Implementing an exclusive human milk diet for preterm infants: real-world experience in diverse NICUs.

BACKGROUND: Human milk-based human milk fortifier (HMB-HMF) makes it possible to provide an exclusive human milk diet (EHMD) to very low birth weight (VLBW) infants in neonatal intensive care units (NICUs). Before the introduction of HMB-HMF in 2006, NICUs relied on bovine milk-based human milk fortifiers (BMB-HMFs) when mother's own milk (MOM) or pasteurized donor human milk (PDHM) could not provide adequate nutrition. Despite evidence supporting the clinical benefits of an EHMD (such as reducing the frequency of morbidities), barriers prevent its widespread adoption, including limited health economics and outcomes data, cost concerns, and lack of standardized feeding guidelines. METHODS: Nine experts from seven institutions gathered for a virtual roundtable discussion in October 2020 to discuss the benefits and challenges to implementing an EHMD program in the NICU environment. Each center provided a review of the process of starting their program and also presented data on various neonatal and financial metrics associated with the program. Data gathered were either from their own Vermont Oxford Network outcomes or an institutional clinical database. As each center utilizes their EHMD program in slightly different populations and over different time periods, data presented was center-specific. After all presentations, the experts discussed issues within the field of neonatology that need to be addressed with regards to the utilization of an EHMD in the NICU population. RESULTS: Implementation of an EHMD program faces many barriers, no matter the NICU size, patient population or geographic location. Successful implementation requires a team approach (including finance and IT support) with a NICU champion. Having pre-specified target populations as well as data tracking is also helpful. Real-world experiences of NICUs with established EHMD programs show reductions in comorbidities, regardless of the institution's size or level of care. EHMD programs also proved to be cost effective. For the NICUs that had necrotizing enterocolitis (NEC) data available, EHMD programs resulted in either a decrease or change in total (medical + surgical) NEC rate and reductions in surgical NEC. Institutions that provided cost and complications data all reported a substantial cost avoidance after EHMD implementation, ranging between $515,113 and $3,369,515 annually per institution. CONCLUSIONS: The data provided support the initiation of EHMD programs in NICUs for very preterm infants, but there are still methodologic issues to be addressed so that guidelines can be created and all NICUs, regardless of size, can provide standardized care that benefits VLBW infants.

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.

Effect of inhaled nitric oxide on oxygen therapy, mechanical ventilation, and hypoxic respiratory failure.

To assess the role of inhaled nitric oxide (iNO) in reducing the need for oxygen therapy, decreasing time on mechanical ventilatory support, and attenuating probability of hypoxic respiratory failure severity progression, we reviewed published reports of phase III iNO studies in neonates with hypoxic respiratory failure and pulmonary hypertension, as well as a novel post-hoc analysis of data from the Clinical Inhaled Nitric Oxide Research Group Initiative (CINRGI) study population not been previously reported. The post-hoc analysis of the CINRGI study showed that iNO shortens the duration of oxygen therapy versus placebo (17 vs. 34 days; P<0.05); the CINRGI retrospective analysis by Konduri et al. showed earlier administration of iNO (oxygenation index [OI] 15-25) yielded a 48% relative reduction vs. placebo in number of patients who progressed to OI≥30 (16.7% vs. 32.2%; P=0.002). Golombek and Young's pooled analysis of phase III studies showed a rapid improvement in oxygenation after initiation of iNO therapy versus controls in each study, and a significant reduction in median ventilation duration (11 vs. 14 days; P=0.003). A study by Gonzalez et al. revealed that earlier iNO administration in infants with mild to moderate hypoxic respiratory failure (OI 10-30) resulted in a decreased duration of oxygen therapy versus placebo (11.5 vs. 18.0 days; P<0.03) and reduced the probability of developing severe hypoxic respiratory failure.

Adult Outcomes After Newborn Respiratory Failure Treated With Extracorporeal Membrane Oxygenation.

OBJECTIVE: To describe the outcome of young adults treated for hypoxemic respiratory failure with extracorporeal membrane oxygenation as neonates. DESIGN: The study was designed as a multisite, cross sectional survey. SETTING: The survey was completed electronically or on paper by subjects and stored in a secure data base. SUBJECTS: Subjects were surviving neonatal extracorporeal membrane oxygenation patients from eight institutions who were18 years old or older. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A questionnaire modified from the 2011 Behavioral Risk Factor Surveillance System and the 2011 National Health Interview Survey with additional unique questions was completed by subjects. Results were compared to age-matched national Behavioral Risk Factor Surveillance System and National Health Interview Survey data. One hundred and forty-six subjects participated (8.9% of eligible candidates). The age at questionnaire submission was 23.7 ± 2.89 years. Subjects differed statistically from national cohorts by being more satisfied with life (93% vs 84.2%); more educated (some college or degree; 80.1% vs 57.7%); more insured for healthcare (89.7% vs 72.3%); less frequent users of healthcare in the last 12 months (47.3% vs 58.2%); more limited because of physical, mental, and developmental problems (19.9% vs 10.9%); and having more medical complications. Furthermore, learning problems occurred in 29.5% of the study cohort. The congenital diaphragmatic hernia group was generally less healthy and less well educated, but equally satisfied with life. Perinatal variables contributed little to outcome prediction. CONCLUSIONS: Most young adult survivors in this study cohort treated with extracorporeal membrane oxygenation as neonates are satisfied with their lives, working and/or in college, in good health and having families. These successes are occurring despite obstacles involving health issues such as asthma, attention deficit disorder, learning difficulties, and vision and hearing problems; this is especially evident in the congenital diaphragmatic hernia cohort. Selection bias inherent in such a long-term study may limit generalizability, and it is imperative to note that our sample may not be representative of the whole.

Congenital myotonic dystrophy: ventriculomegaly and shunt considerations for the pediatric neurosurgeon.

PURPOSE: Ventriculomegaly in infants with congenital myotonic dystrophy (CDM) is common, and the neurosurgical determination of shunting is complex. The natural history of CDM-associated ventriculomegaly from prenatal to natal to postnatal stages is poorly known. The relationship between macrocephaly and ventriculomegaly, incidence of shunt necessity, and early mortality outcomes lack pooled data analysis. This study aims to review clinical features and pathophysiology of CDM, with emphasis on ventriculomegaly progression, ventriculomegaly association with macrocephaly, and incidence of shunting. METHODS: This is a literature review with pooled data analysis and case report. RESULTS: One hundred four CDM patients were reviewed in 13 articles that mentioned CDM with ventriculomegaly and/or head circumference. Data was very limited: only 7 patients had data on the presence or absence of prenatal ventriculomegaly, 97 on ventriculomegaly at birth, and 32 on whether or not the ventricles enlarged post-natally. Three patients of 7 (43 %) had pre-natally diagnosed ventriculomegaly, 43 of 97 (44 %) had ventriculomegaly at birth, and only 5 of 32 (16 %) had progressive enlargement of ventricles post-natally. Only 5 of 104 patients had a documented shunt placement: 1 for obstructive, 1 for a post-hemorrhagic communicating, 2 for a communicating hydrocephalus without hemorrhage, and 1 with unknown indication. Of 13 macrocephalic patients with data about ventricular size, 12 had ventriculomegaly. CONCLUSIONS: Ventriculomegaly occurs regularly with CDM but most often does not require CSF diversion. Decisions regarding neurosurgical intervention will necessarily be based on limited information, but shunting should only occur once dynamic data confirms hydrocephalus.

Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial.

IMPORTANCE: Invasive candidiasis in premature infants causes death and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole are unknown. OBJECTIVE: To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants. DESIGN, SETTING, AND PATIENTS: This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013. INTERVENTIONS: Fluconazole (6 mg/kg of body weight) or placebo. MAIN OUTCOMES AND MEASURES: The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes-defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18 to 22 months corrected age. RESULTS: Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%-22%) vs 21% in the placebo group (95% CI, 15%-28%; odds ratio, 0.73 [95% CI, 0.43-1.23]; P = .24; treatment difference, -5% [95% CI, -13% to 3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%-6%]) vs the placebo group (9% [95% CI, 5%-14%]; P = .02; treatment difference, -6% [95% CI, -11% to -1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole, 31% [95% CI, 21%-41%] vs placebo, 27% [95% CI, 18%-37%]; P = .60; treatment difference, 4% [95% CI, -10% to 17%]). CONCLUSIONS AND RELEVANCE: Among infants with a birth weight of less than 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely low-birth-weight infants. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00734539.

Association of RSV-related hospitalization and non-compliance with palivizumab among commercially insured infants: a retrospective claims analysis.

BACKGROUND: Palivizumab has been shown to decrease the incidence of hospitalization due to respiratory syncytial virus (RSV) in infants at risk of severe RSV disease. We examined the association between compliance with palivizumab dosing throughout the RSV season and risk of RSV-related hospitalization in clinical practice. METHODS: Subjects who were born and discharged from the hospital before the RSV season and received ≥1 palivizumab dose during their first RSV season were identified from a large US commercial health insurance database between 01/01/03 and 12/31/09. Subjects were deemed compliant if they received ≥5 palivizumab doses without gaps (>35 days) and their first dose was received by November 30. RSV-related hospitalizations were identified using ICD-9-CM diagnosis codes and examined over 2 observation periods: post-index dose and RSV season. A Cox proportional hazard model was used to evaluate the association between non-compliance and RSV-related hospitalization. RESULTS: Of the 5,003 subjects who received palivizumab, 62% were deemed non-compliant. Non-compliant subjects had significantly higher unadjusted rates of RSV-related hospitalizations compared to compliant subjects during both observation periods (post-index: 6.1 vs. 2.8 per 100 infant seasons, p < 0.001; RSV season: 5.9% vs. 2.3%; p < 0.001). In multivariate analyses, non-compliance was significantly associated with higher risk of RSV-related hospitalization (HR = 2.01; p < 0.001). Of the 225 RSV-related hospitalizations observed during the RSV season, 61 (27%) occurred before the first dose of palivizumab. CONCLUSIONS: Subjects who did not receive monthly dosing of palivizumab throughout the RSV season had significantly higher rates of RSV-related hospitalizations. The RSV-related hospitalizations prior to the first dose of palivizumab suggest some dosing was started too late.

SHEA Neonatal Intensive Care Unit (NICU) White Paper Series: Practical approaches for the prevention of central-line-associated bloodstream infections.

This document is part of the "SHEA Neonatal Intensive Care Unit (NICU) White Paper Series." It is intended to provide practical, expert opinion, and/or evidence-based answers to frequently asked questions about CLABSI detection and prevention in the NICU. This document serves as a companion to the CDC Healthcare Infection Control Practices Advisory Committee (HICPAC) Guideline for Prevention of Infections in Neonatal Intensive Care Unit Patients. Central line-associated bloodstream infections (CLABSIs) are among the most frequent invasive infections among infants in the NICU and contribute to substantial morbidity and mortality. Infants who survive CLABSIs have prolonged hospitalization resulting in increased healthcare costs and suffer greater comorbidities including worse neurodevelopmental and growth outcomes. A bundled approach to central line care practices in the NICU has reduced CLABSI rates, but challenges remain. This document was authored by pediatric infectious diseases specialists, neonatologists, advanced practice nurse practitioners, infection preventionists, members of the HICPAC guideline-writing panel, and members of the SHEA Pediatric Leadership Council. For the selected topic areas, the authors provide practical approaches in question-and-answer format, with answers based on consensus expert opinion within the context of the literature search conducted for the companion HICPAC document and supplemented by other published information retrieved by the authors. Two documents in the series precede this one: "Practical approaches to Clostridioides difficile prevention" published in August 2018 and "Practical approaches to Staphylococcus aureus prevention," published in September 2020.

Use of Point-of-Care Ultrasonography in the NICU for Diagnostic and Procedural Purposes.

Point-of-care ultrasonography (POCUS) refers to the use of portable imaging performed by the provider clinician at the bedside for diagnostic, therapeutic, and procedural purposes. POCUS could be considered an extension of the physical examination but not a substitute for diagnostic imaging. Use of POCUS in emergency situations can be lifesaving in the NICU if performed in a timely fashion for cardiac tamponade, pleural effusions, pneumothorax, etc, with potential for enhancing quality of care and improving outcomes. In the past 2 decades, POCUS has gained significant acceptance in clinical medicine in many parts of the world and in many subspecialties. Formal accredited training and certification programs are available for neonatology trainees as well as for many other subspecialties in Canada, Australia, and New Zealand. Although no formal training program or certification is available to neonatologists in Europe, POCUS is widely available to providers in NICUs. A formal institutional POCUS fellowship is now available in Canada. In the United States, many clinicians have the skills to perform POCUS and have incorporated it in their daily clinical practice. However, appropriate equipment remains limited, and many barriers exist to POCUS program implementation. Recently, the first international evidence-based POCUS guidelines for use in neonatology and pediatric critical care were published. Considering the potential benefits, a recent national survey of neonatologists confirmed that the majority of clinicians were inclined to adopt POCUS in their clinical practice if the barriers could be resolved. This technical report describes many potential POCUS applications in the NICU for diagnostic and procedural purposes.

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.

Pharmacodynamics and safety of pantoprazole in neonates, preterm infants, and infants aged 1 through 11 months with a clinical diagnosis of gastroesophageal reflux disease.

BACKGROUND: Limited data on proton pump inhibitors in infants led regulatory agencies to request sponsors to conduct pediatric studies. AIM: To determine the pharmacodynamic response to pantoprazole in infants with GERD to aid the dose selection for an efficacy study. METHODS: In two open-label studies, neonates and preterm infants (study 1, ~1.2 mg/kg [high dose]) and infants 1 through 11 months (study 2, ~0.6 [low dose] or ~1.2 mg/kg [high dose]) received once-daily pantoprazole. Twenty-four-hour dual-electrode pH-metry parameters were compared between predose and steady state (≥5 days) (two-sided paired t test). Treatment was administered for ≤6 weeks. RESULTS: In studies 1 and 2, 21 and 24 patients, respectively, were enrolled for pharmacodynamic evaluation. The high dose provided similar responses in the two studies and improved these parameters significantly: mean gastric pH and percent time gastric pH > 4 increased (p < 0.05 both studies), normalized area under the curve (AUC) of gastric H(+) activity decreased (p < 0.05 study 2), and normalized AUC of esophageal H(+) activity decreased (p < 0.05 both studies). The AUC of esophageal pH < 4 decreased. Normalized AUC of esophageal H(+) activity decreased (p < 0.05 both studies), indicating refluxate pH increased, although this was not reflected in any change in mean esophageal pH or reflux index. The normalized AUC of esophageal H(+) activity was a more sensitive measure of changes in esophageal pH. CONCLUSIONS: In neonates, preterm infants, and infants aged 1 through 11 months, pantoprazole (high dose) improved pH-metry parameters after ≥5 consecutive daily doses, and was generally well tolerated for ≤6 weeks.

Transition to a Safe Home Sleep Environment for the NICU Patient.

Of the nearly 3.8 million infants born in the United States in 2018, 8.3% had low birth weight (ie, weight <2500 g) and 10% were born preterm (ie, gestational age of <37 weeks). Ten to fifteen percent of infants (approximately 500 000 annually), including low birth weight and preterm infants and others with congenital anomalies, perinatally acquired infections, and other diseases, require admission to a NICU. Every year, approximately 3600 infants in the United States die of sudden unexpected infant death (SUID), including sudden infant death syndrome (SIDS), unknown and undetermined causes, and accidental suffocation and strangulation in an unsafe sleep environment. Preterm and low birth weight infants are 2 to 3 times more likely than healthy term infants to die suddenly and unexpectedly. Thus, it is important that health care professionals prepare families to maintain their infant in a safe home sleep environment as per recommendations of the American Academy of Pediatrics. Medical needs of the NICU infant often require practices such as nonsupine positioning, which should be transitioned as soon as medically possible and well before hospital discharge to sleep practices that are safe and appropriate for the home environment. This clinical report outlines the establishment of appropriate NICU protocols for the timely transition of these infants to a safe home sleep environment. The rationale for these recommendations is discussed in the accompanying technical report "Transition to a Safe Home Sleep Environment for the NICU Patient," included in this issue of Pediatrics.

Transition to a Safe Home Sleep Environment for the NICU Patient.

Of the nearly 3.8 million infants born in the United States in 2018, 8.3% had low birth weight (<2500 g [5.5 lb]) and 10% were born preterm (gestational age of <37 completed weeks). Many of these infants and others with congenital anomalies, perinatally acquired infections, and other disease require admission to a NICU. In the past decade, admission rates to NICUs have been increasing; it is estimated that between 10% and 15% of infants will spend time in a NICU, representing approximately 500 000 neonates annually. Approximately 3600 infants die annually in the United States from sleep-related deaths, including sudden infant death syndrome International Classification of Diseases, 10th Revision (R95), ill-defined deaths (R99), and accidental suffocation and strangulation in bed (W75). Preterm and low birth weight infants are particularly vulnerable, with an incidence of death 2 to 3 times greater than healthy term infants. Thus, it is important for health care professionals to prepare families to maintain their infant in a safe sleep environment, as per the recommendations of the American Academy of Pediatrics. However, infants in the NICU setting commonly require care that is inconsistent with infant sleep safety recommendations. The conflicting needs of the NICU infant with the necessity to provide a safe sleep environment before hospital discharge can create confusion for providers and distress for families. This technical report is intended to assist in the establishment of appropriate NICU protocols to achieve a consistent approach to transitioning NICU infants to a safe sleep environment as soon as medically possible, well before hospital discharge.

Severity and Cost of RSV Hospitalization Among US Preterm Infants Following the 2014 American Academy of Pediatrics Policy Change.

The American Academy of Pediatrics (AAP) Committee on Infectious Diseases (COID) periodically publishes recommendations for respiratory syncytial virus (RSV) immunoprophylaxis (IP) use in pediatric patients considered to be at highest risk for severe RSV infection. In 2014, for the first time, the AAP COID stopped recommending the use of RSV IP for otherwise healthy infants born at 29 weeks' gestational age (wGA) or later, stating that RSV hospitalization (RSVH) rates in this population are similar to those of term infants. Subsequently, epidemiological studies in the US at national and regional levels provided evidence of the impact of the policy change in 29-34 wGA infants. The results of these studies demonstrated a significant decrease in IP use after 2014 that was associated with an increased rate of RSVH in 29-34 wGA infants and an increase in morbidities. RSVH-related morbidities included pediatric intensive care unit (ICU) admissions, an increased need for mechanical ventilation, and an increase in the length of stay. After the change in recommendations, the costs of RSVH also rose among 29-34 wGA infants. The severity of the illness and expenses associated with RSVH were generally higher among 29-34 wGA infants of younger chronologic age compared with older preterm infants. Overall, these studies underscore that 29-34 wGA infants continue to be a high-risk pediatric population that could benefit from the protection provided by RSV IP. On the basis of these data, in 2018, the National Perinatal Association developed guidelines that recommended RSV IP for all ≤ 32 wGA infants and 32-35 wGA infants with additional risk factors. Re-evaluation of the AAP COID policy is warranted in light of these observations.

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.

Single-dose, multiple-dose, and population pharmacokinetics of pantoprazole in neonates and preterm infants with a clinical diagnosis of gastroesophageal reflux disease (GERD).

PURPOSE: The pharmacokinetic profile of pantoprazole granules was assessed in neonates and preterm infants with gastroesophageal reflux disease (GERD) in a multicenter, randomized, open-label trial. METHODS: Patients were randomly assigned to either the pantoprazole 1.25 mg (approx. 0.6 mg/kg) or 2.5 mg (approx. 1.2-mg/kg) group and treated for > or =5 consecutive days. Blood was sampled either at 0, 2, 8, and 18 h postdose or at 0, 1, 4, and 12 h postdose on day 1 and at 3 and 6 h postdose after > or =5 consecutive doses. Cytochrome P450 2C19 (CYP2C19) and CYP3A4 genotypes were determined. Safety was monitored. Population pharmacokinetics (popPK) analyses were conducted using nonlinear mixed-effects modeling. RESULTS: The popPK modeling of the pantoprazole 1.25 mg and 2.5 mg groups obtained mean (+/-standard deviation) estimates for the area under the plasma concentration versus time curve (AUC) of 3.54 (+/-2.82) and 7.27 (+/-5.30) microg h/mL, respectively, and mean estimates for half-life of 3.1 (+/-1.5) and 2.7 (+/-1.1) h, respectively. Pantoprazole did not accumulate following multiple-dose administration. The two patients with the CYP2C19 poor metabolizer genotype had a substantially higher AUC than extensive metabolizers. No safety-related discontinuations occurred. CONCLUSIONS: In preterm infants and neonates, pantoprazole granules were generally well tolerated, mean exposures with pantoprazole 2.5 mg were slightly higher than that in adults who received 40 mg. While the half-life was longer, accumulation did not occur.

A systematic review of compliance with palivizumab administration for RSV immunoprophylaxis.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) in infants and young children, accounting for approximately 75,000-125,000 hospitalizations per year. It is estimated that in 2000, RSV infection accounted for 1.7 million office visits, 402,000 emergency room visits, and 236,000 hospital outpatient visits per year for children younger than 5 years of age. Palivizumab, a humanized monoclonal antibody directed against RSV, is the only immunoprophylaxis therapy approved by the FDA for prevention of serious lower respiratory tract disease caused by RSV in infants (up to 2 years of age) who meet 1 or more of the following criteria for high risk: (a) gestational age up to 35 weeks;(b) diagnosis of chronic lung disease (CLD, formerly bronchopulmonary dysplasia [BPD]); or (c) diagnosis of cyanotic or complex congenital heart disease. The RSV season typically occurs between November and March but may vary by region. During the period of our review, depending on local duration of the RSV season, infants usually required 5 monthly (every 28-30 days) intramuscular injections of palivizumab. Infants born in the middle of the season received their palivizumab doses from the time of birth to the end of the season and, therefore, may have required less than 5 doses.It is unclear if compliance with monthly doses is a problem and whether noncompliance increases the risk of RSV hospitalizations in routine clinical practice. OBJECTIVES: To (a) identify and describe compliance rates and the factors that influence parental compliance with immunoprophylaxis regimens, (b)review intervention programs and describe those that have been associated with increased compliance, and (c) summarize the association of compliance with RSV hospitalization rates. METHODS: An electronic literature search was conducted using journal databases, including Ovid, Current Contents, Embase, Medline In-Process & Other Non-Indexed Citations; Ovid Medline, PubMed, and Web of Science;and an abstract database, Medical Intelligence Solution, for citations through April 2008. Specific search terms used were palivizumab with patient compliance, patient adherence, or patient persistence. RESULTS: Twenty-five articles and abstracts met the inclusion criteria. Available studies were mostly retrospective or observational prospective.Compliance, defined in various ways across the studies, varied between 25% and 100%, and 12 studies identified some of the factors related to noncompliance. Compliance generally was lower among Medicaid patients,African American patients, and other minorities. Ten studies (3 manuscripts and 7 abstracts) investigated the association of administration of prophylaxis through monthly home visits by a health professional with parental compliance with therapy. Most of the home-based programs were associated with higher compliance rates compared with clinic or office programs.Rates as high as 94% and 64% were achieved when Medicaid infants and infants of minority descent, respectively, received their doses through a home health program. When these infants received their doses at a clinic or office, depending on the definition of compliance, rates were 61%-100% for Medicaid infants and 44% for infants of minority descent. Reminder telephone calls to parents or caregivers, comprehensive multidisciplinary programs that included extensive counseling of parents, calendars with sticker reminders, and education in the language native to parents also were associated with increased compliance, although statistical significance was reported in only 1 study. Several studies recommended educating parents on the benefits of RSV prophylaxis, alleviating transportation and language difficulties, recognizing cultural differences and biases, and clarifying misperception of RSV illness severity. Home health programs had lower rates of RSV hospitalizations than office-based programs in 3 analyses conducted in 2 studies. In 4 other abstracts, the rates of RSV hospitalization for home health programs and office-based administration did not significantly differ. In a large, 4-season, prospective outcome study, compliant infants had lower RSV hospitalization rates than those who were not compliant under one definition of compliance (doses within 35-day intervals). RSV hospitalization rates were not significantly different using another definition of compliance (receipt of anticipated doses, expected vs. observed rates).In a large survey of 10,390 infants identified from pharmacy dispensing records, RSV hospitalization rates were 1.4% in the compliant group versus 3.1% in the noncompliant group (OR = 2.2, 95% CI = 1.4-3.5, P < 0.001).Adjustment for confounding was not reported in these studies. CONCLUSION: Medicaid and minority infants were less likely to receive scheduled palivizumab doses. Home-based programs for the administration of palivizumab have been investigated more than other interventions and are associated with improved compliance compared with office-based administration. Compliance with dosing, in general, was associated with lower RSV hospitalization rates. However, these strategies should be further investigated using well-designed studies.

Inhaled nitric oxide in preterm infants undergoing mechanical ventilation.

BACKGROUND: Bronchopulmonary dysplasia in premature infants is associated with prolonged hospitalization, as well as abnormal pulmonary and neurodevelopmental outcome. In animal models, inhaled nitric oxide improves both gas exchange and lung structural development, but the use of this therapy in infants at risk for bronchopulmonary dysplasia is controversial. METHODS: We conducted a randomized, stratified, double-blind, placebo-controlled trial of inhaled nitric oxide at 21 centers involving infants with a birth weight of 1250 g or less who required ventilatory support between 7 and 21 days of age. Treated infants received decreasing concentrations of nitric oxide, beginning at 20 ppm, for a minimum of 24 days. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age. RESULTS: Among 294 infants receiving nitric oxide and 288 receiving placebo birth weight (766 g and 759 g, respectively), gestational age (26 weeks in both groups), and other characteristics were similar. The rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was 43.9 percent in the group receiving nitric oxide and 36.8 percent in the placebo group (P=0.042). The infants who received inhaled nitric oxide were discharged sooner (P=0.04) and received supplemental oxygen therapy for a shorter time (P=0.006). There were no short-term safety concerns. CONCLUSIONS: Inhaled nitric oxide therapy improves the pulmonary outcome for premature infants who are at risk for bronchopulmonary dysplasia when it is started between 7 and 21 days of age and has no apparent short-term adverse effects. (ClinicalTrials.gov number, NCT00000548 [ClinicalTrials.gov] .).

Updates on an At-Risk Population: Late-Preterm and Early-Term Infants.

The American Academy of Pediatrics published a clinical report on late-preterm (LPT) infants in 2007 that was largely based on a summary of a 2005 workshop convened by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, at which a change in terminology from "near term" to "late preterm" was proposed. This paradigm-shifting recommendation had a remarkable impact: federal agencies (the Centers for Disease Control and Prevention), professional societies (the American Academy of Pediatrics and American College of Obstetricians and Gynecologists), and organizations (March of Dimes) initiated nationwide monitoring and educational plans that had a significant effect on decreasing the rates of iatrogenic LPT deliveries. However, there is now an evolving concern. After nearly a decade of steady decreases in the LPT birth rate that largely contributed to the decline in total US preterm birth rates, the birth rate in LPT infants has been inching upward since 2015. In addition, evidence revealed by strong population health research demonstrates that being born as an early-term infant poses a significant risk to an infant's survival, growth, and development. In this report, we summarize the initial progress and discuss the potential reasons for the current trends in LPT and early-term birth rates and propose research recommendations.