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.

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.

Resting oxygen consumption of premature infants covered with a plastic thermal blanket.

Premature infants in single-wall incubators covered with "thermal blankets" made of plastic packing material have large reductions in insensible water loss (IWL) compared with naked infants. We postulated that such reductions inevaporative heat loss would not result in decreases in caloric expenditure if body temperature were maintained by a servocontrolled heat source. Using an open-circuit technique, we measured oxygen consumption (VO2), carbon dioxide production (VCO2), heart rate (HR), respiratory rate (RR), and abdominal skin (Tabd), cheek, thigh, rectal, incubator air, wall, and room air temperatures in ten infants less than 37 weeks gestational age and from 2 to 24 days of age both naked and covered with a plastic thermal blanket. Tabd temperature was maintained between 36.2 and 36.8 C and rectal temperature between 36.8 and 37.2 C in each environment by manual or automatic servocontrol. A "resting state" was defined by using a combination of subjective and objective criteria. The mean values of VO2 during the "resting state" were 7.31 and 7.59 cc/kg of body weight per minute for naked and covered infants, respectively. There were no significant differences between mean values of VCO2, respiratory quotient, HR, RR, abdominal, cheek, thigh, or rectal temperatures in the two environments. Operant temperatures averaged 0.5 C lower when the infants were covered. These data support the hypothesis that decreases in insensible water loss do not necessarily imply reductions in caloric requirements in infants where Tabd is maintained by servocontrol.

Biological rhythmicity in preterm infants prior to discharge from neonatal intensive care.

OBJECTIVE: The study of biological rhythms and the influence of environmental factors in the timing and synchronization of different rhythmic events have important implications for neonatal health. Preterm infants in the neonatal intensive care unit (NICU) are deprived of the patterned influences of maternal sleep, temperature, heart rate, and hormonal cycles. The impact of the NICU and nursing interventions on the development of the circadian system was studied in 17 stable preterm infants in the Intermediate Intensive Care Nursery at Stanford University for three consecutive days at about 35 weeks postconceptional age. OUTCOME MEASUREMENTS: Rectal temperature, abdominal skin temperature, heart rate, and activity were simultaneously recorded at 2-minute intervals during each 3-day study by a small microcomputer (Vitalog). RESULTS: Very low amplitude circadian rhythms were found for rectal and skin temperatures (maximum range 36.8 to 37.0 degrees C); population mean values for heart rate (158 bpm) and activity (3.5 counts per 2-min bin) did not differ significantly as a function of time of day. Rectal temperature, averaged in 6-hour bins over the 24-hour day as a function of both postconceptional age and postnatal age, was significantly higher during the first part of the circadian cycle. In all infants, rhythmicity in each variable was dominated by ultradian periodicities that were coincident with feedings and related interventions; moreover, several physiological variables charted during feeding differed significantly from values obtained during periods in which caregiving interventions did not occur. CONCLUSION: Quantitative data on the preterm infant circadian system may facilitate evaluation of factors that improve therapeutic responses, recovery, and outcome of neonatal intensive care patients.

Biological rhythmicity in normal infants during the first 3 months of life.

OBJECTIVE: The mammalian "biological clock," which resides in the hypothalamic suprachiasmatic nucleus, has an important role in both the timing and organization of sleep and in the coordination of sleep with other physiological rhythms such as temperature regulation and respiratory control. We wished to describe the development of the circadian system in normal infants during the first 3 months of life. METHODS: Ten healthy full term infants were studied in the infant's home for three consecutive days at 1 month and 3 months postnatal age. Rectal temperature, abdominal skin temperature, heart rate, and activity were recorded at 2-minute intervals during each study using a small microcomputer. RESULTS: Circadian periodicity for most variables was seen at 1 month of age and significantly increased at 3 months. Differences in the pattern of rhythmicity during these two developmental periods were highlighted by an increase in activity during the subjective day and a decrease in Trec during the subjective night at 3 months compared to 1 month. Correlational analysis revealed that all pairs of variables, exclusive of Tsk, showed a significantly higher association at 3 months relative to 1 month. The lengthening of the interfeeding interval at 3 months of age corresponded with an increased consolidation of sleep during the night and a relatively lower nocturnal body temperature minima compared to 1 month of age. CONCLUSION: The results of this study underscore the subtle changes in the nature and interaction of several infant variables during this critical developmental period, which may reflect maturation of the circadian system and its coupling with homeostatic effector systems that are developing in parallel.

Chronic pulmonary disease in neonates after artificial ventilation: distribution of ventilation and pulmonary interstitial emphysema.

To determine pulmonary function abnormalities in patients with neonatal bronchopulmonary dysplasia (BPD), we measured distribution of ventilation by nitrogen washout, minute and tidal volume, and arterial and alveolar gases in three groups of ten preterm infants with similar birth weights (mean = 1,340 g) and gestational ages (mean = 30.3 weeks). Infants in group A were never artificially ventilated, those in group B were ventilated but had no subsequent BPD, and those in group C were ventilated and developed BPD. Infants with BPD had severe maldistribution of ventilation (pulmonary clearance delay 223% versus 47% and 60% for groups A and B). They had decreased tidal volumes (5.3 ml versus 7.0 and 6.2 ml) and higher respiratory rates (60/min versus 47 and 48) but similar minute volumes. They also had increased PaCO2 (53.6 torr versus 41.9 and 43.4 torr) and increased arterial-alveolar carbon dioxide gradients (6.8 torr versus 3.1 and 1.8 torr). There was no statistically significant difference between groups B and C for the time spent in fractional inspired oxygen greater than 0.40 and greater than 0.60, or the time ventilated for intubated, or the incidence of patent ductus arteriosus. Early pulmonary interstitial emphysema was much more common in the infants who subsequently developed BPD (eight of ten versus two of ten, P less than .01).

Congenital central alveolar hypoventilation syndrome in six infants.

Six infants with congenital alveolar hypoventilation syndrome (CCHS) were seen and observed over several years. Two had an association of CCHS with Hirchsprung's disease. All infants were treated by tracheostomy and mechanical ventilation. Three infants have survived (including one with CCHS and Hirchsprung's disease). However, all survivors have required frequent rehospitalization. The infant with the longest survival (now 4 years of age) has developed significant daytime problems involving the "behavioral control" of ventilation. One infant was considered as a "near miss for sudden infant death syndrome" and became significantly symptomatic after establishment of delta (stage 3-4 non-rapid eye movement) sleep, which normally develops between 2 and 4 months of age. CCHS involves autonomic nervous system dysfunction, and the question of a defect involving the integration of chemoreceptor information more than a direct defect of the central chemoreceptor is discussed.

Five cases of near-miss sudden infant death syndrome and development of obstructive sleep apnea syndrome.

Five full-term infants were referred for "near miss" sudden infant death syndrome events, which occurred between 3 and 12 weeks of age. After a complete pediatric evaluation and 24-hour polygraphic monitoring, each infant was monitored at home with a cardiorespiratory monitor. Each was followed regularly (with repeat polygraphic recordings) up to 4 years of age. All five infants developed heavy snoring at night and symptoms of obstructive sleep apnea syndrome. The diagnosis of obstructive sleep apnea syndrome was confirmed by polygraphic recordings; surgery was recommended. Four of the five children underwent adenoidectomies between 3 and 4 years of age, and this significantly improved their condition. These five cases are the first polygraphically documented histories of the development of obstructive sleep apnea syndrome.

Periodic breathing in preterm infants: incidence and characteristics.

The prevalence and characteristics of periodic breathing in preterm infants were measured by 24-hour impedance pneumograms in 66 preterm infants before discharge from the nursery. Four periodic breathing parameters (percentage of periodic breathing per quiet time, number of episodes of periodic breathing per 100 minutes of quiet time, mean duration of periodic breathing, and longest episode of periodic breathing) were compared to data available from healthy term infants and from term infants who subsequently died of sudden infant death syndrome (SIDS). Periodic breathing was found in all preterm infants studied and mean periodic breathing parameter values (12.0%, 8.6 episodes, 1.2 minutes, and 7.3 minutes, respectively) in our preterm population were substantially higher than values from healthy term infants and SIDS victims. Most periodic breathing parameters decreased significantly in infants studied at 39 to 41 weeks' postconceptional age compared with earlier postconceptional age groups. No relationship was found between central apneas of greater than or equal to 15 seconds' duration and postconceptional age or any periodic breathing parameter. Periodic breathing is a common respiratory pattern in preterm infants that is usually not of pathologic significance. Associations between elevated levels of periodic breathing and respiratory dysfunction or SIDS should be made with caution.

'Near-miss' for sudden infant death syndrome infants: a clinical problem.

Three hundred six infants were referred for evaluation of "near-miss" sudden infant death syndrome (SIDS) from 1973 to 1980. Following the hospitalization and medical evaluation, there were 156 infants (115 term and 41 preterm) for whom there was no explanation for the presenting event and who were considered near-miss infants; 88% of these infants were seen during the first 3 months of life. A repeat near-miss event was reported in 63% (term) and 83% (preterm) infants. Twelve percent of term infants and 17% of the preterm infants had ten or more repeat events. A home apnea/cardiac monitor was prescribed for 88% of the infants for an average duration of 5.6 months in term infants and 3.5 months in preterm infants. Monitoring had been discontinued in 69% of the infants by 7 months of age. One full-term infant was later a SIDS victim. The risk of a repeat near-miss event is concluded to be sufficiently great to demand immediate hospitalization, medical evaluation, home monitoring when there is no specific treatment, and close clinical follow-up. Follow-up studies are needed to determine whether there is any long-term morbidity for infants who have had near miss events.

Obstructive sleep apnea and near miss for SIDS: I. Report of an infant with sudden death.

An infant girl followed up from birth to death at the University Medical Center had ""congenital stridor'' and a ""near miss for SIDS'' event at 3 months of age. As part of an ongoing SIDS research project, she underwent 24-hour polygraphic monitoring at 21 weeks of age. Sudden infant death occurred within 30 hours after the polygraphic study. Polygraphic data obtained from this infant are compared with those from control infants and other infants with near miss for SIDS who were of similar ages. The number of mixed and obstructive respiratory events during sleep was abnormally high on the infant's recording. Histologic findings, involving particularly the midline structures of the brain stem, are discussed.

Apnea, hypoxemia, and aborted sudden infant death syndrome.

To find out whether there is any relationship between the ventilatory response to hypoxia and the sudden infant death syndrome (SIDS), we studied the effects of mild induced hypoxia (PIO2, 120 mm Hg = 17% oxygen) in 16 infants aged 2 weeks to 6 months. Eight had recurrent apneic spells (apnea group) (five had aborted SIDS and three had recurrent apnea in the intensive care nursery) and eight were "well" preterm infants about to fly in a pressurized airplane (PIO2, 120 mm Hg) (control group). Mean birth weights were 2,245 and 1,400 gm and mean gestational ages were 35 and 30 weeks. Postconceptual ages (41.8 and 41.3 weeks) were almost identical. Heart rate was obtained from an ECG, and respiratory rate and pattern were obtained from a pneumogram. In addition, end-tidal PCO2 and PN2 or PO2 were obtained with a nasal catheter and gas analyzers. In the apnea group with inhalation of 17% oxygen, we observed an increase in periodic breathing and an increase in both rate and total duration of respiratory pauses. In the control group there were no significant changes. Heart rate and PCO2 did not change in either group. Our findings suggest that infants prone to apnea may have unique respiratory responses to mild induced hypoxia.

Favorable results of neonatal intensive care for very low-birth-weight infants.

From 1961 to 1976, 229 infants with birth weights ranging from 751 to 1,000 gm were admitted to the Stanford University Hospital Intensive Care Nursery. The overall neonatal mortality for these infants was 63% (144/229), and there were ten late deaths. Before 1967, no infant in this group who required mechanical ventilation survived; thereafter, 30% (34/114) of the ventilated patients survived. Of the 75 long-term survivors 60 participated in a high-risk infant follow-up program; these included 23 infants who had received mechanical ventilation. The mean birth weight of these infants was 928 +/- 67 (SD) gm. Seventeen children (28%) had significant morbidity: seven (12%) with severe handicaps and ten (17%) with moderate handicaps. During this same period, seven infants weighing less than 750 gm at birth were also observed. The three infants who had not required ventilatory support thrived; the other four infants had required respirators and were significantly handicapped. More recently, neonatal mortality for infants with birth weights from 751 to 1,000 gm has improved: for 1977 to 1980, it was 28% (33/118). Furthermore, neonatal mortality for ventilated infants in this weight group was 27% (26/95). These data indicate an improved prognosis for very low-birth-weight infants, even with ventilatory support.

Dew-point hygrometry system for measurement of evaporative water loss in infants.

Evaporation of water from the skin is an important mechanism in thermal homeostasis. Resistance hygrometry, in which the water vapor pressure gradient above the skin surface is calculated, has been the measurement method of choice in the majority of pediatric investigations. However, resistance hygrometry is influenced by changes in ambient conditions such as relative humidity, surface temperature, and convection currents. We have developed a ventilated capsule method that minimized these potential sources of measurement error and that allowed second-by-second, long-term, continuous measurements of evaporative water loss in sleeping infants. Air with a controlled reference humidity (dew-point temperature = 0 degree C) is delivered to a small, lightweight skin capsule and mixed with the vapor on the surface of the skin. The dew point of the resulting mixture is measured by using a chilled mirror dew-point hygrometer. The system indicates leaks, is mobile, and is accurate within 2%, as determined by gravimetric calibration. Examples from a recording of a 13-wk-old full-term infant obtained by using the system give evaporative water loss rates of approximately 0.02 mgH2O.cm-2.min-1 for normothermic baseline conditions and values up to 0.4 mgH2O.cm-2. min-1 when the subject was being warmed. The system is effective for clinical investigations that require dynamic measurements of water loss.

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.

Apnea during sleep in the pediatric patient.

Pediatric respiratory disorders during sleep are primarily apneic problems that can be associated with a number of abnormalities. When apnea is secondary to a disease process, the main focus should be on the identification of that disease process and on the institution of appropriate therapy. When the apnea persists or when it is idiopathic, additional evaluation may be required to identify an appropriate course of management.

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.