined criteria to diagnose PH by echocardiogram and relate PH severity to mortality in extremely premature infants with BPD. STUDY DESIGN: Echocardiograms from 46 infants born ≤28 weeks' postmenstrual age with a diagnosis of BPD were assessed for PH by three pediatric cardiologists using predefined criteria, and survival times among categories of PH patients were compared. A total of 458 echocardiograms were reviewed, and 15 (33%) patients were found to have at least moderate PH. Patients with at least moderate PH had similar demographic characteristics to those with no/mild PH. RESULTS: Ninety percent of infants without moderate to severe PH survived to hospital discharge, compared with 67% of infants with at least moderate PH (p = 0.048). Patients with severe PH had decreased survival to hospital discharge (38%) compared with moderate (100%) and no/mild PH (90%) groups. Kaplan-Meier survival curves also differed among PH severity groups (Wilcoxon p < 0.001). CONCLUSION: Using predefined criteria for PH, premature infants with BPD can be stratified into PH severity categories. Patients diagnosed with severe PH by echocardiogram have significantly reduced survival. KEY POINTS: · A composite score definition of PH by echocardiogram showed high inter- and intrarater reliability.. · Infants with severe PH by echocardiogram had decreased survival rates.. · Early diagnosis of PH by echocardiogram dictates treatment which may improve outcomes..

Incidence of group B streptococcus early-onset sepsis in term neonates with second-line prophylaxis maternal intrapartum antibiotics: a multicenter retrospective study.

BACKGROUND: The difference in the incidence of early-onset sepsis caused by group B streptococcus among term neonates whose mothers received first-line vs second-line intrapartum prophylaxis is poorly described. OBJECTIVE: This study aimed to compare the incidence of group B streptococcus early-onset sepsis among term neonates born to mothers who receive first-line, second-line, or no intrapartum antibiotics and to describe the short-term and survival outcomes of neonates who developed group B streptococcus early-onset sepsis stratified by maternal antepartum prophylaxis. STUDY DESIGN: This was a retrospective review of electronic medical records. We queried the Pediatrix Medical Group Clinical Data Warehouse to evaluate the outcomes of term neonates born to group B streptococcus positive mothers between 2003 and 2020 and compared the incidence and outcomes of neonates with group B streptococcus early-onset sepsis whose mothers received first-line vs second-line or no intrapartum prophylaxis. RESULTS: Among the 496,180 neonates, 104,196 (21%) were born to mothers who were group B streptococcus positive. Of 97,983 mothers who were group B streptococcus positive with adequate prenatal antibiotic documentation, 49,234 (50%), 12,679 (13%), and 36,070 (37%) received first-line, second-line, and no intrapartum prophylaxis, respectively. The incidence of group B streptococcus early-onset sepsis among all neonates with maternal group B streptococcus carriage was 0.22% (231/104,196). Neonates whose mothers received second-line intrapartum antibiotics and no antibiotics had a higher risk for group B streptococcus early-onset sepsis infection than those whose mothers received first-line intrapartum antibiotics (adjusted odds ratio, 4.12; 95% confidence interval, 2.66-6.38 and adjusted odds ratio, 3.80; 95% confidence interval, 2.66-5.44, respectively). There was no statistically significant difference in the risk for group B streptococcus early-onset sepsis among neonates born to mothers who received second-line vs no antibiotics (adjusted odds ratio, 0.92; 95% confidence interval, 0.64-1.33). CONCLUSION: Neonates exposed to second-line maternal group B streptococcus prophylaxis had an increased risk for group B streptococcus early-onset sepsis when compared with those exposed to first-line maternal group B streptococcus prophylaxis. There was no statistically significant difference in group B streptococcus early-onset sepsis incidence between second-line antibiotic prophylaxis and no antibiotics in mothers with group B streptococcus carriage.

Patient level factors increase risk of acute kidney disease in hospitalized children with acute kidney injury.

BACKGROUND: Studies in adults have shown that persistent kidney dysfunction ≥7-90 days following acute kidney injury (AKI), termed acute kidney disease (AKD), increases chronic kidney disease (CKD) and mortality risk. Little is known about the factors associated with the transition of AKI to AKD and the impact of AKD on outcomes in children. The aim of this study is to evaluate risk factors for progression of AKI to AKD in hospitalized children and to determine if AKD is a risk factor for CKD. METHODS: Retrospective cohort study of children age ≤18 years admitted with AKI to all pediatric units at a single tertiary-care children's hospital between 2015 and 2019. Exclusion criteria included insufficient serum creatinine values to evaluate for AKD, chronic dialysis, or previous kidney transplant. RESULTS: A total of 528 children with AKI were included in the study. There were 297 (56.3%) hospitalized AKI survivors who developed AKD. Among children with AKD, 45.5% developed CKD compared to 18.7% in the group without AKD (OR 4.0, 95% CI 2.1-7.4, p-value <0.001 using multivariable logistic regression analysis including other covariates). Multivariable logistic regression model identified age at AKI diagnosis, PCICU and NICU admission, prematurity, malignancy, bone marrow transplant, previous AKI, mechanical ventilation, AKI stage, duration of kidney injury, and need for kidney replacement therapy during day 1-7 as risk factors for AKD after AKI. CONCLUSIONS: AKD is common among hospitalized children with AKI and multiple risk factors are associated with AKD. Children that progress from AKI to AKD are at higher risk of developing CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Congenital anomalies of the kidney and urinary tract (CAKUT) in critically ill infants: a multicenter cohort study.

BACKGROUND: The aim of the study was to determine the prevalence of congenital anomalies of the kidney and urinary tract (CAKUT) in the neonatal intensive care unit (NICU) and to evaluate risk factors associated with worse outcomes. We hypothesized that infants with CAKUT with extra-renal manifestations have higher mortality. METHODS: This is a cohort study of all inborn infants who were diagnosed with any form of CAKUT discharged from NICUs managed by the Pediatrix Medical Group from 1997 to 2018. Logistic and linear regression models were used to analyze risk factors associated with in-hospital mortality. RESULTS: The prevalence of CAKUT was 1.5% among infants hospitalized in 419 NICUs. Among the 13,383 infants with CAKUT analyzed, median gestational age was 35 (interquartile range [IQR] 31-38) weeks and median birth weight was 2.34 (IQR 1.54-3.08) kg. Overall in-hospital mortality for infants with CAKUT was 6.8%. Oligohydramnios (adjusted odds ratio [aOR] 4.5, 95% confidence interval [CI] 2.2-9.1, p < 0.001), extra-renal anomalies (aOR 2.5, 95% CI 2.0-3.1, p < 0.001), peak SCr (aOR 1.02, 95% CI 1.01-1.03, p < 0.001) and exposure to nephrotoxic medications (aOR 1.4, 95% CI 1.1-1.7, p = 0.01) were associated with increased mortality, while a history of urological surgery or intervention was associated with lower mortality (aOR 0.6, 95% CI 0.4-0.7, p < 0.001). CONCLUSIONS: Infants hospitalized in the NICU who have CAKUT and the independent risk factors for mortality (e.g., oligohydramnios and presence of extra-renal anomalies) require close monitoring, minimizing of exposure to nephrotoxic drugs, and timely urological surgery or intervention. A higher resolution version of the Graphical abstract is available as Supplementary information.

You & Me: Test and Treat study protocol for promoting COVID-19 test and treatment access to underserved populations.

BACKGROUND: Infections and deaths from the COVID-19 pandemic have disproportionately affected underserved populations. A community-engaged approach that supports decision making around safe COVID-19 practices is needed to promote equitable access to testing and treatment. You & Me: Test and Treat (YMTT) will evaluate a systematic and scalable community-engaged protocol that provides rapid access to COVID-19 at-home tests, education, guidance on next steps, and information on local resources to facilitate treatment in underserved populations. METHODS: This direct-to-participant observational study will distribute at-home, self-administered, COVID-19 testing kits to people in designated communities. YMTT features a Public Health 3.0 framework and Toolkit prescribing a tiered approach to community engagement. We will partner with two large community organizations, Merced County United Way (Merced County, CA) and Pitt County Health Department (Pitt County, NC), who will coordinate up to 20 local partners to distribute 40,000 COVID tests and support enrollment, consenting, and data collection over a 15-month period. Participants will complete baseline questions about their demographics, experience with COVID-19 infection, and satisfaction with the distribution event. Community partners will also complete engagement surveys. In addition, participants will receive guidance on COVID-19 mitigation and health-promoting resources, and accessible and affordable therapeutics if they test positive for COVID-19. Data collection will be completed using a web-based platform that enables creation and management of electronic data capture forms. Implementation measures include evaluating 1) the Toolkit as a method to form community-academic partnerships for COVID-19 test access, 2) testing results, and 3) the efficacy of a YMTT protocol coupled with local resourcing to provide information on testing, guidance, treatment, and links to resources. Findings will be used to inform innovative methods to address community needs in public health research that foster cultural relevance, improve research quality, and promote health equity. DISCUSSION: This work will promote access to COVID-19 testing and treatment for underserved populations by leveraging a community-engaged research toolkit. Future dissemination of the toolkit can support effective community-academic partnerships for health interventions in underserved settings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05455190 . Registered 13 July 2022.

Power analysis for idiographic (within-subject) clinical trials: Implications for treatments of rare conditions and precision medicine.

Power analysis informs a priori planning of behavioral and medical research, including for randomized clinical trials that are nomothetic (i.e., studies designed to infer results to the general population based on interindividual variabilities). Far fewer investigations and resources are available for power analysis of clinical trials that follow an idiographic approach, which emphasizes intraindividual variabilities between baseline (control) phase versus one or more treatment phases. We tested the impact on statistical power to detect treatment outcomes of four idiographic trial design factors that are under researchers' control, assuming a multiple baseline design: sample size, number of observations per participant, proportion of observations in the baseline phase, and competing statistical models (i.e., hierarchical modeling versus piecewise regression). We also tested the impact of four factors that are largely outside of researchers' control: population size, proportion of intraindividual variability due to residual error, treatment effect size, and form of outcomes during the treatment phase (phase jump versus gradual change). Monte Carlo simulations using all combinations of the factors were sampled with replacement from finite populations of 200, 1750, and 3500 participants. Analyses characterized the unique relative impact of each factor individually and all two-factor combinations, holding all others constant. Each factor impacted power, with the greatest impact being from larger treatment effect sizes, followed respectively by more observations per participant, larger samples, less residual variance, and the unexpected improvement in power associated with assigning closer to 50% of observations to the baseline phase. This study's techniques and R package better enable a priori rigorous design of idiographic clinical trials for rare diseases, precision medicine, and other small-sample studies.

Pharmacodynamics of Meropenem and Tobramycin for Neonatal Meningoencephalitis: Novel Approaches to Facilitate the Development of New Agents to Address the Challenge of Antimicrobial Resistance.

Neonatal sepsis is an underrecognized burden on health care systems throughout the world. Antimicrobial drug resistance (AMR) is increasingly prevalent and compromises the use of currently recommended first-line agents. The development of new antimicrobial agents for neonates and children is mandated by regulatory agencies. However, there remains uncertainty about suitable development pathways, especially because of the propensity of premature babies to develop meningoencephalitis as a complication of neonatal sepsis and difficulties studying this disease in clinical settings. We developed a new platform and approach to accelerate the development of antimicrobial agents for neonatal bacterial meningoencephalitis using Pseudomonas aeruginosa as the challenge organism. We defined the pharmacodynamics of meropenem and tobramycin in these models. The percentage of partitioning of meropenem and tobramycin into the cerebrospinal fluid was comparable at 14.3 and 13.7%, respectively. Despite this similarity, there were striking differences in their pharmacodynamics. Meropenem resulted in bactericidal activity in both the cerebrospinal fluid and cerebrum, whereas tobramycin had minimal antibacterial activity. A hollow fiber infection model (HFIM) using neonatal CSF concentration time profiles yielded pharmacodynamics comparable to those observed in the rabbit model. These new experimental models can be used to estimate the pharmacodynamics of currently licensed agents and those in development and their potential efficacy for neonatal bacterial meningoencephalitis.

Medication Use in the Neonatal Intensive Care Unit and Changes from 2010 to 2018.

OBJECTIVE: To provide up-to-date medication prescribing patterns in US neonatal intensive care units (NICUs) and to examine trends in prescribing patterns over time. STUDY DESIGN: We performed a cohort study of 799 016 infants treated in NICUs managed by the Pediatrix Medical Group from 2010 to 2018. We used 3 different methods to report counts of medication: exposure, courses, and days of use. We defined the change in frequency of medication administration by absolute change and relative change. We examined the Food and Drug Administration (FDA) package insert for each medication to determine whether a medication was labeled for use in infants and used PubMed to search for pharmacokinetics (PK) studies. RESULTS: The most frequently prescribed medications included ampicillin, gentamicin, caffeine citrate, poractant alfa, morphine, vancomycin, furosemide, fentanyl, midazolam, and acetaminophen. Of the top 50 medications used in infants with extremely low birth weight, only 20 (40%) are FDA-labeled for use in infants; of the 30 that are not labeled for use in infants, 13 (43%) had at least 2 published PK studies. The medications with the greatest relative increase in use from 2010 to 2018 included dexmedetomidine, clonidine, rocuronium, levetiracetam, atropine, and diazoxide. The medications with the greatest relative decrease in use included tromethamine acetate, pancuronium, chloral hydrate, imipenem + cilastatin, and amikacin. CONCLUSION: Trends of medication use in the NICU change substantially over time. It is imperative to identify changes in medication use in the NICU to better inform further prospective studies.

Beyond pain control: Outcome and treatment preferences in pediatric migraine.

OBJECTIVE: The objective of this study was to describe treatment preferences and perceived quality of existing outcome measures among children and adolescents with migraine and their caregivers. BACKGROUND: Across disciplines, there is increasing recognition of the value of direct input from stakeholders. Little empirical work has been done to determine what outcomes matter most to pediatric patients with migraine and their caregivers. METHODS: In this qualitative study, we recruited participants from the multicenter, prospective Pediatric Migraine Registry. We used stratified purposive sampling to recruit children and adolescents of varied ages and headache frequency. Patients with migraine and their caregivers completed semistructured interviews targeting treatment preferences and perceived quality of existing outcome measures. Emergent themes and subthemes were identified using conventional content analysis. RESULTS: Thirty dyads of children/adolescents and their caregivers were enrolled and completed 59 interviews (n = 29 children/adolescent interviews and n = 30 caregiver interviews). Three themes emerged. (1) Symptom relief: Looking beyond headache resolution: Participants described the value of outcomes in addition to pain relief, including a reduction in migraine intensity and improvement in non-pain symptoms. (2) Trade-offs between side effects and relief: Participants described cost-benefit analyses that can occur with headache treatment and acknowledged the impact of drug side effects on daily life and medication adherence. (3) Child-centered treatment: Participants described medication attributes salient to the pediatric context, including age-appropriate routes of administration and adequate safety data. CONCLUSIONS: Children, adolescents, and caregivers impacted by migraine value outcomes in addition to traditionally studied migraine endpoints. Participants valued decreased pain severity, even in the absence of pain resolution. Participants also prioritized the absence of side effects and key medication attributes, including fast onset and age-appropriate routes of administration. These results highlight an opportunity to design patient-centered clinical trials, develop drugs, and support product labeling that align with the outcomes valued most by children and adolescents with migraine and their caregivers.

Association Between Digoxin Use and Cardiac Function in Infants With Single-Ventricle Congenital Heart Disease During the Interstage Period.

OBJECTIVES: To examine the association between digoxin use and cardiac function assessed by echocardiographic indices in infants with single-ventricle (SV) congenital heart disease (CHD) during the interstage period. DESIGN: Retrospective cohort study. SETTING: Fifteen North American hospitals. PATIENTS: Infants discharged home following stage 1 palliation (S1P) and prior to stage 2 palliation (S2P). Infants with no post-S1P and pre-S2P echocardiograms were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 373 eligible infants who met inclusion criteria, 140 (37.5%) were discharged home on digoxin. In multivariable linear and logistic regressions, we found that compared with infants discharged home without digoxin, those discharged with digoxin had a smaller increase in end-systolic volume (ß = -8.17 [95% CI, -15.59 to -0.74]; p = 0.03) and area (ß = -1.27 [-2.45 to -0.09]; p = 0.04), as well as a smaller decrease in ejection fraction (ß = 3.38 [0.47-6.29]; p = 0.02) and fractional area change (ß = 2.27 [0.14-4.41]; p = 0.04) during the interstage period. CONCLUSIONS: Digoxin may partially mitigate the expected decrease in cardiac function during the interstage period through its positive inotropic effects. Prospective clinical trials are needed to establish the pharmacokinetics, safety, and efficacy of digoxin use in SV CHD.

A systematic review of clinical study evidence for pulmonary vasodilator therapy following surgery with cardiopulmonary bypass in children with CHD.

OBJECTIVES: Complications from pulmonary hypertension are one of the leading contributors to morbidity and mortality post-cardiopulmonary bypass surgery in children with CHD. Pulmonary vasodilator therapies are commonly used post-operatively, but the optimal target patient population, therapy choice, timing of therapy initiation, and duration of therapy are not well defined. METHODS: We used PubMed and EMBASE to identify studies from 2000 to 2020 investigating the use of pulmonary vasodilator therapy post-cardiopulmonary bypass in children aged 0-18 years. To ensure eligibility criteria, studies were systematically reviewed by two independent reviewers. RESULTS: We identified 26 studies of 42,971 children across four medication classes; 23 were single centre, 14 were prospective, and 11 involved randomisation (four of which employed a placebo-control arm). A disproportionate number of children were from a single retrospective study of 41,872 patients. Definitions varied, but change in pulmonary haemodynamics was the most common primary outcome, used in 14 studies. Six studies had clinical endpoints, with mortality the primary endpoint for two studies. Treatment with inhaled nitric oxide, iloprost, and sildenafil all resulted in improved haemodynamics in specific cohorts of children with post-operative pulmonary hypertension, although improved outcomes were not consistently demonstrated across all treated children. Iloprost may be a cheaper alternative to inhaled nitric oxide with similar haemodynamic response. CONCLUSION: Studies were predominantly single-centre, a control arm was rarely used in randomised studies, and haemodynamic endpoints varied significantly. Further research is needed to reduce post-operative morbidity and mortality from pulmonary hypertension in children with CHD.

The relationship between simulated milrinone exposure and hypotension in children.

INTRODUCTION: Hypotension is an adverse event that may be related to systemic exposure of milrinone; however, the true exposure-safety relationship is unknown. METHODS: Using the Pediatric Trials Network multicentre repository, we identified children ≤17 years treated with milrinone. Hypotension was defined according to age, using the Pediatric Advanced Life Support guidelines. Clinically significant hypotension was defined as hypotension with concomitant lactate >3 mg/dl. A prior population pharmacokinetic model was used to simulate milrinone exposures to evaluate exposure-safety relationships. RESULTS: We included 399 children with a median (quarter 1, quarter 3) age of 1 year (0,5) who received 428 intravenous doses of milrinone (median infusion rate 0.31 mcg/kg/min [0.29,0.5]). Median maximum plasma milrinone concentration was 110.7 ng/ml (48.4,206.2). Median lowest systolic and diastolic blood pressures were 74 mmHg (60,85) and 35 mmHg (25,42), respectively. At least 1 episode of hypotension occurred in 178 (45%) subjects; clinically significant hypotension occurred in 10 (2%). The maximum simulated milrinone plasma concentrations were higher in subjects with clinically significant hypotension (251 ng/ml [129,329]) versus with hypotension alone (86 ng/ml [44, 173]) versus without hypotension (122 ng/ml [57, 208], p = 0.002); however, this relationship was not retained on multivariable analysis (odds ratio 1.01; 95% confidence interval 0.998, 1.01). CONCLUSIONS: We successfully leveraged a population pharmacokinetic model and electronic health record data to evaluate the relationship between simulated plasma concentration of milrinone and systemic hypotension occurrence, respectively, supporting the broader applicability of our novel, efficient, and cost-effective study design for examining drug exposure-response and -safety relationships.

A systematic review of the evidence supporting post-operative antithrombotic use following cardiopulmonary bypass in children with CHD.

OBJECTIVES: To determine the optimal antithrombotic agent choice, timing of initiation, dosing and duration of therapy for paediatric patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: We used PubMed and EMBASE to systematically review the existing literature of clinical trials involving antithrombotics following cardiac surgery from 2000 to 2020 in children 0-18 years. Studies were assessed by two reviewers to ensure they met eligibility criteria. RESULTS: We identified 10 studies in 1929 children across three medications classes: vitamin K antagonists, cyclooxygenase inhibitors and indirect thrombin inhibitors. Four studies were retrospective, five were prospective observational cohorts (one of which used historical controls) and one was a prospective, randomised, placebo-controlled, double-blind trial. All included were single-centre studies. Eight studies used surrogate biomarkers and two used clinical endpoints as the primary endpoint. There was substantive variability in response to antithrombotics in the immediate post-operative period. Studies of warfarin and aspirin showed that laboratory monitoring levels were frequently out of therapeutic range (variably defined), and findings were mixed on the association of these derangements with bleeding or thrombotic events. Heparin was found to be safe at low doses, but breakthrough thromboembolic events were common. CONCLUSION: There are few paediatric prospective randomised clinical trials evaluating antithrombotic therapeutics post-cardiac surgery; most studies have been observational and seldom employed clinical endpoints. Standardised, validated endpoints and pragmatic trial designs may allow investigators to determine the optimal drug, timing of initiation, dosing and duration to improve outcomes by limiting post-operative morbidity and mortality related to bleeding or thrombotic events.

External Evaluation of Two Pediatric Population Pharmacokinetics Models of Oral Trimethoprim and Sulfamethoxazole.

The antibiotic combination trimethoprim (TMP)-sulfamethoxazole (SMX) has a broad spectrum of activity and is used for the treatment of numerous infections, but pediatric pharmacokinetic (PK) data are limited. We previously published population PK (popPK) models of oral TMP-SMX in pediatric patients based on sparse opportunistically collected data (POPS study) (J. Autmizguine, C. Melloni, C. P. Hornik, S. Dallefeld, et al., Antimicrob Agents Chemother 62:e01813-17, 2017, https://doi.org/10.1128/AAC.01813-17). We performed a separate PK study of oral TMP-SMX in infants and children with more-traditional PK sample collection and independently developed new popPK models of TMP-SMX using this external data set. The POPS data set and the external data set were each used to evaluate both popPK models. The external TMP model had a model and error structure identical to those of the POPS TMP model, with typical values for PK parameters within 20%. The external SMX model did not identify the covariates in the POPS SMX model as significant. The external popPK models predicted higher exposures to TMP (median overprediction of 0.13 mg/liter for the POPS data set and 0.061 mg/liter for the external data set) and SMX (median overprediction of 1.7 mg/liter and 0.90 mg/liter) than the POPS TMP (median underprediction of 0.016 mg/liter and 0.39 mg/liter) and SMX (median underprediction of 1.2 mg/liter and 14 mg/liter) models. Nonetheless, both models supported TMP-SMX dose increases in infants and young children for resistant pathogens with a MIC of 1 mg/liter, although the required dose increase based on the external model was lower. (The POPS and external studies have been registered at ClinicalTrials.gov under registration no. NCT01431326 and NCT02475876, respectively.).

Population pharmacokinetics of olanzapine in children.

AIMS: The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed paediatric dosing scheme. METHODS: The PopPK of olanzapine was characterized using opportunistically collected plasma samples from children receiving olanzapine per standard of care for any indication. A nonlinear mixed effect modelling approach was employed for model development using the software NONMEM (v7.4). Simulations from the developed PopPK model were used to devise a paediatric dosing scheme that targeted comparable plasma exposures to adolescents and adults. RESULTS: Forty-five participants contributed 83 plasma samples towards the analysis. The median (range) postnatal age and body weight of participants were 3.8 years (0.2-19.2) and 14.1 kg (4.2-111.7), respectively. The analysis was restricted to pharmacokinetic (PK) samples collected following enteral administration (oral and feeding tube). A one-compartment model with linear elimination provided an appropriate fit to the data. The final model included the covariates body weight and postmenstrual age (PMA) on apparent olanzapine clearance (CL/F). Typical CL/F and apparent volume of distribution (scaled to 70 kg) were 16.8 L/h (21% RSE) and 663 L (13% RSE), respectively. Developed dosing schemes used weight-normalized doses for children ≤6 months postnatal age or <15 kg and fixed doses for children ≥15 kg. CONCLUSION: We developed a paediatric PopPK model for enterally-administered olanzapine. To our knowledge, this analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and PMA were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance.