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Objective: The objective of this paper was to determine inhaled corticosteroid (IC) use in infants with bronchopulmonary dysplasia (BPD), define the interhospital variation of IC administration to infants with BPD, and compare clinical, demographic, and hospital factors associated with IC use., Study Design: Using the Pediatric Health Information System database, a retrospective multicenter cohort of 4,551 infants born at <32 weeks of gestation with developing BPD was studied. The clinical, demographic, and hospital characteristics of infants exposed and not exposed to ICs were compared., Results: IC use varied markedly between hospitals, ranging from 0 to 66% of infants with BPD exposed to ICs. Increased annual BPD census was not associated with IC use. In total, 25% (1,144 out of 4,551) of patients with BPD and 43% (536 out of 1,244) of those with severe BPD received ICs. Increased IC exposure was associated with lower birth weight and gestational age, days on respiratory support, need for positive pressure ventilation at 36-week postmenstrual age, need for tracheostomy, and increased use of systemic steroids, bronchodilators, and diuretics., Conclusion: IC exposure is common in infants with BPD, with substantial interhospital variability. IC use was associated with more severe disease. Hospital experience did not account for the wide variability in IC use by the hospital. Further research into the effects of ICs use is urgently needed to help guide their use in this vulnerable population., Key Points: · The risks and benefits of IC use in infants with BPD are incompletely understood.. · IC use is common in infants with BPD (25%) and severe BPD (43%) varies widely by hospital (0-66% of patients with BPD received an IC).. · Hospital experience did not account for the wide interhospital variation in IC use.., Competing Interests: Dr. McCulloh occasionally provides expert advice on legal matters., (Thieme. All rights reserved.)

Rare diseases impact all socio-economic, geographic, and racial groups indiscriminately. Newborn screening (NBS) is an exemplary international public health initiative that identifies infants with rare conditions early in life to reduce morbidity and mortality. NBS theoretically promotes equity through universal access, regardless of financial ability. There is however heterogeneity in access to newborn screening and conditions that are screened throughout the world. In the United States and some other developed countries, NBS is provided to all babies, subsidized by the local or federal government. Although NBS is an equitable test, infants admitted to neonatal intensive care units (NICUs) may not receive similar benefits to healthier infants. Newborns in the NICU may receive delayed and/or multiple newborn screens due to known limitations in interpreting the results with prematurity, total parenteral nutrition, blood transfusions, infection, and life support. Thus, genomic technologies might be needed in addition to NBS for equitable care of this vulnerable population. Whole exome (WES) and genome sequencing (WGS) have been recently studied in critically ill newborns across the world and have shown promising results in shortening diagnostic odysseys and providing clinical utility. However, in certain circumstances several barriers might limit access to these tests. Here, we discuss some of the existing barriers to genomic sequencing in NICUs in the United States, explore the ethical implications related to low access, consider ways to increase access to genomic testing, and offer some suggestions for future research in these areas.

Importance: Whole-genome sequencing (WGS) shows promise as a first-line genetic test for acutely ill infants, but widespread adoption and implementation requires evidence of an effect on clinical management., Objective: To determine the effect of WGS on clinical management in a racially and ethnically diverse and geographically distributed population of acutely ill infants in the US., Design, Setting, and Participants: This randomized, time-delayed clinical trial enrolled participants from September 11, 2017, to April 30, 2019, with an observation period extending to July 2, 2019. The study was conducted at 5 US academic medical centers and affiliated children's hospitals. Participants included infants aged between 0 and 120 days who were admitted to an intensive care unit with a suspected genetic disease. Data were analyzed from January 14 to August 20, 2020., Interventions: Patients were randomized to receive clinical WGS results 15 days (early) or 60 days (delayed) after enrollment, with the observation period extending to 90 days. Usual care was continued throughout the study., Main Outcomes and Measures: The main outcome was the difference in the proportion of infants in the early and delayed groups who received a change of management (COM) 60 days after enrollment. Additional outcome measures included WGS diagnostic efficacy, within-group COM at 90 days, length of hospital stay, and mortality., Results: A total of 354 infants were randomized to the early (n = 176) or delayed (n = 178) arms. The mean participant age was 15 days (IQR, 7-32 days); 201 participants (56.8%) were boys; 19 (5.4%) were Asian; 47 (13.3%) were Black; 250 (70.6%) were White; and 38 (10.7%) were of other race. At 60 days, twice as many infants in the early group vs the delayed group received a COM (34 of 161 [21.1%; 95% CI, 15.1%-28.2%] vs 17 of 165 [10.3%; 95% CI, 6.1%-16.0%]; P = .009; odds ratio, 2.3; 95% CI, 1.22-4.32) and a molecular diagnosis (55 of 176 [31.0%; 95% CI, 24.5%-38.7%] vs 27 of 178 [15.0%; 95% CI, 10.2%-21.3%]; P < .001). At 90 days, the delayed group showed a doubling of COM (to 45 of 161 [28.0%; 95% CI, 21.2%-35.6%]) and diagnostic efficacy (to 56 of 178 [31.0%; 95% CI, 24.7%-38.8%]). The most frequent COMs across the observation window were subspecialty referrals (39 of 354; 11%), surgery or other invasive procedures (17 of 354; 4%), condition-specific medications (9 of 354; 2%), or other supportive alterations in medication (12 of 354; 3%). No differences in length of stay or survival were observed., Conclusions and Relevance: In this randomized clinical trial, for acutely ill infants in an intensive care unit, introduction of WGS was associated with a significant increase in focused clinical management compared with usual care. Access to first-line WGS may reduce health care disparities by enabling diagnostic equity. These data support WGS adoption and implementation in this population., Trail Registration: ClinicalTrials.gov Identifier: NCT03290469.

Objective: To determine clinical, demographic, and hospital factors associated with inhaled bronchodilator (IB) use in infants with bronchopulmonary dysplasia (BPD) and specifically severe BPD., Study Design: Retrospective multicenter cohort study of 4986 infants born <32 weeks gestation with developing BPD at 28 days of life. We used the Pediatric Health Information System database to compare hospital experience and the demographic and clinical characteristics of infants exposed and not exposed to IBs., Results: Twenty-five percent of BPD patients (1224/4986) and 48% of severe BPD patients (664/1390) received IBs. IB exposure was higher in infants with the tracheostomy, prolonged steroid and diuretic exposure, and longer duration of respiratory support. IB use varied markedly between hospitals (0-59%). Average annual BPD census was not associated with IB use., Conclusion: Bronchodilator exposure is common in BPD patients with substantial variability in its use. Hospital experience did not account for the between-hospital variation in practice.

Background: Pain control in infants is an important clinical concern, with potential long-term adverse neurodevelopmental effects. Intravenous morphine is routinely administered for postoperative pain management; however, its dose-concentration-response relationship in neonates and infants has not been well characterized. Although the current literature provides dosing guidelines for the average infant, it fails to control for the large unexplained variability in morphine clearance and response in individual patients. Bayesian estimation can be used to control for some of this variability. The authors aimed to evaluate morphine pharmacokinetics (PKs) and exposure in critically ill neonates and infants receiving standard-of-care morphine therapy and compare a population-based approach to the model-informed Bayesian techniques., Methods: The PKs and exposure of morphine and its active metabolites were evaluated in a prospective opportunistic PK study using 221 discarded blood samples from 57 critically ill neonates and infants in the neonatal intensive care unit. Thereafter, a population-based PK model was compared with a Bayesian adaptive control strategy to predict an individual's PK profile and morphine exposure over time., Results: Among the critically ill neonates and infants, morphine clearance showed substantial variability with a 40-fold range (ie, 2.2 to 87.1, mean 23.7 L/h/70 kg). Compared with the observed morphine concentrations, the population-model based predictions had an R of 0.13, whereas the model-based Bayesian predictions had an R of 0.61., Conclusions: Model-informed Bayesian estimation is a better predictor of morphine exposure than PK models alone in critically ill neonates and infants. A large variability was also identified in morphine clearance. A further study is warranted to elucidate the predictive covariates and precision dosing strategies that use morphine concentration and pain scores as feedbacks.

We have previously reported the influences of OCT1 ontogeny and genetic variation on morphine clearance in neonatal and pediatric patients. In the latter study, plasma morphine-glucuronide levels correlated with patient genotype for the rs4793665 single-nucleotide polymorphism (SNP) at the locus of MRP3, an efflux transporter of morphine glucuronides between hepatocytes and circulating blood. The link between MRP3 activity and overall morphine clearance has not been thoroughly investigated however, and the developmental profile of hepatic MRP3 protein expression remains thinly defined between neonates and adults. In the current study, previously determined morphine clearance values for neonatal (24-58 weeks postmenstrual age, N = 57) and pediatric (5-16 years, n = 85) patients were reanalyzed for correlation to the SNP genotype of patient rs4793665. Among OCT1 wild-type patients, pediatric morphine clearance showed a significant decreasing trend by MRP3 genotypes in the order of CC > CT > TT (P = .014), whereas for neonates, an identical but nonsignificant trend was observed. Pharmacogenetic differences in MRP3 and OCT1 ontogeny were evaluated by Western blot of hepatic membrane fractions from 50 subjects aged 1 day postnatal to 33 years old. Hepatic MRP3 protein level did not vary by rs4793665 genotype, and followed an atypical developmental pattern of increase up to 1-2 years of age, thereafter decreasing during preadolescence before increasing again to adult levels at maturity (17-33 years). By comparison, OCT1 expression was significantly decreased in OCT1 *1/*3 genotyped patients older than 1 year and followed a trajectory consistent with prior studies. Our results suggest that consideration of MRP3 pharmacogenetics and ontogeny may aid in identifying pediatric patients having different/atypical morphine requirements., (© 2020, The American College of Clinical Pharmacology.)

Objectives: Assess trends in inpatient acute gastroenteritis (AGE) management across children's hospitals and identify elements of AGE management associated with resource use., Methods: We examined inpatient stays for children 6 months to 18 years hospitalized with AGE from 2009 to 2018 using the Pediatric Health Information System database. We characterized demographics, hospital-level resource use (ie, medications, laboratories, and imaging), and outcomes (ie, cost per case, 14-day revisit rates, and length of stay [LOS]). We compared demographic characteristics and resource use between 2009 to 2013 and 2014 to 2018 using χ 2 and Wilcoxon rank-sum tests. We grouped hospitals on the basis of 2009 use of each resource and trended use over time using logistic regression. Annual change in mean cost and LOS were estimated by using models of log-transformed data., Results: Across 32 354 hospitalizations at 38 hospitals, there was a high use of electrolyte testing (85.4%) and intravenous fluids (84.1%) without substantial changes over time. There were significant reductions in the majority of laboratory, medication, and imaging resources across hospitals over the study period. The most notable reductions were for rotavirus and stool testing. Many hospitals saw a decrease in LOS, with only 3 noting an increased revisit rate. Reductions in cost per case over time were most associated with decreases in imaging, laboratory testing, and LOS., Conclusions: Significant variation in resource use for children hospitalized with AGE coupled with high use of resources discouraged in AGE guidelines highlights potential opportunities to improve resource use that may be addressed in future AGE guidelines and quality improvement initiatives., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Morphine is the opioid most commonly used for neonatal pain management. In intravenous form, it is administered as continuous infusions and intermittent injections, mostly based on empirically established protocols. Inadequate pain control in neonates can cause long-term adverse consequences; however, providing appropriate individualized morphine dosing is particularly challenging due to the interplay of rapid natural physiological changes and multiple life-sustaining procedures in patients who cannot describe their symptoms. At most institutions, morphine dosing in neonates is largely carried out as an iterative process using a wide range of starting doses and then titrating to effect based on clinical response and side effects using pain scores and levels of sedation. Our background data show that neonates exhibit large variability in morphine clearance resulting in a wide range of exposures, which are poorly predicted by dose alone. Here, we describe the development and implementation of an electronic health record-integrated, model-informed decision support platform for the precision dosing of morphine in the management of neonatal pain. The platform supports pharmacokinetic model-informed dosing guidance and has functionality to incorporate real-time drug concentration information. The feedback is inserted directly into prescribers' workflows so that they can make data-informed decisions. The expected outcomes are better clinical efficacy and safety with fewer side effects in the neonatal population., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Morphine is commonly used for analgesia in the neonatal intensive care unit (NICU) despite having highly variable pharmacokinetics (PKs) between individual patients. The pharmacogenetic (PG) effect of variants at the loci of organic cation transporter 1 (OCT1) and UDP-glucuronosyltransferase 2B7 (UGT2B7) on age-dependent morphine clearance were evaluated in a cohort of critically ill neonatal patients using an opportunistic sampling design. Our primary results demonstrate the significant influence of OCT1 genotype (P < 0.05) and gestational age (P ≤ 0.005) on morphine PKs. A physiologically based pharmacokinetic (PBPK) model for morphine that accounted for OCT1 ontogeny and PG effect in post-term neonates adequately described the clinically observed variability in morphine PKs. This study serves as a proof of concept for genotype-dependent drug transporter ontogeny in neonates., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Evidence for dosing, efficacy, and safety of most medications used to treat neonates is sparse. Thus, dosing is usually derived by extrapolation from adult and pediatric pharmacologic data with scaling by body weight or body surface area. This may lead to drug dosing that is unsafe or ineffective. However, new strategies are being developed and studied to dose medications in critically ill neonates. Mass spectroscopy technology capable of quickly analyzing drug levels is readily available. Software that integrates population pharmacokinetics and pharmacodynamics with data from sparse samples from neonates allows for timely adjustments of dosing to achieve the desired effect while minimizing adverse outcomes. Some genetic polymorphisms that affect drug response in neonates have also been reported. This review highlights aspects of drug response and how it is impacted by prematurity, assesses pharmacogenomic studies in neonates, and offers suggestions for innovative pharmacokinetic/pharmacodynamic model-based approaches that combine population- or physiology-based pharmacology data, Bayesian analysis, and electronic decision support tools for precision dosing in neonates while illustrating examples where this approach can be used to optimize medical therapy in neonates. Barriers to implementing precision dosing in neonates and how to overcome them are also discussed., (© 2018, The American College of Clinical Pharmacology.)

Background: Little is known about the clinical significance of coronary artery dilation (CAD) and left ventricular hypertrophy (LVH) in patients with sickle cell disease (SCD)., Procedure: In a retrospective cohort, we studied the prevalence of CAD and LVH in 101 children with SCD in comparison to 93 healthy African-American patients without SCD. Hospital days, number of admissions, and intensive care unit admission after the echocardiogram were assessed as measures of morbidity., Results: Multivariable analysis of echocardiographic measures of LVH and CAD did not predict subsequent intensive care unit admission, hospital days/year or number of hospital admissions/year during a median follow-up time of 6.1 years. LVH as measured by left ventricular mass index was present in 46% of children with SCD and was inversely related to age (P = 0.0004). Height-indexed dimensions in children with SCD demonstrated that the prevalence of dilation was 49% for the left main coronary artery (LMCA), 29% for the left anterior descending (LAD), and 6% for the right coronary artery (RCA). LMCA dilation was related to relative wall thickness (P = 0.006), inversely to age (P < 0.0006) and weakly to disease severity as determined by hemoglobin (P = 0.03). CAD and LVH were not related to a clinical history of vaso-occlusive pain episode, acute chest syndrome, or cerebrovascular accident., Conclusion: LVH and CAD are common findings in children with SCD; however, they are not associated with need for subsequent hospital or intensive care unit admission., (© 2014 Wiley Periodicals, Inc.)