Reliable and developmentally appropriate study end points are needed to achieve drug development for treatment of pediatric pulmonary arterial hypertension.

OBJECTIVE: To identify suitable end points and surrogates for pediatric pulmonary arterial hypertension (PAH) as the lack of developmentally appropriate end point and clinical trials contribute to the unmet medical need. STUDY DESIGN: Reviewed the efficacy end points and surrogates for all trials (1995 to 2013) that were submitted to the Food and Drug Administration (FDA) to support the approval of PAH therapy and conducted literature search. RESULTS: An increase in the 6 min walking distance (6MWD) was used as a primary end point in 8/9 adult PAH trials. This end point is not suitable for infants and young children because of performance limitations and lack of control data. One adult PAH trial used time to the first morbidity or mortality event as a primary end point, which could potentially be used in pediatric PAH trials. In the sildenafil pediatric PAH trial, the change in pulmonary vascular resistance index or mean pulmonary artery pressure was used as a surrogate for the 6MWD to assess exercise capacity. However, two deaths and three severe adverse events during the catheterizations made this an unacceptably high-risk surrogate. The INOmax persistent pulmonary hypertension of the newborn trial used a reduction in initiation of extracorporeal membrane oxygenation treatment as a primary end point, which is not feasible for other pediatric PAH trials. A Literature review revealed none of the existing noninvasive markers are fully validated as surrogates to assess PAH efficacy and long-term safety. CONCLUSIONS: For pediatric PAH trials, clinical end points are acceptable, and novel validated surrogates would be helpful. FDA seeks collaboration with academia, industry and parents to develop other suitable and possibly more efficient efficacy end points to facilitate pediatric PAH drug development.

Inhaled nitric oxide use in preterm infants in California neonatal intensive care units.

OBJECTIVE: To describe inhaled nitric oxide (iNO) exposure in preterm infants and variation in neonatal intensive care unit (NICU) use. STUDY DESIGN: This was a retrospective cohort study of infants, 22 to 33+6/7 weeks of gestational age (GA), during 2005 to 2013. Analyses were stratified by GA and included population characteristics, iNO use over time and hospital variation. RESULTS: Of the 65 824 infants, 1718 (2.61%) received iNO. Infants, 22 to 24+6/7 weeks of GA, had the highest incidence of iNO exposure (6.54%). Community NICUs (n=77, median hospital use rate 0.7%) used less iNO than regional NICUs (n=23, median hospital use rate 5.8%). In 22 to 24+6/7 weeks of GA infants, the median rate in regional centers was 10.6% (hospital interquartile range 3.8% to 22.6%). CONCLUSION: iNO exposure varied with GA and hospital level, with the most use in extremely premature infants and regional centers. Variation reflects a lack of consensus regarding the appropriate use of iNO for preterm infants.

Infant formula and neurocognitive outcomes: impact of study end-point selection.

OBJECTIVES: Assessing validity and reliability of end points used in docosahexanoic and arachidonic acids (DHA and ARA) infant formula supplementation trials as an example for addressing the impact of end-point selection and critical need for well-defined, reliable and validated clinical outcome assessments for neurocognitive assessment in neonates and infants. STUDY DESIGN: We searched eight electronic databases and reviewed all randomized, controlled human trials using DHA/ARA supplements with neurodevelopment clinical outcomes. We systematically evaluated the validity and reliability of end-point measures based on the criteria for studying nutritional additives recommended by the Institute of Medicine, criteria described in the Food and Drug Administration guidance for clinical outcome assessment, development and literature review. RESULTS: We identified 29 articles that met the selection criteria. The end points that were used for neurodevelopment measures in 23 out of 29 original short-term studies included the Bayley Scale of Infant Development (BSID)-I and -II (n=12), Brunet-Lezine test (n=2), videotape infant's movements (n=1), record time to milestones including sitting, crawling, standing and walking (n=1), problem-solving test (n=2), brainstem auditory-evoked potential (n=1), Touwen examination (n=1), Fagan test of infant intelligence (n=2) and visual habituation protocol (n=1). None of these end points have a long-term predictive property for neurocognitive assessment. Compared with standard infant formula, the beneficial effects of DHA/ARA supplementation on neurodevelopment were reported in 2 out of 12 studies using BSID vs 8 out of 11 studies using other end-point measures. In addition, 6 out of 29 long-term follow-up studies used the end points including Stanford-Binet IQ test (n=1), Wechsler Preschool and Primary Scale of Intelligence (n=4) and Bracken Basic Concept Scale (n=1), which are generally scales of intellectual ability and typically do not change substantively in the short term. None of these long-term follow-up studies demonstrated beneficial effects of DHA/ARA supplementation on neurodevelopment. CONCLUSION: The choice of end-point measures affects the outcomes of DHA/ARA-supplemented infant formula trials. Available data are currently inadequate to conclude that DHA/ARA supplementation has a clinically meaningful beneficial effect upon neurological development. Although BSID is validated to assess early developmental delays, it is not designed to predict long-term neurocognitive outcome. A well-defined, valid and reliable clinical outcome assessment that measures neurocognitive function in neonates and infants is essential to provide the scientific evidence required for future clinical trials.

Can magnetic resonance spectroscopy predict neurodevelopmental outcome in very low birth weight preterm infants?

OBJECTIVE: To determine if metabolite ratios at near-term age predict outcome in very low birth weight preterm infants at 18 to 24 months adjusted age. STUDY DESIGN: Thirty-six infants (birth weight

Survey of neonatology training programs: 2002 to 2003.

The Committee on Research in Neonatology from the Section on Perinatal Pediatrics, American Academy of Pediatrics presents an overview of the update of the Neonatal-Perinatal Training Program Survey obtained in 2002 to 2003. Our goal was to update the last survey in 1996 and to begin to assess research resources and the potential for training life-career physician scientists (basic and clinical investigators).

Fewer spontaneous arousals during prone sleep in preterm infants at 1 and 3 months corrected age.

OBJECTIVE: This study was performed to determine if there were fewer spontaneous arousals in prone sleep than in supine sleep. STUDY DESIGN: Home polysomnography/video recordings were done during daytime naps in 14 preterm infants: four at corrected age of 1 month, nine at both 1 and 3 months, and one only at 3 month. A body movement lasting 3 to 60 s during sleep was used as an indicator of spontaneous arousals. RESULTS: Most arousals had a heart rate increase and change in respiration pattern. The mean duration of the intervals between successive arousals in active and quiet sleep was significantly longer in prone at 1 and 3 months of age. The duration of arousals was significantly shorter at 3 months corrected age compared with one month corrected age during active sleep. The duration of arousals was shorter during quiet sleep at one month compared with active sleep. CONCLUSION: There were fewer spontaneous arousals that is, longer interval between successive arousals in prone, which may, in part, explain the increase in risk of Sudden Infant Death Syndrome.

Diffusion tensor brain imaging findings at term-equivalent age may predict neurologic abnormalities in low birth weight preterm infants.

BACKGROUND AND PURPOSE: Low birth weight preterm infants are at high risk of brain injury, particularly injury to the white matter. Diffusion tensor imaging is thought to be more sensitive than conventional MR imaging for detecting subtle white matter abnormalities. The objective of this study was to examine whether diffusion tensor imaging could detect abnormalities that may be associated with later neurologic abnormalities in infants with otherwise normal or minimally abnormal conventional MR imaging findings. METHODS: We prospectively studied 137 low birth weight (<1800 g) preterm infants. Neonatal conventional MR imaging and diffusion tensor imaging were performed near term-equivalent age before discharge, and neurologic development of the infants was later followed up at 18 to 24 months of age. RESULTS: Among the preterm infants who were fully studied, 63 underwent normal conventional MR imaging. Three of these infants developed cerebral palsy, and 10 others showed abnormal neurologic outcome. Diffusion tensor imaging results for these infants showed a significant reduction of fractional anisotropy in the posterior limb of the internal capsule in neurologically abnormal infants (including those with cerebral palsy) compared with control preterm infants with normal neurologic outcomes. CONCLUSION: These results suggest that neonatal diffusion tensor imaging may allow earlier detection of specific anatomic findings of microstructural abnormalities in infants at risk for neurologic abnormalities and disability. The combination of conventional MR imaging and diffusion tensor imaging may increase the predictive value of neonatal MR imaging for later neurologic outcome abnormalities and may become the basis for future interventional clinical studies to improve outcomes.

Cisapride associated with QTc prolongation in very low birth weight preterm infants.

OBJECTIVE: No systematic study has been performed to evaluate the effect of cisapride on the QT interval in premature infants. Cisapride, which has recently been withdrawn by the Food and Drug Administration and is no longer an approved therapy, was commonly used for preterm infant care to improve the advance of enteral feedings and to reduce reflux and associated apnea. Our aim was to evaluate the effect of recommended doses of cisapride on the QT interval in this population. STUDY DESIGN: Prospective blinded evaluation of electrocardiogram for QT, JT, QTc, and JTc measurements in 25 preterm infants before and after cisapride administration. RESULTS: Twelve of 25 infants (48%) developed repolarization abnormalities with cisapride administration: 32% of the infants (8/25) studied had QTc prolongation (>/=0.450 seconds), whereas 10/25 had JTc prolongation (>/=0.360 seconds). Preterm infants <32 weeks significantly prolonged their QTc interval from 0.41 +/- 0.02 to 0.44 +/- 0.02. The QTc and/or JTc was prolonged in 54% of infants receiving 0.1 mg/kg/dose and 42% receiving 0.2 mg/kg/dose. CONCLUSIONS: The QTc and JTc interval significantly prolonged in preterm infants <32 weeks on the recommended dose of cisapride therapy. A QTc >/=0.450 seconds developed in 32% of infants treated with cisapride, whereas the JTc prolonged in 40%. A significant percentage of infants (54%) developed prolonged QTc intervals at a dose of 0.1 mg/kg/dose. From these data we conclude that there is a higher risk of prolongation of the QTc interval and risk of arrhythmias with greater prematurity.

Cisapride decreases gastroesophageal reflux in preterm infants.

OBJECTIVE: Gastrointestinal prokinetic agents, such as cisapride, are commonly used in pediatric practice to improve gastric emptying, to decrease emesis, to improve lower esophageal sphincter tone, and to improve irritability and feeding aversion associated with gastroesophageal reflux (GER). Although cisapride seems to be effective in infants from 2 months to 14 years old, data for younger and preterm infants are not available. Whether reflux is a significant cause of reflex apnea or feeding intolerance in the preterm infant is controversial. The objective of this 1-year prospective study, started in 1998, was to determine the efficacy of cisapride for treatment of reflux and reflux-associated apnea (RAAP) in preterm infants. Before this study, the diagnosis of reflux was often made clinically and the effect of therapy on reflux or the decision to increase the dose of cisapride was made empirically. The clinical bias was that persistent apnea, not responding to caffeine, was caused by GER. We reasoned that a systematic approach to the diagnosis and treatment of reflux would improve the care of preterm infants and reduce the risk of toxicity, especially if an increased dose of cisapride showed no improvement in reflux or apnea. STUDY DESIGN: Twenty-four preterm infants (24-36 weeks' gestational age) had clinical apnea/pH studies when they were referred by the attending neonatologist for suspected GER. These infants were born at 28.8 +/- 3.1 weeks with birth weight of 1169 +/- 387 g (range: 631-2263 g). Each infant was studied before and 8 days after starting cisapride treatment. Cisapride dose was 0.09 to 0.25 mg/kg every 6 hours enterally. Treatment decisions regarding dose of cisapride were the responsibility of the attending neonatologist. The pH was recorded continuously for 24 hours at 0.25 Hz and was analyzed using EsopHogram software. A single sensor pH catheter was inserted to ~2 cm above the esophageal gastric junction. GER was defined as a drop in esophageal pH below 4.0 for a least 5 seconds, or pathologic GER was defined as a reflux index (RI) >2 standard deviation (SD) from the mean based on published norms for term infants. The following parameters were calculated from the pH recording: number of reflux events per 24 hours, duration of the longest episode, number of episodes >5 minutes per 24 hours, and RI, ie, percentage of time with pH <4.0. Each study had a combined time-lapse video recording and multichannel digital recording. Recorded parameters were: continuous pulse oximetry, electrocardiogram, respiratory effort (piezo sensor), and airflow (temperature sensor at nostrils and mouth). The recording was scored for central apneas of 10 to 14 seconds and >/=15 seconds (prolonged) and >/=10 seconds for obstructive and mixed apneas. RAAP was scored when an apnea (irrespective of the type) occurred within 1 minute of a GER event. Baseline, after cisapride, and follow-up electrocardiograms were performed because of concern about prolonged QTc and cardiac arrhythmias. The infants were 35.6 +/- 4.5 weeks postconceptional age when first studied. Twelve infants (mean birth weight: 1821 +/- 749 g; gestational age: 32 +/- 2 weeks; postconceptional age: 35.6 +/- 2.6 weeks) were identified retrospectively as controls because their baseline GER parameters were within the normal range using Vandenplas' criteria. RESULTS: Overall, cisapride treatment significantly improved the RI from 16.6 +/- 15.2 to 9.1 +/- 8.4 SD. The number of reflux episodes >/=5 minutes was reduced from 7.1 +/- 5.8 to 4.3 +/- 4.4 SD. No significant effect was seen on the total number of refluxes (/24 hours). Eight infants (33%) had no decrease in the RI after a week of treatment. Three of these infants improved after cisapride dose was increased from 0.09 to 0.25 mg/kg/dose every 6 hours. Although 0.09 mg/kg/day is the minimum effective dose, 67% of our infants did respond to this low dose. Cisapride was discontinued in 3 infants because of prolonged QTc >/=0.450 seconds (0.473 in 1 and 0.470 in 2). More data about the effect of cisapride on QTc interval are reported in Pediatrics in a separate article. Only 1 infant showed no improvement with increased dose. Caffeine treatment had no effect on the baseline or follow-up GER values. Although apnea indexes for central and obstructive apnea were similar before and after cisapride, mixed apnea was less during treatment. There was a significant decrease (0.32 +/- 0.40 to 0.12 +/- 0.17/hour) in RAAP when the one infant who had increased reflux on increased dose of cisapride was excluded as an outlier. The statistical difference, before and after cisapride, for the group is significant with the outlier omitted. The clinical significance is unclear because ~50% of the infants had minimal changes in their apnea indexes. Furthermore, ~40% of infants did not have RAAP. (ABSTRACT TRUNCATED)

Influence of light in the NICU on the development of circadian rhythms in preterm infants.

The fetal biological clock is an endogenous clock capable of generating circadian rhythms and responding to maternal entraining signals. By at least the third trimester of pregnancy fetal diurnal rhythms are entrainable by maternal day-night rhythms. Maternal illness during pregnancy and premature birth are obvious clinical factors that may adversely affect circadian rhythm development. Premature birth of the fetus has a most dramatic impact on maternal fetal interactions. The effect on biorhythms appears to be temporary and is greatest on the most immature infants. The results to date support the importance of fetal circadian rhythms and the relative lack of these rhythms in the preterm infant. It is well known that growth and development in the prematurely born infant are influenced by a multitude of factors; clearly, the neonatal intensive care unit is not a surrogate for the maternal placental unit. This article reviews what is known about circadian development in the human infant with an emphasis on the unique circumstances of the preterm infant. The research on the short- and long-term effects of environmental interventions on circadian, sleep, and neurologic development is discussed. Although an earlier onset of circadian development did not result with cycled lighting in the neonatal nursery, there may still be important biological effects that have not been studied. There are sufficient data to state that there is no reason for continuing a chaotic, noncircadian environmental approach for the care of the prematurely born infant.

Predictive value of neonatal neurological tests for developmental outcome of preterm infants.

BACKGROUND: There is a need to identify, as early as possible, infants who are at risk for long-term neurological morbidity. METHODS: To predict neurodevelopment outcome of preterm infants <30 weeks' gestation in a population of 100 infants, we used several neonatal and neurobehavioral tests, including cranial ultrasonography, the Prechtl neurological test, quality of spontaneous general movements, and quality of sleep-wake organization. RESULTS: The Prechtl test at corrected term age and findings on cranial sonograms both had high specificity, but the Prechtl test had better overall positive predictive power for normal neurological and developmental outcomes at 2 years' corrected age. Developmental changes in sleep and the amount of indeterminate sleep did not correlate with outcome. Scoring general movement quality did not predict outcome and did not augment the positive predictive power of the Prechtl test. CONCLUSIONS: The Prechtl test at corrected term age (independent of the other tests) is the best positive predictor of normal neurological outcome and Bayley test results at 2 years' corrected age.

Effects of prone and supine position on sleep characteristics in preterm infants.

The purpose of this study was to address the influence of sleep position on sleep characteristics in preterm infants. We studied 16 infants at a mean post-conceptional age of 36.5 weeks. Infants were successfully recorded with videopolysomnograph in the supine and prone position. Between the two positions, there were no significant differences in percentage of active sleep and quiet sleep (QS), the occurrence of arousal, and the incidence of apnea. The first QS after the feeding was longer in the prone position. The sleep position could affect sleep characteristics but not respiratory characteristics in preterm infants.

More awakenings and heart rate variability during supine sleep in preterm infants.

OBJECTIVE: The Task Force of The American Academy of Pediatrics (1996) recommends the nonprone sleeping position for asymptomatic preterm infants to prevent sudden infant death syndrome. The mechanism by which the nonprone sleeping position reduces the rate of sudden infant death syndrome is unclear for full-term infants and the precise effect of sleeping position on sleep and cardiorespiratory characteristics has never been addressed in preterm infants. The purpose of the present study was to clarify the effect of sleeping position on sleep and cardiorespiratory characteristics in preterm infants at an age when they are ready for discharge. STUDY DESIGN: Sixteen asymptomatic preterm infants were studied in both supine and prone sleeping positions at 36.5 +/- 0.6 weeks' postconceptional age using videosomnography. Sleep, respiratory, and heart rate characteristics were compared between the two positions using each infant as his/her own control. RESULTS: More awakenings (ie, arousals >/=60 seconds) were seen during all sleep states in the supine sleeping position but overall the total sleep and percent sleep state were not affected by sleeping position. After each feeding, the first quiet sleep was significantly shorter, with more heart rate variability and awakenings in the supine position. There were no significant differences in the occurrence of arousals (<60 seconds) or the incidence or severity of apnea and periodic breathing. No clinically significant apnea (>/=15 seconds), bradycardia, or oxygen desaturations were seen. CONCLUSION: In 36-week-postconceptional age preterm infants, the supine sleeping position had less quiet sleep and was associated with greater heart rate variability during the first sleep cycle after the feeding. More awakenings were seen during all sleep states in the supine position. These data support the American Academy of Pediatrics recommendation for "Back to Sleep" for asymptomatic preterm infants because more awakenings and lower threshold for arousal may provide some benefit for the infant responding to a life-threatening event. However, further studies are needed to address positional effect on the physiologic measures in preterm infants at older ages (later stages of development). Precisely what constitutes the most healthy or advantageous sleep for newborn infants remains an important question.

Aerosolized albuterol improves airway reactivity in infants with acute respiratory failure from respiratory syncytial virus.

The objective of this investigation was to measure the bronchodilator effect of aerosolized albuterol on infants with respiratory syncytial virus (RSV)-induced respiratory failure. Infants who required intubation and mechanical ventilator support for RSV disease were eligible for this prospective, nonrandomized study. Pulmonary function tests, including respiratory mechanics by least mean square analysis, small airway function by rapid thoraco-abdominal compression, and functional residual capacity by nitrogen washout were performed before and 20 min after inhalation of 20-40 breaths of undiluted (0.5%) albuterol solution via a small-volume nebulizer. Analysis of maximum expiratory flow at functional residual capacity (V'maxFRC) before and after albuterol administration was performed using a t-test for paired comparisons. A two-tailed P-value of less than 0.05 was considered statistically significant. Twenty-five infants (mean +/-SD postconceptional age = 45 +/- 5 weeks) were enrolled. Thirteen of the 25 infants had a prior history of prematurity and/or cardiorespiratory disease. After aerosolized albuterol, mean V'maxFRC increased significantly from 48 +/- 46 ml/sec to 65 +/- 59 ml/sec (P = 0.03); however, only three patients had an increase into the normal range. Three patients had a substantial (40-50%) decrease in V'maxFRC. These findings suggest that during the acute phase of severe RSV respiratory infection some of this group of very young infants had airway reactivity that improved in response to inhaled albuterol.

Survey of sleeping position after hospital discharge in healthy preterm infants.

OBJECTIVE: To evaluate the prevalence of nonprone (supine or side) versus prone sleeping position in healthy preterm infants. STUDY DESIGN: A questionnaire on sleeping position was mailed to mothers of 167 preterm infants discharged from the intermediate nursery at Packard Children's Hospital at Stanford. The prevalence of nonprone sleeping at 1 month (term corrected age) and 3 months (2 months corrected age) after nursery discharge was analyzed by an unpaired t test. RESULTS: Nonprone position sleeping occurred in 64% initially and dropped to 35% at 2 months corrected age. CONCLUSIONS: Overall, nonprone sleeping was widespread in our healthy preterm infants after hospital discharge but may not persist. A majority of these infants were sleeping prone during a high-risk period for sudden infant death syndrome.

Safety, tolerance and pharmacokinetics of a humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. MEDI-493 Study Group.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants. MEDI-493 (palivizumab) is a humanized monoclonal antibody to the fusion protein of RSV and is active in animal models for prevention of pulmonary RSV replication. OBJECTIVE: To describe the safety, tolerance, immunogenicity and pharmacokinetics of repeat intravenous doses of MEDI-493 in premature infants or infants with bronchopulmonary dysplasia. DESIGN: Phase I/II multicenter, randomized, double blind, placebo-controlled, dose escalation trial. PATIENT POPULATION: Infants born prematurely (< or = 35 weeks of gestation) who were < or = 6 months of age and infants with bronchopulmonary dysplasia who were < or = 24 months of age were eligible for study participation. STUDY AGENTS: Participants received 3, 10 or 15 mg/kg MEDI-493 or 0.9% saline intravenously every 30 days for up to five doses. RESULTS: MEDI-493 was safe and well-tolerated and did not induce a specific anti-MEDI-493 response. The mean half-life of 20 days was comparable with that of other immunoglobulin G preparations. Mean trough serum concentrations 30 days after Infusion 1 were 6.8, 36.1 and 60.6 microg/ml for the 3-, 10- and 15-mg/kg dose groups, respectively. After Infusion 2 the trough concentrations were 11.9, 45.2 and 70.7 microg/ml. After subsequent doses the mean trough values ranged from 14 to 18 microg/ml in those given 3 mg/kg and were > 40 microg/ml for patients who received 10 or 15 mg/kg MEDI-493 (46 to 72 microg/ml and 88 to 96 microg/ml, respectively). CONCLUSIONS: MEDI-493 was safe and well-tolerated in this high risk pediatric population. Mean serum concentrations of MEDI-493 that have been shown to produce a 2-log reduction in pulmonary RSV titer in cotton rats were maintained when 10 or 15 mg/kg MEDI-493 was given every 30 days to pediatric patients at high risk for serious RSV disease. Monthly doses of 15 mg/kg maintained concentrations of > 40 microg/ml for the majority of patients.