Krisa Van Meurs

All Publications

• Neonatal outcomes of moderately preterm infants compared to extremely preterm infants. Pediatric research Walsh, M. C., Bell, E. F., Kandefer, S., Saha, S., Carlo, W. A., D'Angio, C. T., Laptook, A. R., Sanchez, P. J., Stoll, B. J., Shankaran, S., Van Meurs, K. P., Cook, N., Higgins, R. D., Das, A., Newman, N. S., Schibler, K., Schmidt, B., Cotten, C. M., Poindexter, B. B., Watterberg, K. L., Truog, W. E. 2017

  Abstract

  BackgroundExtremely preterm infants (EPT, <29 weeks' gestation) represent only 0.9% of births in the United States; yet these infants are the focus of most published research. Moderately preterm neonates (MPT, 29-33(6/7) weeks) are an understudied group of high-risk infants.MethodsTo determine the neonatal outcomes of MPT infants across the gestational age spectrum, and to compare these with EPT infants. A prospective observational cohort was formed in 18 level 3-4 neonatal intensive care units (NICUs) in the Eunice Kennedy Shriver NICHD Neonatal Research Network. Participants included all MPT infants admitted to NICUs and all EPT infants born at sites between January 2012 and November 2013. Antenatal characteristics and neonatal morbidities were abstracted from records using pre-specified definitions by trained neonatal research nurses.ResultsMPT infants experienced morbidities similar to, although at lower rates than, those of EPT infants. The main cause of mortality was congenital malformation, accounting for 43% of deaths. Central Nervous System injury occurred, including intraventricular hemorrhage. Most MPT infants required respiratory support, but sequelae such as bronchopulmonary dysplasia were rare. The primary contributors to hospitalization beyond 36 weeks' gestation were inability to achieve adequate oral intake and persistent apnea.ConclusionsMPT infants experience morbidity and prolonged hospitalization. Such morbidity deserves focused research to improve therapeutic and prevention strategies.Pediatric Research advance online publication, 24 May 2017; doi:10.1038/pr.2017.46.

  View details for DOI 10.1038/pr.2017.46

  View details for PubMedID 28419085

• Erythropoietin and Brain Magnetic Resonance Imaging Findings in Hypoxic-Ischemic Encephalopathy: Volume of Acute Brain Injury and 1-Year Neurodevelopmental Outcome. journal of pediatrics Mulkey, S. B., Ramakrishnaiah, R. H., McKinstry, R. C., Chang, T., Mathur, A. M., Mayock, D. E., Van Meurs, K. P., Schaefer, G. B., Luo, C., Bai, S., Juul, S. E., Wu, Y. W. 2017

  Abstract

  In the Neonatal Erythropoietin and Therapeutic Hypothermia Outcomes study, 9/20 erythropoietin-treated vs 12/24 placebo-treated infants with hypoxic-ischemic encephalopathy had acute brain injury. Among infants with acute brain injury, the injury volume was lower in the erythropoietin than the placebo group (P = .004). Higher injury volume correlated with lower 12-month neurodevelopmental scores.ClinicalTrials.gov: NCT01913340.

  View details for DOI 10.1016/j.jpeds.2017.03.053

  View details for PubMedID 28456387

• Improving the Identification of Neonatal Encephalopathy: Utility of a Web-Based Video Tool AMERICAN JOURNAL OF PERINATOLOGY Ivy, A. S., Clark, C. L., Bahm, S. M., Van Meurs, K. P., Wusthoff, C. J. 2017; 34 (5): 520-522

  View details for DOI 10.1055/5-0036-1593846

  View details for Web of Science ID 000398011100015

• Brain-focused care in the neonatal intensive care unit: the time has come. Jornal de pediatria Van Meurs, K. P., Bonifacio, S. L. 2017

  View details for DOI 10.1016/j.jped.2017.03.002

  View details for PubMedID 28359015

• Decreased Morphine Clearance in Neonates With Hypoxic Ischemic Encephalopathy Receiving Hypothermia JOURNAL OF CLINICAL PHARMACOLOGY Frymoyer, A., Bonifacio, S. L., Drover, D. R., Su, F., Wustoff, C. J., Van Meurs, K. P. 2017; 57 (1): 64-76

  Abstract

  Morphine is commonly used in neonates with hypothermic ischemic encephalopathy (HIE) during therapeutic hypothermia to provide comfort and analgesia. However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, two-center, clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight 1.82-5.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine-3-glucuronide and morphine-6-gluronide) were measured via a validated dried blood spot LC-MS/MS assay. From the available concentration data (n = 106 for morphine; n = 106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). The clearance of morphine and glucuronide metabolites were best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5 kg neonate, morphine clearance was 0.77 L/h (CV 48%) and the steady-state volume of distribution was 8.0 L (CV 49%). Compared to previous studies in full-term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n = 1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10-40 ng/ml. An optimized morphine loading dose of 50 μg/kg followed by a continuous infusion of 5 μg/kg/h was predicted across birthweight. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jcph.775

  View details for Web of Science ID 000392014300006

  View details for PubMedID 27225747

• Improving publication rates in a collaborative clinical trials research network. Seminars in perinatology Archer, S. W., Carlo, W. A., Truog, W. E., Stevenson, D. K., Van Meurs, K. P., Sánchez, P. J., Das, A., Devaskar, U., Nelin, L. D., Petrie Huitema, C. M., Crawford, M. M., Higgins, R. D. 2016; 40 (6): 410-417

  Abstract

  Unpublished results can bias biomedical literature, favoring positive over negative findings, primary over secondary analyses, and can lead to duplicate studies that unnecessarily endanger subjects and waste resources. The Neonatal Research Network's (NRN) publication policies for approving, reviewing, and tracking abstracts and papers work to combat these problems. In 2003, the NRN restricted investigators with unfinished manuscripts from proposing new ones and in 2010, urged authors to complete long-outstanding manuscripts. Data from 1991 to 2015 were analyzed to determine effectiveness of these policy changes. The NRN has achieved an overall publication rate of 78% for abstracts. For 1990-2002, of 137 abstracts presented, 43 (31%) were published within 2 years; for 2003-2009, after the manuscript completion policy was instituted, of 140 abstracts presented, 68 (49%) were published within 2 years. Following the effort in 2010, the rate increased to 64%. The NRN surpassed reported rates by developing a comprehensive process, holding investigators accountable and tracking abstracts from presentation to publication.

  View details for DOI 10.1053/j.semperi.2016.05.003

  View details for PubMedID 27423510

• Inhaled nitric oxide therapy for pulmonary disorders of the term and preterm infant. Seminars in perinatology Sokol, G. M., Konduri, G. G., Van Meurs, K. P. 2016; 40 (6): 356-369

  Abstract

  The 21st century began with the FDA approval of inhaled nitric oxide therapy for the treatment of neonatal hypoxic respiratory failure associated with pulmonary hypertension in recognition of the 2 randomized clinical trials demostrating a significant reduction in the need for extracorporeal support in the term and near-term infant. Inhaled nitric oxide is one of only a few therapeutic agents approved for use through clinical investigations primarily in the neonate. This article provides an overview of the pertinent biology and chemistry of nitric oxide, discusses potential toxicities, and reviews the results of pertinent clinical investigations and large randomized clinical trials including neurodevelopmental follow-up in term and preterm neonates. The clinical investigations conducted by the Eunice Kennedy Shriver NICHD Neonatal Research Network will be discussed and placed in context with other pertinent clinical investigations exploring the efficacy of inhaled nitric oxide therapy in neonatal hypoxic respiratory failure.

  View details for DOI 10.1053/j.semperi.2016.05.007

  View details for PubMedID 27480246

• Growth Outcomes of Preterm Infants Exposed to Different Oxygen Saturation Target Ranges from Birth. journal of pediatrics Navarrete, C. T., Wrage, L. A., Carlo, W. A., Walsh, M. C., Rich, W., Gantz, M. G., Das, A., Schibler, K., Newman, N. S., Piazza, A. J., Poindexter, B. B., Shankaran, S., Sánchez, P. J., Morris, B. H., Frantz, I. D., Van Meurs, K. P., Cotten, C. M., Ehrenkranz, R. A., Bell, E. F., Watterberg, K. L., Higgins, R. D., Duara, S. 2016; 176: 62-68 e4

  Abstract

  To test whether infants randomized to a lower oxygen saturation (peripheral capillary oxygen saturation [SpO2]) target range while on supplemental oxygen from birth will have better growth velocity from birth to 36 weeks postmenstrual age (PMA) and less growth failure at 36 weeks PMA and 18-22 months corrected age.We evaluated a subgroup of 810 preterm infants from the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, randomized at birth to lower (85%-89%, n = 402, PMA 26 ± 1 weeks, birth weight 839 ± 186 g) or higher (91%-95%, n = 408, PMA 26 ± 1 weeks, birth weight 840 ± 191 g) SpO2 target ranges. Anthropometric measures were obtained at birth, postnatal days 7, 14, 21, and 28; then at 32 and 36 weeks PMA; and 18-22 months corrected age. Growth velocities were estimated with the exponential method and analyzed with linear mixed models. Poor growth outcome, defined as weight <10th percentile at 36 weeks PMA and 18-22 months corrected age, was compared across the 2 treatment groups by the use of robust Poisson regression.Growth outcomes including growth at 36 weeks PMA and 18-22 months corrected age, as well as growth velocity were similar in the lower and higher SpO2 target groups.Targeting different oxygen saturation ranges between 85% and 95% from birth did not impact growth velocity or reduce growth failure in preterm infants.

  View details for DOI 10.1016/j.jpeds.2016.05.070

  View details for PubMedID 27344218

• Inhaled nitric oxide use in preterm infants in California neonatal intensive care units. Journal of perinatology Handley, S. C., Steinhorn, R. H., Hopper, A. O., Govindaswami, B., BHATT, D. R., Van Meurs, K. P., Ariagno, R. L., Gould, J. B., Lee, H. C. 2016; 36 (8): 635-639

  Abstract

  To describe inhaled nitric oxide (iNO) exposure in preterm infants and variation in neonatal intensive care unit (NICU) use.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.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%).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.Journal of Perinatology advance online publication, 31 March 2016; doi:10.1038/jp.2016.49.

  View details for DOI 10.1038/jp.2016.49

  View details for PubMedID 27031320

• High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial PEDIATRICS Wu, Y. W., Mathur, A. M., Chang, T., McKinstry, R. C., Mulkey, S. B., Mayock, D. E., Van Meurs, K. P., Rogers, E. E., Gonzalez, F. F., Comstock, B. A., Juul, S. E., Msall, M. E., Bonifacio, S. L., Glass, H. C., Massaro, A. N., Dong, L., Tan, K. W., Heagerty, P. J., Ballard, R. A. 2016; 137 (6)

  Abstract

  To determine if multiple doses of erythropoietin (Epo) administered with hypothermia improve neuroradiographic and short-term outcomes of newborns with hypoxic-ischemic encephalopathy.In a phase II double-blinded, placebo-controlled trial, we randomized newborns to receive Epo (1000 U/kg intravenously; n = 24) or placebo (n = 26) at 1, 2, 3, 5, and 7 days of age. All infants had moderate/severe encephalopathy; perinatal depression (10 minute Apgar <5, pH <7.00 or base deficit ≥15, or resuscitation at 10 minutes); and received hypothermia. Primary outcome was neurodevelopment at 12 months assessed by the Alberta Infant Motor Scale and Warner Initial Developmental Evaluation. Two independent observers rated MRI brain injury severity by using an established scoring system.The mean age at first study drug was 16.5 hours (SD, 5.9). Neonatal deaths did not significantly differ between Epo and placebo groups (8% vs 19%, P = .42). Brain MRI at mean 5.1 days (SD, 2.3) showed a lower global brain injury score in Epo-treated infants (median, 2 vs 11, P = .01). Moderate/severe brain injury (4% vs 44%, P = .002), subcortical (30% vs 68%, P = .02), and cerebellar injury (0% vs 20%, P = .05) were less frequent in the Epo than placebo group. At mean age 12.7 months (SD, 0.9), motor performance in Epo-treated (n = 21) versus placebo-treated (n = 20) infants were as follows: Alberta Infant Motor Scale (53.2 vs 42.8, P = .03); Warner Initial Developmental Evaluation (28.6 vs 23.8, P = .05).High doses of Epo given with hypothermia for hypoxic-ischemic encephalopathy may result in less MRI brain injury and improved 1-year motor function.

  View details for DOI 10.1542/peds.2016-0191

  View details for Web of Science ID 000378520100042

  View details for PubMedID 27244862

• Chorioamnionitis and Culture-Confirmed, Early-Onset Neonatal Infections. Pediatrics Wortham, J. M., Hansen, N. I., Schrag, S. J., Hale, E., Van Meurs, K., Sánchez, P. J., Cantey, J. B., Faix, R., Poindexter, B., Goldberg, R., Bizzarro, M., Frantz, I., Das, A., Benitz, W. E., Shane, A. L., Higgins, R., Stoll, B. J. 2016; 137 (1): 1-11

  Abstract

  Current guidelines for prevention of neonatal group B streptococcal disease recommend diagnostic evaluations and empirical antibiotic therapy for well-appearing, chorioamnionitis-exposed newborns. Some clinicians question these recommendations, citing the decline in early-onset group B streptococcal disease rates since widespread intrapartum antibiotic prophylaxis implementation and potential antibiotic risks. We aimed to determine whether chorioamnionitis-exposed newborns with culture-confirmed, early-onset infections can be asymptomatic at birth.Multicenter, prospective surveillance for early-onset neonatal infections was conducted during 2006-2009. Early-onset infection was defined as isolation of a pathogen from blood or cerebrospinal fluid collected ≤ 72 hours after birth. Maternal chorioamnionitis was defined by clinical diagnosis in the medical record or by histologic diagnosis by placental pathology. Hospital records of newborns with early-onset infections born to mothers with chorioamnionitis were reviewed retrospectively to determine symptom onset.Early-onset infections were diagnosed in 389 of 396,586 live births, including 232 (60%) chorioamnionitis-exposed newborns. Records for 229 were reviewed; 29 (13%) had no documented symptoms within 6 hours of birth, including 21 (9%) who remained asymptomatic at 72 hours. Intrapartum antibiotic prophylaxis exposure did not differ significantly between asymptomatic and symptomatic infants (76% vs 69%; P = .52). Assuming complete guideline implementation, we estimated that 60 to 1400 newborns would receive diagnostic evaluations and antibiotics for each infected asymptomatic newborn, depending on chorioamnionitis prevalence.Some infants born to mothers with chorioamnionitis may have no signs of sepsis at birth despite having culture-confirmed infections. Implementation of current clinical guidelines may result in early diagnosis, but large numbers of uninfected asymptomatic infants would be treated.

  View details for DOI 10.1542/peds.2015-2323

  View details for PubMedID 26719293

  View details for PubMedCentralID PMC4702021

• Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012. JAMA Stoll, B. J., Hansen, N. I., Bell, E. F., Walsh, M. C., Carlo, W. A., Shankaran, S., Laptook, A. R., Sánchez, P. J., Van Meurs, K. P., Wyckoff, M., Das, A., Hale, E. C., Ball, M. B., Newman, N. S., Schibler, K., Poindexter, B. B., Kennedy, K. A., Cotten, C. M., Watterberg, K. L., D'Angio, C. T., DeMauro, S. B., Truog, W. E., Devaskar, U., Higgins, R. D. 2015; 314 (10): 1039-1051

  Abstract

  Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality.To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers.Prospective registry of 34,636 infants, 22 to 28 weeks' gestation, birth weight of 401 to 1500 g, and born at 26 network centers between 1993 and 2012.Extremely preterm birth.Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes and were adjusted for study center, race/ethnicity, gestational age, birth weight for gestational age, and sex.Use of antenatal corticosteroids increased from 1993 to 2012 (24% [348 of 1431 infants]) to 87% (1674 of 1919 infants]; P < .001), as did cesarean delivery (44% [625 of 1431 births] to 64% [1227 of 1921]; P < .001). Delivery room intubation decreased from 80% (1144 of 1433 infants) in 1993 to 65% (1253 of 1922) in 2012 (P < .001). After increasing in the 1990s, postnatal steroid use declined to 8% (141 of 1757 infants) in 2004 (P < .001), with no significant change thereafter. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 7% (120 of 1666 infants) in 2002 to 11% (190 of 1756 infants) in 2012 (P < .001). Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each gestational age (median, 26 weeks [37% {109 of 296} to 27% {85 of 320}]; adjusted relative risk [RR], 0.93 [95% CI, 0.92-0.94]). Rates of other morbidities declined, but bronchopulmonary dysplasia increased between 2009 and 2012 for infants at 26 to 27 weeks' gestation (26 weeks, 50% [130 of 258] to 55% [164 of 297]; P < .001). Survival increased between 2009 and 2012 for infants at 23 weeks' gestation (27% [41 of 152] to 33% [50 of 150]; adjusted RR, 1.09 [95% CI, 1.05-1.14]) and 24 weeks (63% [156 of 248] to 65% [174 of 269]; adjusted RR, 1.05 [95% CI, 1.03-1.07]), with smaller relative increases for infants at 25 and 27 weeks' gestation, and no change for infants at 22, 26, and 28 weeks' gestation. Survival without major morbidity increased approximately 2% per year for infants at 25 to 28 weeks' gestation, with no change for infants at 22 to 24 weeks' gestation.Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks' gestation and survival without major morbidity increased for infants aged 25 to 28 weeks. These findings may be valuable in counseling families and developing novel interventions.clinicaltrials.gov Identifier: NCT00063063.

  View details for DOI 10.1001/jama.2015.10244

  View details for PubMedID 26348753

• Definitions of Cardiovascular Insufficiency and Relation to Outcomes in Critically Ill Newborn Infants. American journal of perinatology Fernandez, E., Watterberg, K. L., Faix, R. G., Yoder, B. A., Walsh, M. C., Lacy, C. B., Osborne, K. A., Das, A., Kendrick, D. E., Stoll, B. J., Poindexter, B. B., Laptook, A. R., Kennedy, K. A., Schibler, K., Bell, E. F., Van Meurs, K. P., Frantz, I. D., Goldberg, R. N., Shankaran, S., Carlo, W. A., Ehrenkranz, R. A., Sánchez, P. J., Higgins, R. D. 2015; 32 (11): 1024-1030

  Abstract

  Background We previously reported on the overall incidence, management, and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short-term outcomes in term and late preterm newborn infants. Objective This study aims to evaluate how four definitions of CVI relate to short-term outcomes and death. Study Design The previously reported study was a multicenter, prospective cohort study of 647 infants ≥ 34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short-term outcomes at discharge and four different definitions of CVI were further analyzed. Results All the four definitions were associated with greater number of days on MV and days on O2. The definition using a threshold blood pressure (BP) measurement alone was not associated with days of full feeding, days in the NICU or death. The definition based on the treatment of CVI was associated with all the outcomes including death. Conclusions The definition using a threshold BP alone was not consistently associated with adverse short-term outcomes. Using only a threshold BP to determine therapy may not improve outcomes.

  View details for DOI 10.1055/s-0035-1547321

  View details for PubMedID 25825962

• Screening Cranial Imaging at Multiple Time Points Improves Cystic Periventricular Leukomalacia Detection. American journal of perinatology Sarkar, S., Shankaran, S., Laptook, A. R., Sood, B. G., Do, B., Stoll, B. J., Van Meurs, K. P., Bell, E. F., Das, A., Barks, J. 2015; 32 (10): 973-979

  Abstract

  Objective The aim of this study is to determine whether the cystic periventricular leukomalacia (cPVL) detection rate differs between imaging studies performed at different time points. Design We retrospectively reviewed the prospectively collected data of 31,708 infants from the NICHD Neonatal Research Network. Inclusion criteria were infants < 1,000 g birth weight or < 29 weeks' gestational age who had cranial imaging performed using both early criterion (cranial ultrasound [CUS] < 28 days chronological age) and late criterion (CUS, magnetic resonance imaging, or computed tomography closest to 36 weeks postmenstrual age [PMA]). We compared the frequency of cPVL diagnosed by early and late criteria. Results About 664 (5.2%) of the 12,739 infants who met inclusion criteria had cPVL using either early or late criteria; 569 using the late criterion, 250 using the early criterion, and 155 patients at both times. About 95 (14.3%) of 664 cPVL cases seen on early imaging were no longer visible on repeat screening closest to 36 weeks PMA. Such disappearance of cPVL was more common in infants < 26 weeks' gestation versus infants of 26 to 28 weeks' gestation (18.5 vs. 11.5%; p = 0.013). Conclusions Cranial imaging at both < 28 days chronological age and closest to 36 weeks PMA improves cPVL detection, especially for more premature infants.

  View details for DOI 10.1055/s-0035-1545666

  View details for PubMedID 25730135

• Screening Cranial Imaging at Multiple Time Points Improves Cystic Periventricular Leukomalacia Detection AMERICAN JOURNAL OF PERINATOLOGY Sarkar, S., Shankaran, S., Laptook, A. R., Sood, B. G., Do, B., Stoll, B. J., Van Meurs, K. P., Bell, E. F., Das, A., Barks, J. 2015; 32 (10): 973-979

  View details for DOI 10.1055/s-0035-1545666

  View details for Web of Science ID 000359881100012

• Amplitude-integrated electroencephalography: a survey of practices in the United States. American journal of perinatology Shah, N. A., Van Meurs, K. P., Davis, A. S. 2015; 32 (8): 755-760

  Abstract

  Objective Amplitude-integrated electroencephalography (aEEG) is a simplified method for continuous monitoring of brain activity in the neonatal intensive care unit (NICU). Our objective was to describe current aEEG use in the United States. Study Design An online survey was distributed to the American Academy of Pediatrics Section on Perinatal Pediatrics' list serve. Result A total of 654 surveys were received; 55% of respondents reported using aEEG. aEEG was utilized more often in academic and levels III and IV NICUs; hypoxic-ischemic encephalopathy and suspected seizures were the most common indications for use. aEEG was primarily interpreted by neonatologists (87%), with approximately half reporting either self-teaching or hospital-based training for interpretation. For those not using aEEG, uncertain clinical benefit (40%) and cost (17%) were reported as barriers to use. Conclusion More than half of neonatologists utilize aEEG, with practice variation by NICU setting. Barriers to wider adoption include education regarding potential benefit, training, and cost.

  View details for DOI 10.1055/s-0034-1395483

  View details for PubMedID 25519200

• Amplitude-Integrated Electroencephalography: A Survey of Practices in the United States AMERICAN JOURNAL OF PERINATOLOGY Shah, N. A., Van Meurs, K. P., Davis, A. S. 2015; 32 (8): 755-759

  View details for DOI 10.1055/s-0034-1395483

  View details for Web of Science ID 000356992300006

  View details for PubMedID 25519200

• Serial aEEG recordings in a cohort of extremely preterm infants: feasibility and safety JOURNAL OF PERINATOLOGY Davis, A. S., Gantz, M. G., Do, B., Shankaran, S., Hamrick, S. E., Kennedy, K. A., TYSON, J. E., Chalak, L. F., Laptook, A. R., Goldstein, R. F., Hintz, S. R., Das, A., Higgins, R. D., Ball, M. B., HALE, E. C., Van Meurs, K. P. 2015; 35 (5): 373-378

  Abstract

  Objective:Amplitude-integrated electroencephalography (aEEG) monitoring is increasing in the neonatal population, but the safety and feasibility of performing aEEG in extremely preterm infants have not been systematically evaluated.Study Design:Inborn infants 23(0/7) to 28(6/7) weeks gestation or birth weight 401 to 1000 g were eligible. Serial, 6-h aEEG recordings were obtained from first week of life until 36 weeks postmenstrual age. Adverse events were documented, and surveys evaluated the impact of the aEEGs on routine care. Success of performing aEEGs according to protocol and aEEG quality were assessed.Result:A total of 102 infants were enrolled, with 755 recordings performed. 83% of recordings were performed according to schedule, and 96% were without adverse event. Bedside nurses reported no interference with routine care for 89% of recordings. 92% of recordings had acceptable signal quality.Conclusion:Serial aEEG monitoring is safe in preterm infants, with few adverse events and general acceptance by nursing staff.Journal of Perinatology advance online publication, 4 December 2014; doi:10.1038/jp.2014.217.

  View details for DOI 10.1038/jp.2014.217

  View details for Web of Science ID 000353565200013

  View details for PubMedID 25474559

• Development and Validation of the Proxy-Reported Pulmonary Outcomes Scale for Premature Infants AMERICAN JOURNAL OF PERINATOLOGY Price, W. A., Aliaga, S. R., Massie, S. E., DeWalt, D. A., Laughon, M. M., Malcolm, W. F., Van Meurs, K., Klein, J. M., El-Ferzli, G., Magnus, B. E., Tolleson-Rinehart, S. 2015; 32 (6): 583-589

  Abstract

  Test the feasibility of using a bedside nurse-reported tool (Proxy-Reported Pulmonary Outcome Scale, PRPOS) for evaluating the severity of bronchopulmonary dysplasia (BPD) by assessing functional, disease-related measures.Bedside nurses tested the 26-item instrument by observing preterm infants (23-30 weeks at birth) at 36 to 37(4/7) weeks postmenstrual age before, during, and after a care time. We analyzed item reliability, validity, and model fit to determine the six items to include in the final measurement tool.We completed assessments on 188 preterm infants. The frequency of an abnormal PRPOS item score increased with increasing National Institute of Child Health and Development (NICHD) BPD category. The six-candidate items produced an internally consistent scale. Addition of the NICHD BPD classification increased reliability moderately; addition of feeding items decreased reliability. The PRPOS score correlated with postmenstrual age at discharge. Infants discharged on oxygen or diuretics had higher median PRPOS scores than did infants who were not prescribed those therapies.The PRPOS is an internally consistent, proxy-reported measure of respiratory function in premature infants, based on observable, functional performance measures. Initial testing demonstrates known-groups validity and ongoing testing can assess predictive validity.

  View details for DOI 10.1055/s-0035-1544946

  View details for Web of Science ID 000354342400011

  View details for PubMedID 25715315

• A randomized clinical trial of therapeutic hypothermia mode during transport for neonatal encephalopathy. journal of pediatrics Akula, V. P., Joe, P., Thusu, K., Davis, A. S., Tamaresis, J. S., Kim, S., Shimotake, T. K., Butler, S., Honold, J., Kuzniewicz, M., Desandre, G., Bennett, M., Gould, J., Wallenstein, M. B., Van Meurs, K. 2015; 166 (4): 856-61 e1 2

  Abstract

  To determine if temperature regulation is improved during neonatal transport using a servo-regulated cooling device when compared with standard practice.We performed a multicenter, randomized, nonmasked clinical trial in newborns with neonatal encephalopathy cooled during transport to 9 neonatal intensive care units in California. Newborns who met institutional criteria for therapeutic hypothermia were randomly assigned to receive cooling according to usual center practices vs device servo-regulated cooling. The primary outcome was the percentage of temperatures in target range (33°-34°C) during transport. Secondary outcomes included percentage of newborns reaching target temperature any time during transport, time to target temperature, and percentage of newborns in target range 1 hour after cooling initiation.One hundred newborns were enrolled: 49 to control arm and 51 to device arm. Baseline demographics did not differ with the exception of cord pH. For each subject, the percentage of temperatures in the target range was calculated. Infants cooled using the device had a higher percentage of temperatures in target range compared with control infants (median 73% [IQR 17-88] vs 0% [IQR 0-52], P < .001). More subjects reached target temperature during transport using the servo-regulated device (80% vs 49%, P <.001), and in a shorter time period (44 ± 31 minutes vs 63 ± 37 minutes, P = .04). Device-cooled infants reached target temperature by 1 hour with greater frequency than control infants (71% vs 20%, P < .001).Cooling using a servo-regulated device provides more predictable temperature management during neonatal transport than does usual care for outborn newborns with neonatal encephalopathy.

  View details for DOI 10.1016/j.jpeds.2014.12.061

  View details for PubMedID 25684087

• A Randomized Clinical Trial of Therapeutic Hypothermia Mode during Transport for Neonatal Encephalopathy. journal of pediatrics Akula, V. P., Joe, P., Thusu, K., Davis, A. S., Tamaresis, J. S., Kim, S., Shimotake, T. K., Butler, S., Honold, J., Kuzniewicz, M., Desandre, G., Bennett, M., Gould, J., Wallenstein, M. B., Van Meurs, K. 2015; 166 (4): 856-861 e2

  View details for DOI 10.1016/j.jpeds.2014.12.061

  View details for PubMedID 25684087

• Causes and timing of death in extremely premature infants from 2000 through 2011. New England journal of medicine Patel, R. M., Kandefer, S., Walsh, M. C., Bell, E. F., Carlo, W. A., Laptook, A. R., Sánchez, P. J., Shankaran, S., Van Meurs, K. P., Ball, M. B., Hale, E. C., Newman, N. S., Das, A., Higgins, R. D., Stoll, B. J. 2015; 372 (4): 331-340

  Abstract

  Understanding the causes and timing of death in extremely premature infants may guide research efforts and inform the counseling of families.We analyzed prospectively collected data on 6075 deaths among 22,248 live births, with gestational ages of 22 0/7 to 28 6/7 weeks, among infants born in study hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. We compared overall and cause-specific in-hospital mortality across three periods from 2000 through 2011, with adjustment for baseline differences.The number of deaths per 1000 live births was 275 (95% confidence interval [CI], 264 to 285) from 2000 through 2003 and 285 (95% CI, 275 to 295) from 2004 through 2007; the number decreased to 258 (95% CI, 248 to 268) in the 2008-2011 period (P=0.003 for the comparison across three periods). There were fewer pulmonary-related deaths attributed to the respiratory distress syndrome and bronchopulmonary dysplasia in 2008-2011 than in 2000-2003 and 2004-2007 (68 [95% CI, 63 to 74] vs. 83 [95% CI, 77 to 90] and 84 [95% CI, 78 to 90] per 1000 live births, respectively; P=0.002). Similarly, in 2008-2011, as compared with 2000-2003, there were decreases in deaths attributed to immaturity (P=0.05) and deaths complicated by infection (P=0.04) or central nervous system injury (P<0.001); however, there were increases in deaths attributed to necrotizing enterocolitis (30 [95% CI, 27 to 34] vs. 23 [95% CI, 20 to 27], P=0.03). Overall, 40.4% of deaths occurred within 12 hours after birth, and 17.3% occurred after 28 days.We found that from 2000 through 2011, overall mortality declined among extremely premature infants. Deaths related to pulmonary causes, immaturity, infection, and central nervous system injury decreased, while necrotizing enterocolitis-related deaths increased. (Funded by the National Institutes of Health.).

  View details for DOI 10.1056/NEJMoa1403489

  View details for PubMedID 25607427

• Neuroimaging and neurodevelopmental outcome in extremely preterm infants. Pediatrics Hintz, S. R., Barnes, P. D., Bulas, D., Slovis, T. L., Finer, N. N., Wrage, L. A., Das, A., Tyson, J. E., Stevenson, D. K., Carlo, W. A., Walsh, M. C., Laptook, A. R., Yoder, B. A., Van Meurs, K. P., Faix, R. G., Rich, W., Newman, N. S., Cheng, H., Heyne, R. J., Vohr, B. R., Acarregui, M. J., Vaucher, Y. E., Pappas, A., Peralta-Carcelen, M., Wilson-Costello, D. E., Evans, P. W., Goldstein, R. F., Myers, G. J., Poindexter, B. B., McGowan, E. C., Adams-Chapman, I., Fuller, J., Higgins, R. D. 2015; 135 (1): e32-42

  Abstract

  Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months' corrected age.Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks' gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors.Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3-6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8-35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes.Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging.

  View details for DOI 10.1542/peds.2014-0898

  View details for PubMedID 25554820

• Neuroimaging and neurodevelopmental outcome in extremely preterm infants. Pediatrics Hintz, S. R., Barnes, P. D., Bulas, D., Slovis, T. L., Finer, N. N., Wrage, L. A., Das, A., Tyson, J. E., Stevenson, D. K., Carlo, W. A., Walsh, M. C., Laptook, A. R., Yoder, B. A., Van Meurs, K. P., Faix, R. G., Rich, W., Newman, N. S., Cheng, H., Heyne, R. J., Vohr, B. R., Acarregui, M. J., Vaucher, Y. E., Pappas, A., Peralta-Carcelen, M., Wilson-Costello, D. E., Evans, P. W., Goldstein, R. F., Myers, G. J., Poindexter, B. B., McGowan, E. C., Adams-Chapman, I., Fuller, J., Higgins, R. D. 2015; 135 (1): e32-42

  View details for DOI 10.1542/peds.2014-0898

  View details for PubMedID 25554820

• Antenatal magnesium sulfate exposure and acute cardiorespiratory events in preterm infants AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY De Jesus, L. C., Sood, B. G., Shankaran, S., Kendrick, D., Das, A., Bell, E. F., Stoll, B. J., Laptook, A. R., Walsh, M. C., Carlo, W. A., Sanchez, P. J., Van Meurs, K. P., Bara, R., Hale, E. C., Newman, N. S., Ball, M. B., Higgins, R. D. 2015; 212 (1)

  Abstract

  Antenatal magnesium (anteMg) is used for various obstetric indications including fetal neuroprotection. Infants exposed to anteMg may be at risk for respiratory depression and delivery room (DR) resuscitation. The study objective was to compare the risk of acute cardiorespiratory events among preterm infants who were and were not exposed to anteMg.This was a retrospective analysis of prospective data collected in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's Generic Database from April 1, 2011, through March 31, 2012. The primary outcome was DR intubation or respiratory support at birth or on day 1 of life. Secondary outcomes were invasive mechanical ventilation, hypotension treatment, neonatal morbidities, and mortality. Logistic regression analysis evaluated the risk of primary outcome after adjustment for covariates.We evaluated 1544 infants <29 weeks' gestational age (1091 in anteMg group and 453 in nonexposed group). Mothers in the anteMg group were more likely to have higher education, pregnancy-induced hypertension, and antenatal corticosteroids, while their infants were younger in gestation and weighed less (P < .05). The primary outcome (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.88-1.65) was similar between groups. Hypotension treatment (OR, 0.70; 95% CI, 0.51-0.97) and invasive mechanical ventilation (OR, 0.54; 95% CI, 0.41-0.72) were significantly less in the anteMg group.Among preterm infants age <29 weeks' gestation, anteMg exposure was not associated with an increase in cardiorespiratory events in the early newborn period. The safety of anteMg as measured by the need for DR intubation or respiratory support on day 1 of life was comparable between groups.

  View details for DOI 10.1016/j.ajog.2014.07.023

  View details for Web of Science ID 000346585700032

  View details for PubMedID 25046806

  View details for PubMedCentralID PMC4275326

• Effect of Depth and Duration of Cooling on Deaths in the NICU Among Neonates With Hypoxic Ischemic Encephalopathy A Randomized Clinical Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Shankaran, S., Laptook, A. R., Pappas, A., McDonald, S. A., Das, A., Tyson, J. E., Poindexter, B. B., Schibler, K., Bell, E. F., Heyne, R. J., Pedroza, C., Bara, R., Van Meurs, K. P., Grisby, C., Huitema, C. M., Garg, M., Ehrenkranz, R. A., Shepherd, E. G., Chalak, L. F., Hamrick, S. E., Khan, A. M., Reynolds, A. M., Laughon, M. M., Truog, W. E., Dysart, K. C., Carlo, W. A., Walsh, M. C., Watterberg, K. L., Higgins, R. D. 2014; 312 (24): 2629-2639

  Abstract

  Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models.To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.A randomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours.The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours' vs 120 hours' duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes).The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92-2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69-2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07-0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%.Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.clinicaltrials.gov Identifier: NCT01192776.

  View details for DOI 10.1001/jama.2014.16058

  View details for Web of Science ID 000346966100015

  View details for PubMedID 25536254

• Incidence, Management, and Outcomes of Cardiovascular Insufficiency in Critically III Term and Late Preterm Newborn Infants AMERICAN JOURNAL OF PERINATOLOGY Fernandez, E., Watterberg, K. L., Faix, R. G., Yoder, B. A., Walsh, M. C., Lacy, C. B., Osborne, K. A., Das, A., Kendrick, D. E., Stoll, B. J., Poindexter, B. B., Laptook, A. R., Kennedy, K. A., Schibler, K., Bell, E. F., Van Meurs, K. P., Frantz, I. D., Goldberg, R. N., Shankaran, S., Carlo, W. A., Ehrenkranz, R. A., Sanchez, P. J., Higgins, R. D. 2014; 31 (11): 947-955

  View details for DOI 10.1055/s-0034-1368089

  View details for Web of Science ID 000343344800004

• Association between vancomycin trough concentration and area under the concentration-time curve in neonates. Antimicrobial agents and chemotherapy Frymoyer, A., Hersh, A. L., El-Komy, M. H., Gaskari, S., Su, F., Drover, D. R., Van Meurs, K. 2014; 58 (11): 6454-6461

  Abstract

  National treatment guidelines for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections recommend targeting a vancomycin 24-hour area under the curve (AUC24)/MIC >400. The range of vancomycin trough concentrations that best predicts AUC24 >400 in neonates is not known. This understanding would help clarify target trough concentrations for neonates when treating MRSA. A retrospective chart review from a level III neonatal intensive care unit was performed to identify neonates treated with vancomycin over a 5-year period. Vancomycin concentrations and clinical covariates were utilized to develop a one-compartment population pharmacokinetic model and examine relationships between trough and AUC24 in study neonates. Monte Carlo simulations were performed to examine the effect of dose, post-menstrual age (PMA), and serum creatinine on trough and AUC24 achievement. A total of 1702 vancomycin concentrations from 249 neonates were available for analysis. The median [interquartile range] PMA was 39 wks [32-42 wks] and weight was 2.9 kg [1.6-3.7kg]. Vancomycin clearance was predicted by weight, PMA, and creatinine. At a trough of 10 mg/L, 89% of study neonates had an AUC24 >400. Monte Carlo simulations demonstrated that troughs ranging from 7-11 mg/L were highly predictive of an AUC24 >400 across a range of PMA, serum creatinine, and vancomycin doses. However, a trough ≥10 mg/L was not readily achieved in most simulated subgroups using routine starting doses. Higher starting doses frequently resulted in troughs >20 mg/L. A vancomycin trough of ∼10 mg/L is likely adequate for most neonates with invasive MRSA infections based on AUC24 considerations. Due to pharmacokinetic and clinical heterogeneity in neonates, consistently achieving this target vancomycin exposure with routine starting doses will be difficult. More robust clinical dosing support tools are needed to help clinicians with dose individualization.

  View details for DOI 10.1128/AAC.03620-14

  View details for PubMedID 25136027

• Inhaled nitric oxide usage in preterm infants in the NICHD Neonatal Research Network: inter-site variation and propensity evaluation. Journal of perinatology Truog, W. E., Nelin, L. D., Das, A., Kendrick, D. E., Bell, E. F., Carlo, W. A., Higgins, R. D., Laptook, A. R., Sanchez, P. J., Shankaran, S., Stoll, B. J., Van Meurs, K. P., Walsh, M. C. 2014; 34 (11): 842-846

  Abstract

  The use of inhaled nitric oxide (iNO) in preterm infants remains controversial. In October 2010, a National Institutes of Health consensus development conference cautioned against use of iNO in preterm infants. This study aims (1) to determine the prevalence and variability in use of iNO in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) before and after the consensus conference and (2) separately, to examine associations between iNO use and severe bronchopulmonary dysplasia (BPD) or death.The NICHD NRN Generic Database collects data including iNO use on very preterm infants. A total of 13 centers contributed data across the time period 2008 to 2011. Infants exposed or not to iNO were compared using logistic regression, which included factors related to risk as well as their likelihood of being exposed to iNO.A total of 4885 infants were assessed between 2008 and 2011; 128 (2.6%) received iNO before day 7, 140 (2.9%) between day 7 and 28, and 47 (1.0%) at >28 days. Center-specific iNO use during 2008 to 2010 ranged from 21.9 to 0.4%; 12 of 13 sites reduced usage and overall NRN iNO usage decreased from 4.6 to 1.6% (P<0.001) in 2011. The use of iNO started between day 7 and day 14 was more prevalent among younger infants with more severe courses in week 1 and associated with increased risk of severe BPD or death (odds ratio 2.24; 95% confidence interval 1.23 to 4.07).The variability and total use of iNO decreased in 2011 compared with 2008 to 2010. iNO administration started at ⩾ day 7 was associated with more severe outcomes compared with infants without iNO exposure.

  View details for DOI 10.1038/jp.2014.105

  View details for PubMedID 24901452

• Incidence, management, and outcomes of cardiovascular insufficiency in critically ill term and late preterm newborn infants. American journal of perinatology Fernandez, E., Watterberg, K. L., Faix, R. G., Yoder, B. A., Walsh, M. C., Lacy, C. B., Osborne, K. A., Das, A., Kendrick, D. E., Stoll, B. J., Poindexter, B. B., Laptook, A. R., Kennedy, K. A., Schibler, K., Bell, E. F., Van Meurs, K. P., Frantz, I. D., Goldberg, R. N., Shankaran, S., Carlo, W. A., Ehrenkranz, R. A., Sanchez, P. J., Higgins, R. D. 2014; 31 (11): 947-956

  Abstract

  The objective of this study was to characterize the incidence, management, and short-term outcomes of cardiovascular insufficiency (CVI) in mechanically ventilated newborns, evaluating four separate prespecified definitions.Multicenter, prospective cohort study of infants ≥34 weeks gestational age (GA) and on mechanical ventilation during the first 72 hours. CVI was prospectively defined as either (1) mean arterial pressure (MAP) < GA; (2) MAP < GA + signs of inadequate perfusion; (3) any therapy for CVI; or (4) inotropic therapy. Short-term outcomes included death, days on ventilation, oxygen, and to full feedings and discharge.Of 647 who met inclusion criteria, 419 (65%) met ≥1 definition of CVI. Of these, 98% received fluid boluses, 36% inotropes, and 17% corticosteroids. Of treated infants, 46% did not have CVI as defined by a MAP < GA ± signs of inadequate perfusion. Inotropic therapy was associated with increased mortality (11.1 vs. 1.3%; p < 0.05).More than half of the infants met at least one definition of CVI. However, almost half of the treated infants met none of the definitions. Inotropic therapy was associated with increased mortality. These findings can help guide the design of future studies of CVI in newborns.

  View details for DOI 10.1055/s-0034-1368089

  View details for PubMedID 24515617

• Prophylactic indomethacin and intestinal perforation in extremely low birth weight infants. Pediatrics Kelleher, J., Salas, A. A., Bhat, R., Ambalavanan, N., Saha, S., Stoll, B. J., Bell, E. F., Walsh, M. C., Laptook, A. R., Sánchez, P. J., Shankaran, S., VanMeurs, K. P., Hale, E. C., Newman, N. S., Ball, M. B., Das, A., Higgins, R. D., Peralta-Carcelen, M., Carlo, W. A. 2014; 134 (5): e1369-77

  Abstract

  Prophylactic indomethacin reduces severe intraventricular hemorrhage but may increase spontaneous intestinal perforation (SIP) in extremely low birth weight (ELBW) infants. Early feedings improve nutritional outcomes but may increase the risk of SIP. Despite their benefits, use of these therapies varies largely by physician preferences in part because of the concern for SIP.This was a cohort study of 15,751 ELBW infants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from 1999 to 2010 who survived beyond 12 hours after birth. The risk of SIP was compared between groups of infants with and without exposure to prophylactic indomethacin and early feeding in unadjusted analyses and in analyses adjusted for center and for risks of SIP.Among infants exposed to prophylactic indomethacin, the risk of SIP did not differ between the indomethacin/early-feeding group compared with the indomethacin/no-early-feeding group (adjusted relative risk [RR] 0.74, 95% confidence interval [CI] 0.49-1.11). The risk of SIP was lower in the indomethacin/early-feeding group compared with the no indomethacin/no-early-feeding group (adjusted RR 0.58, 95% CI 0.37-0.90, P = .0159). Among infants not exposed to indomethacin, early feeding was associated with a lower risk of SIP compared with the no early feeding group (adjusted RR 0.53, 95% CI 0.36-0.777, P = .0011).The combined or individual use of prophylactic indomethacin and early feeding was not associated with an increased risk of SIP in ELBW infants.

  View details for DOI 10.1542/peds.2014-0183

  View details for PubMedID 25349317

• Association between Vancomycin Trough Concentration and Area under the Concentration-Time Curve in Neonates ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Frymoyer, A., Hersh, A. L., El-Komy, M. H., Gaskari, S., Su, F., Drover, D. R., Van Meurs, K. 2014; 58 (11): 6454-6461

  View details for DOI 10.1128/AAC.03620-14

  View details for Web of Science ID 000344158600014

• Inhaled nitric oxide usage in preterm infants in the NICHD neonatal research network: inter-site variation and propensity evaluation JOURNAL OF PERINATOLOGY Truog, W. E., Nelin, L. D., Das, A., Kendrick, D. E., Bell, E. F., Carlo, W. A., Higgins, R. D., Laptook, A. R., Sanchez, P. J., Shankaran, S., Stoll, B. J., Van Meurs, K. P., Walsh, M. C. 2014; 34 (11): 842-846

  View details for DOI 10.1038/jp.2014.105

  View details for Web of Science ID 000344046800009

• Prophylactic Indomethacin and Intestinal Perforation in Extremely Low Birth Weight Infants PEDIATRICS Kelleher, J., Salas, A. A., Bhat, R., Ambalavanan, N., Saha, S., Stoll, B. J., Bell, E. F., Walsh, M. C., Laptook, A. R., Sanchez, P. J., Shankaran, S., VanMeurs, K. P., Hale, E. C., Newman, N. S., Ball, M. B., Das, A., Higgins, R. D., Peralta-Carcelen, M., Carlo, W. A. 2014; 134 (5): E1369-E1377

  View details for DOI 10.1542/peds.2014-0183

  View details for Web of Science ID 000344385900013

• Surgery and neurodevelopmental outcome of very low-birth-weight infants. JAMA pediatrics Morriss, F. H., Saha, S., Bell, E. F., Colaizy, T. T., Stoll, B. J., Hintz, S. R., Shankaran, S., Vohr, B. R., Hamrick, S. E., Pappas, A., Jones, P. M., Carlo, W. A., Laptook, A. R., Van Meurs, K. P., Sánchez, P. J., Hale, E. C., Newman, N. S., Das, A., Higgins, R. D. 2014; 168 (8): 746-754

  Abstract

  Reduced death and neurodevelopmental impairment among infants is a goal of perinatal medicine.To assess the association between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low-birth-weight infants.A retrospective cohort analysis was conducted of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998 through 2009 and evaluated at 18 to 22 months' corrected age. Twenty-two academic neonatal intensive care units participated. Inclusion criteria were birth weight 401 to 1500 g, survival to 12 hours, and availability for follow-up. A total of 12 111 infants were included in analyses.Surgical procedures; surgery also was classified by expected anesthesia type as major (general anesthesia) or minor (nongeneral anesthesia).Multivariable logistic regression analyses planned a priori were performed for the primary outcome of death or neurodevelopmental impairment and for the secondary outcome of neurodevelopmental impairment among survivors. Multivariable linear regression analyses were performed as planned for the adjusted mean scores of the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development, Second Edition, for patients born before 2006.A total of 2186 infants underwent major surgery, 784 had minor surgery, and 9141 infants did not undergo surgery. The risk-adjusted odds ratio of death or neurodevelopmental impairment for all surgery patients compared with those who had no surgery was 1.29 (95% CI, 1.08-1.55). For patients who had major surgery compared with those who had no surgery, the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% CI, 1.24-1.87). Patients classified as having minor surgery had no increased adjusted risk. Among survivors who had major surgery compared with those who had no surgery, the adjusted risk of neurodevelopmental impairment was greater and the adjusted mean Bayley scores were lower.Major surgery in very low-birth-weight infants is independently associated with a greater than 50% increased risk of death or neurodevelopmental impairment and of neurodevelopmental impairment at 18 to 22 months' corrected age. The role of general anesthesia is implicated but remains unproven.

  View details for DOI 10.1001/jamapediatrics.2014.307

  View details for PubMedID 24934607

• Hypothermia Therapy for Neonatal Hypoxic Ischemic Encephalopathy in the State of California. journal of pediatrics Kracer, B., Hintz, S. R., Van Meurs, K. P., Lee, H. C. 2014; 165 (2): 267-273

  Abstract

  To characterize the implementation of hypothermia for neonatal hypoxic ischemic encephalopathy (HIE) in a population-based cohort.Using the California Perinatal Quality Care Collaborative and California Perinatal Transport System linked 2010-2012 datasets, we categorized infants ≥36 weeks' gestation with HIE as receiving hypothermia or normothermia. Sociodemographic and clinical factors were compared, and multivariable logistic regression was used to determine factors associated with hypothermia therapy.There were 238 reported encephalopathy cases in 2010, 280 in 2011, and 311 in 2012. Hypothermia therapy use in newborns with HIE increased from 59% to 73% across the study period, mainly occurring in newborns with mild or moderate encephalopathy. A total of 36 centers provided hypothermia and cared for 94% of infants, with the remaining 6% being cared for at one of 25 other centers. Of the centers providing hypothermia, 12 centers performed hypothermia therapy to more than 20 patients during the 3-year study period, and 24 centers cared for <20 patients receiving hypothermia. In-hospital mortality was 13%, which primarily was associated with the severity of encephalopathy.Our findings highlight an opportunity to explore practice-site variation and to develop quality improvement interventions to assure consistent evidence-based care of term infants with HIE and appropriate application of hypothermia therapy for eligible newborns.

  View details for DOI 10.1016/j.jpeds.2014.04.052

  View details for PubMedID 24929331

• Developmental outcomes of very preterm infants with tracheostomies. journal of pediatrics DeMauro, S. B., D'Agostino, J. A., Bann, C., Bernbaum, J., Gerdes, M., Bell, E. F., Carlo, W. A., D'Angio, C. T., Das, A., Higgins, R., Hintz, S. R., Laptook, A. R., Natarajan, G., Nelin, L., Poindexter, B. B., Sanchez, P. J., Shankaran, S., Stoll, B. J., Truog, W., Van Meurs, K. P., Vohr, B., Walsh, M. C., Kirpalani, H. 2014; 164 (6): 1303-10 e2

  Abstract

  To evaluate the neurodevelopmental outcomes of very preterm (<30 weeks) infants who underwent tracheostomy.Retrospective cohort study from 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network over 10 years (2001-2011). Infants who survived to at least 36 weeks (N = 8683), including 304 infants with tracheostomies, were studied. Primary outcome was death or neurodevelopmental impairment (NDI; a composite of ≥1 of developmental delay, neurologic impairment, profound hearing loss, severe visual impairment) at a corrected age of 18-22 months. Outcomes were compared using multiple logistic regression. We assessed the impact of timing by comparing outcomes of infants who underwent tracheostomy before and after 120 days of life.Tracheostomies were associated with all neonatal morbidities examined and with most adverse neurodevelopmental outcomes. Death or NDI occurred in 83% of infants with tracheostomies and 40% of those without (OR adjusted for center 7.0, 95% CI 5.2-9.5). After adjustment for potential confounders, odds of death or NDI remained higher (OR 3.3, 95% CI 2.4-4.6), but odds of death alone were lower (OR 0.4, 95% CI 0.3-0.7) among infants with tracheostomies. Death or NDI was lower in infants who received their tracheostomies before, rather than after, 120 days of life (aOR 0.5, 95% CI 0.3-0.9).Tracheostomy in preterm infants is associated with adverse developmental outcomes and cannot mitigate the significant risk associated with many complications of prematurity. These data may inform counseling about tracheostomy in this vulnerable population.

  View details for DOI 10.1016/j.jpeds.2013.12.014

  View details for PubMedID 24472229

• Developmental outcomes of very preterm infants with tracheostomies. journal of pediatrics DeMauro, S. B., D'Agostino, J. A., Bann, C., Bernbaum, J., Gerdes, M., Bell, E. F., Carlo, W. A., D'Angio, C. T., Das, A., Higgins, R., Hintz, S. R., Laptook, A. R., Natarajan, G., Nelin, L., Poindexter, B. B., Sanchez, P. J., Shankaran, S., Stoll, B. J., Truog, W., Van Meurs, K. P., Vohr, B., Walsh, M. C., Kirpalani, H. 2014; 164 (6): 1303-1310 e2

  View details for DOI 10.1016/j.jpeds.2013.12.014

  View details for PubMedID 24472229

• Predictors of bronchopulmonary dysplasia or death in premature infants with a patent ductus arteriosus. Pediatric research Chock, V. Y., Punn, R., Oza, A., Benitz, W. E., Van Meurs, K. P., Whittemore, A. S., Behzadian, F., Silverman, N. H. 2014; 75 (4): 570-575

  Abstract

  Background:Preterm infants with a PDA are at risk for death or development of BPD. However, PDA treatment remains controversial. We investigated if PDA treatment and other clinical or echocardiographic (ECHO) factors were associated with the development of death or BPD.Methods:We retrospectively studied clinical and ECHO characteristics of preterm infants with birth weight <1500 g and ECHO diagnosis of a PDA. Logistic regression and classification and regression tree (CART) analyses were performed to assess variables associated with the combined outcome of death or BPD.Results:Of 187 preterm infants with a PDA, 75% were treated with indomethacin or surgery and 25% were managed conservatively. Death or BPD occurred in 80 (43%). Logistic regression found lower gestational age (OR 0.5), earlier year of birth during the study period (OR 0.9), and larger ductal diameter (OR 4.3) were associated with the decision to treat the PDA, while gestational age was the only variable associated with death or BPD (OR 0.6, 95% CI 0.5-0.8).Conclusion:Only lower gestational age and not PDA treatment or ECHO score was associated with the adverse outcome of death or BPD. Further investigation of PDA management strategies and effects on adverse outcomes of prematurity is needed.Pediatric Research (2013); doi:10.1038/pr.2013.253.

  View details for DOI 10.1038/pr.2013.253

  View details for PubMedID 24378897

• Apolipoprotein E genotype and outcome in infants with hypoxic-ischemic encephalopathy. Pediatric research Cotten, C. M., Goldstein, R. F., McDonald, S. A., Goldberg, R. N., Salhab, W. A., Carlo, W. A., Tyson, J. E., Finer, N. N., Walsh, M. C., Ehrenkranz, R. A., Laptook, A. R., Guillet, R., Schibler, K., Van Meurs, K. P., Poindexter, B. B., Stoll, B. J., O'Shea, T. M., Duara, S., Das, A., Higgins, R. D., Shankaran, S. 2014; 75 (3): 424-430

  Abstract

  Background:Adults with the apolipoprotein E (APOE) gene alleles e4 and e2 are at high risk of poor neurological outcome after brain injury. The e4 allele has been associated with cerebral palsy (CP), and the e2 allele has been associated with worse neurological outcome with congenital heart disease. This study was done to test the hypothesis that the APOE genotype is associated with outcome among neonates who survive after hypoxic-ischemic encephalopathy (HIE).Methods:We conducted a cohort study of infants who survived HIE and had 18-22 mo standardized neurodevelopmental evaluations to assess associations between disability and the APOE genotypes e3/e3, e4/-, and e2/-.Results:A total of 139 survivors were genotyped. Of these, 86 (62%) were of the e3/e3, 41 (29%) were of the e4/-, and 14 (10%) were of the e2/- genotypes. One hundred and twenty-nine infants had genotype and follow-up data; 26% had moderate or severe disabilities. Disability prevalence was 30 and 19% among those with and without the e3/e3 genotype, 25 and 26% among those with and without the e2 allele, and 18 and 29% among those with and without the e4 allele, respectively. None of the differences were statistically significant. CP prevalence was also similar among genotype groups.Conclusion:Disability was not associated with the APOE genotype in this cohort of HIE survivors.

  View details for DOI 10.1038/pr.2013.235

  View details for PubMedID 24322171

• Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials. Trials Sood, B. G., Keszler, M., Garg, M., Klein, J. M., Ohls, R., Ambalavanan, N., Cotten, C. M., Malian, M., Sanchez, P. J., Lakshminrusimha, S., Nelin, L. D., Van Meurs, K. P., Bara, R., Saha, S., Das, A., Wallace, D., Higgins, R. D., Shankaran, S. 2014; 15: 486-?

  Abstract

  Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF.Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations.No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported.These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment.CLINICALTRIALS.GOV: Pilot one: NCT number: 00598429 registered on 10 January 2008. Last updated: 3 February 2011. Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013.

  View details for DOI 10.1186/1745-6215-15-486

  View details for PubMedID 25496504

  View details for PubMedCentralID PMC4414424

• Impact of early surfactant and inhaled nitric oxide therapies on outcomes in term/late preterm neonates with moderate hypoxic respiratory failure. Journal of perinatology Konduri, G. G., Sokol, G. M., Van Meurs, K. P., Singer, J., Ambalavanan, N., Lee, T., Solimano, A. 2013; 33 (12): 944-949

  Abstract

  Objective:We conducted a post-hoc analysis of early inhaled nitric oxide (iNO)-randomized controlled trial data to identify associations pertinent to the management of moderate hypoxic respiratory failure in term/late preterm infants.Study design:Univariate and multivariate logistic regression analyses were used to determine risk factors for the progression of respiratory failure and extracorporeal membrane oxygenation (ECMO)/death.Result:Among the 299 enrolled infants, oxygenation index (OI) <20 at enrollment (odds ratio 0.52, confidence interval (CI) 0.27 to 0.97) and surfactant use before randomization (odds ratio 0.47, CI 0.24 to 0.91) were associated with decreased ECMO/death rates. Early surfactant use for respiratory distress syndrome, perinatal aspiration syndrome and pneumonia/sepsis was associated with lower risk of ECMO/death (P<0.001). Early iNO (OI 15 to 25) decreased the progression of respiratory failure to OI >30 (P=0.002) and to composite outcome of OI >30 or ECMO/death (P=0.02).Conclusion:This post-hoc analysis suggests that early use of surfactant and iNO in moderate respiratory failure is associated with improved outcomes.Journal of Perinatology advance online publication, 18 July 2013; doi:10.1038/jp.2013.83.

  View details for DOI 10.1038/jp.2013.83

  View details for PubMedID 23867958

• Serum Tocopherol Levels in Very Preterm Infants After a Single Dose of Vitamin E at Birth PEDIATRICS Bell, E. F., Hansen, N. I., Brion, L. P., Ehrenkranz, R. A., Kennedy, K. A., Walsh, M. C., Shankaran, S., Acarregui, M. J., Johnson, K. J., Hale, E. C., Messina, L. A., Crawford, M. M., Laptook, A. R., Goldberg, R. N., Van Meurs, K. P., Carlo, W. A., Poindexter, B. B., Faix, R. G., Carlton, D. P., Watterberg, K. L., Ellsbury, D. L., Das, A., Higgins, R. D. 2013; 132 (6): E1626-E1633

  View details for DOI 10.1542/peds.2013-1684

  View details for Web of Science ID 000329163900021

  View details for PubMedID 24218460

• Serum tocopherol levels in very preterm infants after a single dose of vitamin E at birth. Pediatrics Bell, E. F., Hansen, N. I., Brion, L. P., Ehrenkranz, R. A., Kennedy, K. A., Walsh, M. C., Shankaran, S., Acarregui, M. J., Johnson, K. J., Hale, E. C., Messina, L. A., Crawford, M. M., Laptook, A. R., Goldberg, R. N., Van Meurs, K. P., Carlo, W. A., Poindexter, B. B., Faix, R. G., Carlton, D. P., Watterberg, K. L., Ellsbury, D. L., Das, A., Higgins, R. D. 2013; 132 (6): e1626-33

  Abstract

  Our aim was to examine the impact of a single enteral dose of vitamin E on serum tocopherol levels. The study was undertaken to see whether a single dose of vitamin E soon after birth can rapidly increase the low α-tocopherol levels seen in very preterm infants. If so, this intervention could be tested as a means of reducing the risk of intracranial hemorrhage.Ninety-three infants <27 weeks' gestation and <1000 g were randomly assigned to receive a single dose of vitamin E or placebo by gastric tube within 4 hours of birth. The vitamin E group received 50 IU/kg of vitamin E as dl-α-tocopheryl acetate (Aquasol E). The placebo group received sterile water. Blood samples were taken for measurement of serum tocopherol levels by high-performance liquid chromatography before dosing and 24 hours and 7 days after dosing.Eighty-eight infants received the study drug and were included in the analyses. The α-tocopherol levels were similar between the groups at baseline but higher in the vitamin E group at 24 hours (median 0.63 mg/dL vs. 0.42 mg/dL, P = .003) and 7 days (2.21 mg/dL vs 1.86 mg/dL, P = .04). There were no differences between groups in γ-tocopherol levels. At 24 hours, 30% of vitamin E infants and 62% of placebo infants had α-tocopherol levels <0.5 mg/dL.A 50-IU/kg dose of vitamin E raised serum α-tocopherol levels, but to consistently achieve α-tocopherol levels >0.5 mg/dL, a higher dose or several doses of vitamin E may be needed.

  View details for DOI 10.1542/peds.2013-1684

  View details for PubMedID 24218460

• Blood stream infection is associated with altered heptavalent pneumococcal conjugate vaccine immune responses in very low birth weight infants JOURNAL OF PERINATOLOGY Wynn, J. L., Li, L., Cotten, C. M., Phelps, D. L., Shankaran, S., Goldberg, R. N., Carlo, W. A., Van Meurs, K., Das, A., Vohr, B. R., Higgins, R. D., Stoll, B. J., D'Angio, C. T. 2013; 33 (8): 613-618

  Abstract

  OBJECTIVE:Sepsis in older children and adults modifies immune system function. We compared serotype-specific antibody responses to heptavalent pneumococcal conjugate vaccine (PCV7) in very low birth weight infants (<1500 g,VLBWs) with and without blood stream infection (BSI) during their birth hospitalization.STUDY DESIGN:Retrospective analysis of prospectively collected data for the Neonatal Research Network study of PCV7 responses among VLBWs. Infants received PCV7 at 2, 4 and 6 months after birth with blood drawn 4 to 6 weeks after third dose. Serotype antibodies were compared between infants with or without a history of BSI. Regression models were constructed with BW groups and other confounding factors identified in the primary study.RESULT:In all, 244 infants completed the vaccine series and had serum antibody available; 82 had BSI. After adjustment, BSI was not associated with reduced odds of serum antibody 0.35 μg ml(-1).CONCLUSION:BSI was not associated with reduced odds of World Health Organization-defined protective PCV7 responses in VLBWs.Journal of Perinatology advance online publication, 31 January 2013; doi:10.1038/jp.2013.5.

  View details for DOI 10.1038/jp.2013.5

  View details for Web of Science ID 000322442700008

  View details for PubMedID 23370608

• Ten-year review of major birth defects in VLBW infants. Pediatrics Adams-Chapman, I., Hansen, N. I., Shankaran, S., Bell, E. F., Boghossian, N. S., Murray, J. C., Laptook, A. R., Walsh, M. C., Carlo, W. A., Sánchez, P. J., Van Meurs, K. P., Das, A., Hale, E. C., Newman, N. S., Ball, M. B., Higgins, R. D., Stoll, B. J. 2013; 132 (1): 49-61

  Abstract

  OBJECTIVE:Birth defects (BDs) are an important cause of infant mortality and disproportionately occur among low birth weight infants. We determined the prevalence of BDs in a cohort of very low birth weight (VLBW) infants cared for at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers over a 10-year period and examined the relationship between anomalies, neonatal outcomes, and surgical care.METHODS:Infant and maternal data were collected prospectively for infants weighing 401 to 1500 g at NRN sites between January 1, 1998, and December 31, 2007. Poisson regression models were used to compare risk of outcomes for infants with versus without BDs while adjusting for gestational age and other characteristics.RESULTS:A BD was present in 1776 (4.8%) of the 37 262 infants in our VLBW cohort. Yearly prevalence of BDs increased from 4.0% of infants born in 1998 to 5.6% in 2007, P < .001. Mean gestational age overall was 28 weeks, and mean birth weight was 1007 g. Infants with BDs were more mature but more likely to be small for gestational age compared with infants without BDs. Chromosomal and cardiovascular anomalies were most frequent with each occurring in 20% of affected infants. Mortality was higher among infants with BDs (49% vs 18%; adjusted relative risk: 3.66 [95% confidence interval: 3.41-3.92]; P < .001) and varied by diagnosis. Among those surviving >3 days, more infants with BDs underwent major surgery (48% vs 13%, P < .001).CONCLUSIONS:Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants.

  View details for DOI 10.1542/peds.2012-3111

  View details for PubMedID 23733791

• Use of antihypotensive therapies in extremely preterm infants. Pediatrics Batton, B., Li, L., Newman, N. S., Das, A., Watterberg, K. L., Yoder, B. A., Faix, R. G., Laughon, M. M., Stoll, B. J., Van Meurs, K. P., Carlo, W. A., Poindexter, B. B., Bell, E. F., Sánchez, P. J., Ehrenkranz, R. A., Goldberg, R. N., Laptook, A. R., Kennedy, K. A., Frantz, I. D., Shankaran, S., Schibler, K., Higgins, R. D., Walsh, M. C. 2013; 131 (6): e1865-73

  Abstract

  To investigate the relationships among blood pressure (BP) values, antihypotensive therapies, and in-hospital outcomes to identify a BP threshold below which antihypotensive therapies may be beneficial.Prospective observational study of infants 23(0/7) to 26(6/7) weeks' gestational age. Hourly BP values and antihypotensive therapy use in the first 24 hours were recorded. Low BP was investigated by using 15 definitions. Outcomes were examined by using regression analysis controlling for gestational age, the number of low BP values, and illness severity.Of 367 infants enrolled, 203 (55%) received at least 1 antihypotensive therapy. Treated infants were more likely to have low BP by any definition (P < .001), but for the 15 definitions of low BP investigated, therapy was not prescribed to 3% to 49% of infants with low BP and, paradoxically, was administered to 28% to 41% of infants without low BP. Treated infants were more likely than untreated infants to develop severe retinopathy of prematurity (15% vs 8%, P = .03) or severe intraventricular hemorrhage (22% vs 11%, P < .01) and less likely to survive (67% vs 78%, P = .02). However, with regression analysis, there were no significant differences between groups in survival or in-hospital morbidity rates.Factors other than BP contributed to the decision to use antihypotensive therapies. Infant outcomes were not improved with antihypotensive therapy for any of the 15 definitions of low BP investigated.

  View details for DOI 10.1542/peds.2012-2779

  View details for PubMedID 23650301

• Early Sepsis Does Not Increase the Risk of Late Sepsis in Very Low Birth Weight Neonates JOURNAL OF PEDIATRICS Wynn, J. L., Hansen, N. I., Das, A., Cotten, C. M., Goldberg, R. N., Sanchez, P. J., Bell, E. F., Van Meurs, K. P., Carlo, W. A., Laptook, A. R., Higgins, R. D., Benjamin, D. K., Stoll, B. J. 2013; 162 (5): 942-U92

  Abstract

  To examine whether preterm very low birth weight (VLBW) infants have an increased risk of late-onset sepsis (LOS) following early-onset sepsis (EOS).Retrospective analysis of VLBW infants (401-1500 g) born September 1998 through December 2009 who survived >72 hours and were cared for within the National Institute of Child Health and Human Development Neonatal Research Network. Sepsis was defined by growth of bacteria or fungi in a blood culture obtained ≤72 hours of birth (EOS) or >72 hours (LOS) and antimicrobial therapy for ≥5 days or death <5 days while receiving therapy. Regression models were used to assess risk of death or LOS by 120 days and LOS by 120 days among survivors to discharge or 120 days, adjusting for gestational age and other covariates.Of 34 396 infants studied, 504 (1.5%) had EOS. After adjustment, risk of death or LOS by 120 days did not differ overall for infants with EOS compared with those without EOS [risk ratio (RR): 0.99 (0.89-1.09)] but was reduced in infants born at <25 weeks gestation [RR: 0.87 (0.76-0.99), P = .048]. Among survivors, no difference in LOS risk was found overall for infants with versus without EOS [RR: 0.88 (0.75-1.02)], but LOS risk was reduced in infants with birth weight 401-750 g who had EOS [RR: 0.80 (0.64-0.99), P = .047].Risk of LOS after EOS was not increased in VLBW infants. Surprisingly, risk of LOS following EOS appeared to be reduced in the smallest, most premature infants, underscoring the need for age-specific analyses of immune function.

  View details for DOI 10.1016/j.jpeds.2012.11.027

  View details for Web of Science ID 000317836300016

  View details for PubMedID 23295144

• Therapeutic hypothermia during neonatal transport: data from the California Perinatal Quality Care Collaborative (CPQCC) and California Perinatal Transport System (CPeTS) for 2010 JOURNAL OF PERINATOLOGY Akula, V. P., Gould, J. B., DAVIS, A. S., Hackel, A., Oehlert, J., Van Meurs, K. P. 2013; 33 (3): 194-197

  Abstract

  To evaluate cooling practices and neonatal outcomes in the state of California during 2010 using the California Perinatal Quality Care Collaborative and California Perinatal Transport System databases.Database analysis to determine the perinatal and neonatal demographics and outcomes of neonates cooled in transport or after admission to a cooling center.Of the 223 infants receiving therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE) in California during 2010, 69% were cooled during transport. Despite the frequent use of cooling in transport, cooling center admission temperature was in the target range (33-34 °C) in only 62 (44%). Among cooled infants, gestational age was <35 weeks in 10 (4.5%). For outborn and transported infants, chronologic age at the time of cooling initiation was >6 h in 20 (11%). When initiated at the birth hospital, cooling was initiated at <6 h of age in 131 (92.9%).More than half of the infants cooled in transport do not achieve target temperature by the time of arrival at the cooling center. The use of cooling devices may improve temperature regulation on transport.

  View details for DOI 10.1038/jp.2012.144

  View details for Web of Science ID 000315664700006

  View details for PubMedID 23223159

• Efficacy of phototherapy devices and outcomes among extremely low birth weight infants: multi-center observational study JOURNAL OF PERINATOLOGY Morris, B. H., TYSON, J. E., Stevenson, D. K., Oh, W., Phelps, D. L., O'Shea, T. M., MCDAVID, G. E., Van Meurs, K. P., Vohr, B. R., Grisby, C., Yao, Q., Kandefer, S., Wallace, D., Higgins, R. D. 2013; 33 (2): 126-133

  Abstract

  Evaluate the efficacy of phototherapy (PT) devices and the outcomes of extremely premature infants treated with those devices.This substudy of the National Institute of Child Health and Human Development Neonatal Research Network PT trial included 1404 infants treated with a single type of PT device during the first 24±12 h of treatment. The absolute (primary outcome) and relative decrease in total serum bilirubin (TSB) and other measures were evaluated. For infants treated with one PT type during the 2-week intervention period (n=1223), adjusted outcomes at discharge and 18 to 22 months corrected age were determined.In the first 24 h, the adjusted absolute (mean (±s.d.)) and relative (%) decrease in TSB (mg dl(-1)) were: light-emitting diodes (LEDs) -2.2 (±3), -22%; Spotlights -1.7 (±2), -19%; Banks -1.3 (±3), -8%; Blankets -0.8 (±3), -1%; (P<0.0002). Some findings at 18 to 22 months differed between groups.LEDs achieved the greatest initial absolute reduction in TSB but were similar to Spots in the other performance measures. Long-term effects of PT devices in extremely premature infants deserve rigorous evaluation.

  View details for DOI 10.1038/jp.2012.39

  View details for Web of Science ID 000314434200008

  View details for PubMedID 22499082

• HYPOXIC ISCHEMIC ENCEPHALOPATHY IN THE COOLING ERA: SHORT TERM OUTCOMES IN THE STATE OF CALIFORNIA Western Regional Meeting of the American-Federation-for-Medical-Research Kracer, B., Hintz, S. R., Van Meurs, K. P., Lee, H. C. LIPPINCOTT WILLIAMS & WILKINS. 2013: 166–66

  View details for Web of Science ID 000312657900204

• Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION Shankaran, S., Barnes, P. D., Hintz, S. R., Laptook, A. R., Zaterka-Baxter, K. M., McDonald, S. A., Ehrenkranz, R. A., Walsh, M. C., Tyson, J. E., Donovan, E. F., Goldberg, R. N., Bara, R., Das, A., Finer, N. N., Sanchez, P. J., Poindexter, B. B., Van Meurs, K. P., Carlo, W. A., Stoll, B. J., Duara, S., Guillet, R., Higgins, R. D. 2012; 97 (6): F398-F404

  Abstract

  The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic-ischaemic encephalopathy treated with hypothermia.Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18-22 months of age.Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability.Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18-22 months following hypothermia for neonatal encephalopathy.

  View details for DOI 10.1136/archdischild-2011-301524

  View details for Web of Science ID 000311022800003

  View details for PubMedID 23080477

• Does aggressive phototherapy increase mortality while decreasing profound impairment among the smallest and sickest newborns? JOURNAL OF PERINATOLOGY Tyson, J. E., Pedroza, C., Langer, J., Green, C., Morris, B., Stevenson, D., Van Meurs, K. P., Oh, W., Phelps, D., O'Shea, M., MCDAVID, G. E., Grisby, C., Higgins, R. 2012; 32 (9): 677-684

  Abstract

  Aggressive phototherapy (AgPT) is widely used and assumed to be safe and effective for even the most immature infants. We assessed whether the benefits and hazards for the smallest and sickest infants differed from those for other extremely low-birth-weight (ELBW; ≤ 1000 g) infants in our Neonatal Research Network trial, the only large trial of AgPT.ELBW infants (n=1974) were randomized to AgPT or conservative phototherapy at age 12 to 36 h. The effect of AgPT on outcomes (death, impairment, profound impairment, death or impairment (primary outcome), and death or profound impairment) at 18 to 22 months of corrected age was related to BW stratum (501 to 750 g; 751 to 1000 g) and baseline severity of illness using multilevel regression equations. The probability of benefit and of harm was directly assessed with Bayesian analyses.Baseline illness severity was well characterized using mechanical ventilation and FiO(2) at 24 h age. Among mechanically ventilated infants ≤ 750 g BW (n=684), a reduction in impairment and in profound impairment was offset by higher mortality (P for interaction <0.05) with no significant effect on composite outcomes. Conservative Bayesian analyses of this subgroup identified a 99% (posterior) probability that AgPT increased mortality, a 97% probability that AgPT reduced impairment, and a 99% probability that AgPT reduced profound impairment.Findings from the only large trial of AgPT suggest that AgPT may increase mortality while reducing impairment and profound impairment among the smallest and sickest infants. New approaches to reduce their serum bilirubin need development and rigorous testing.

  View details for DOI 10.1038/jp.2012.64

  View details for Web of Science ID 000308278000006

  View details for PubMedID 22652561

• Empiric Antifungal Therapy and Outcomes in Extremely Low Birth Weight Infants with Invasive Candidiasis JOURNAL OF PEDIATRICS Greenberg, R. G., Benjamin, D. K., Gantz, M. G., Cotten, C. M., Stoll, B. J., Walsh, M. C., Sanchez, P. J., Shankaran, S., Das, A., Higgins, R. D., Miller, N. A., Auten, K. J., Walsh, T. J., Laptook, A. R., Carlo, W. A., Kennedy, K. A., Finer, N. N., Duara, S., Schibler, K., Ehrenkranz, R. A., Van Meurs, K. P., Frantz, I. D., Phelps, D. L., Poindexter, B. B., Bell, E. F., O'Shea, T. M., Watterberg, K. L., Goldberg, R. N., Smith, P. B. 2012; 161 (2): 264-?

  Abstract

  To assess the impact of empiric antifungal therapy for invasive candidiasis on subsequent outcomes in premature infants.This was a cohort study of infants with a birth weight ≤ 1000 g receiving care at Neonatal Research Network sites. All infants had at least one positive culture for Candida. Empiric antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of empiric antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI).A total of 136 infants developed invasive candidiasis. The incidence of death or NDI was lower in infants who received empiric antifungal therapy (19 of 38; 50%) compared with those who had not (55 of 86; 64%; OR, 0.27; 95% CI, 0.08-0.86). There was no significant difference between the groups for any single outcome or other combined outcomes.Empiric antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.

  View details for DOI 10.1016/j.jpeds.2012.01.053

  View details for Web of Science ID 000306693800020

  View details for PubMedID 22424952

  View details for PubMedCentralID PMC3380169

• Feasibility Study of Early Blood Pressure Management in Extremely Preterm Infants JOURNAL OF PEDIATRICS Batton, B. J., Li, L., Newman, N. S., Das, A., Watterberg, K. L., Yoder, B. A., Faix, R. G., Laughon, M. M., Van Meurs, K. P., Carlo, W. A., Higgins, R. D., Walsh, M. C. 2012; 161 (1): 65-?

  Abstract

  To assess the feasibility of a randomized placebo controlled trial (RCT) of blood pressure (BP) management for extremely preterm infants.This was a prospective pilot RCT of infants 23-0/7 to 26-6/7 weeks gestation who had protocol-defined low BP in the first 24 postnatal hours. Enrolled infants were administered a study infusion (dopamine or placebo) and a study syringe medication (hydrocortisone or placebo).Of the 366 infants screened, 119 (33%) had low BP, 58 (16%) met all entry criteria, and 10 (3%) were enrolled. A total of 161 infants (44%) were ineligible because they received early indomethacin. Only 17% of eligible infants were enrolled. Problems with consent included insufficient time, parent unavailability, and physician unwillingness to enroll critically ill infants. Two infants were withdrawn from the study because of the potential risk of intestinal perforation with simultaneous administration of hydrocortisone and indomethacin.This pilot RCT was not feasible because of low eligibility and consent rates. An RCT of BP management for extremely preterm infants may require a waiver of consent for research in emergency care. The frequent use of early indomethacin and the associated risk of intestinal perforation when used with hydrocortisone may limit future investigations to only inotropic medications.

  View details for DOI 10.1016/j.jpeds.2012.01.014

  View details for Web of Science ID 000305753700016

  View details for PubMedID 22336574

• Outcome Trajectories in Extremely Preterm Infants PEDIATRICS Ambalavanan, N., Carlo, W. A., Tyson, J. E., Langer, J. C., Walsh, M. C., Parikh, N. A., Das, A., Van Meurs, K. P., Shankaran, S., Stoll, B. J., Higgins, R. D. 2012; 130 (1): E115-E125

  Abstract

  Methods are required to predict prognosis with changes in clinical course. Death or neurodevelopmental impairment in extremely premature neonates can be predicted at birth/admission to the ICU by considering gender, antenatal steroids, multiple birth, birth weight, and gestational age. Predictions may be improved by using additional information available later during the clinical course. Our objective was to develop serial predictions of outcome by using prognostic factors available over the course of NICU hospitalization.Data on infants with birth weight ≤ 1.0 kg admitted to 18 large academic tertiary NICUs during 1998-2005 were used to develop multivariable regression models following stepwise variable selection. Models were developed by using all survivors at specific times during hospitalization (in delivery room [n = 8713], 7-day [n = 6996], 28-day [n = 6241], and 36-week postmenstrual age [n = 5118]) to predict death or death/neurodevelopmental impairment at 18 to 22 months.Prediction of death or neurodevelopmental impairment in extremely premature infants is improved by using information available later during the clinical course. The importance of birth weight declines, whereas the importance of respiratory illness severity increases with advancing postnatal age. The c-statistic in validation models ranged from 0.74 to 0.80 with misclassification rates ranging from 0.28 to 0.30.Dynamic models of the changing probability of individual outcome can improve outcome predictions in preterm infants. Various current and future scenarios can be modeled by input of different clinical possibilities to develop individual "outcome trajectories" and evaluate impact of possible morbidities on outcome.

  View details for DOI 10.1542/peds.2011-3693

  View details for Web of Science ID 000305905900016

  View details for PubMedID 22689874

• Cerebral Autoregulation in Neonates with a Hemodynamically Significant Patent Ductus Arteriosus JOURNAL OF PEDIATRICS Chock, V. Y., Ramamoorthy, C., Van Meurs, K. P. 2012; 160 (6)

  Abstract

  Very low birth weight (VLBW) preterm infants are at risk for impaired cerebral autoregulation with pressure passive blood flow. Fluctuations in cerebral perfusion may occur in infants with a hemodynamically significant patent ductus arteriosus (hsPDA), especially during ductal closure. Our goal was to compare cerebral autoregulation using near-infrared spectroscopy in VLBW infants treated for an hsPDA.This prospective observational study enrolled 28 VLBW infants with an hsPDA diagnosed by echocardiography and 12 control VLBW infants without an hsPDA. Near-infrared spectroscopy cerebral monitoring was applied during conservative treatment, indomethacin treatment, or surgical ligation. A cerebral pressure passivity index (PPI) was calculated, and PPI differences were compared using a mixed-effects regression model. Cranial ultrasound and magnetic resonance imaging data were also assessed.Infants with surgically ligated hsPDAs were more likely to have had a greater PPI within 2 hours following ligation than were those treated with conservative management (P=.04) or indomethacin (P=.0007). These differences resolved by 6 hours after treatment.Cerebral autoregulation was better preserved after indomethacin treatment of an hsPDA compared with surgical ligation. Infants requiring surgical hsPDA ligation may be at increased risk for cerebral pressure passivity in the 6 hours following surgery.

  View details for DOI 10.1016/j.jpeds.2011.11.054

  View details for Web of Science ID 000304377300012

  View details for PubMedID 22226574

• Therapeutic Hypothermia during Neonatal Transport: Current Practices in California AMERICAN JOURNAL OF PERINATOLOGY Akula, V. P., Davis, A. S., Gould, J. B., Van Meurs, K. 2012; 29 (5): 319-326

  Abstract

  Therapeutic hypothermia initiated at <6 hours of age reduces death and disability in newborns ≥ 36 weeks' gestation with moderate to severe hypoxic ischemic encephalopathy. Given the limited therapeutic window, cooling during transport becomes a necessity. Our goal was to describe the current practice of therapeutic hypothermia during transport used in the state of California. All level III neonatal intensive care units (NICUs) were contacted to identify those units providing therapeutic hypothermia. An electronic questionnaire was sent to obtain basic information. Responses were received from 28 (100%) NICUs performing therapeutic hypothermia; 26 NICUs were cooling newborns and two were in the process of program development. Eighteen (64%) centers had cooled a patient in transport, six had not yet cooled in transport, and two do not plan to cool in transport. All 18 centers use passive cooling, except for two that perform both passive and active cooling, and 17 of 18 centers recommend initiation of cooling at the referral hospital. Reported difficulties include overcooling, undercooling, and bradycardia. Cooling on transport is being performed by majority of NICUs providing therapeutic hypothermia. Clinical protocols and devices for cooling in transport are essential to ensure safety and efficacy.

  View details for DOI 10.1055/s-0031-1295661

  View details for Web of Science ID 000302962200001

  View details for PubMedID 22143969

• The effects of aggressive vs. conservative phototherapy on the brainstem auditory evoked responses of extremely-low-birth-weight infants PEDIATRIC RESEARCH Lasky, R. E., Church, M. W., Orlando, M. S., Morris, B. H., Parikh, N. A., Tyson, J. E., McDavid, G. E., Oh, W., Stevenson, D. K., Van Meurs, K. P., Guillet, R., Phelps, D. L. 2012; 71 (1): 77-84

  Abstract

  This study was a two-center, stratified, parallel-group randomized trial comparing the effects of aggressive vs. conservative phototherapy on brainstem auditory evoked response (BAER) latencies in infants with extremely low birth weight (ELBW, ≤ 1,000 g).BAER latencies of 751-1,000 g birth-weight infants were shorter by 0.37 ms (95% confidence interval (CI) = 0.02, 0.73) for wave V, 0.39 ms (0.08, 0.70) for wave III, and 0.33 ms (0.01, 0.65) for wave I after aggressive phototherapy at one center. Interwave intervals did not differ significantly. Similar nonsignificant trends were recorded for 501-750 g birth-weight infants. At the other participating center, no significant differences were recorded, cautioning against overgeneralizing these results.The effects of bilirubin on the auditory pathway in ELBW infants depend on a complex interaction of bilirubin exposure, newborn characteristics, and clinical management.Aggressive phototherapy was initiated sooner and continued at lower bilirubin levels than conservative phototherapy. A total of 174 ELBW infants were enrolled in the study; 111 infants were successfully tested at 35 weeks postmenstrual age (PMA); 57 died; and 6 were not successfully tested.

  View details for DOI 10.1038/pr.2011.17

  View details for Web of Science ID 000303453600012

  View details for PubMedID 22289854

• Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy. Archives of disease in childhood 2012

  Abstract

  OBJECTIVE: The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic-ischaemic encephalopathy treated with hypothermia. DESIGN AND PATIENTS: Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18-22 months of age. RESULTS: Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability. CONCLUSIONS: Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18-22 months following hypothermia for neonatal encephalopathy.

  View details for DOI 10.1136/archdischild-2011-301524

  View details for PubMedID 22806232

• Association of Antenatal Corticosteroids With Mortality and Neurodevelopmental Outcomes Among Infants Born at 22 to 25 Weeks' Gestation JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Carlo, W. A., McDonald, S. A., Fanaroff, A. A., Vohr, B. R., Stoll, B. J., Ehrenkranz, R. A., Andrews, W. W., Wallace, D., Das, A., Bell, E. F., Walsh, M. C., Laptook, A. R., Shankaran, S., Poindexter, B. B., Hale, E. C., Newman, N. S., Davis, A. S., Schibler, K., Kennedy, K. A., Sanchez, P. J., Van Meurs, K. P., Goldberg, R. N., Watterberg, K. L., Faix, R. G., Frantz, I. D., Higgins, R. D. 2011; 306 (21): 2348-2358

  Abstract

  Current guidelines, initially published in 1995, recommend antenatal corticosteroids for mothers with preterm labor from 24 to 34 weeks' gestational age, but not before 24 weeks due to lack of data. However, many infants born before 24 weeks' gestation are provided intensive care.To determine if use of antenatal corticosteroids is associated with improvement in major outcomes for infants born at 22 and 23 weeks' gestation.Cohort study of data collected prospectively on inborn infants with a birth weight between 401 g and 1000 g (N = 10,541) born at 22 to 25 weeks' gestation between January 1, 1993, and December 31, 2009, at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4924 (86.5%) of the infants born between 1993 and 2008 who survived to 18 to 22 months. Logistic regression models generated adjusted odds ratios (AORs), controlling for maternal and neonatal variables.Mortality and neurodevelopmental impairment at 18 to 22 months' corrected age.Death or neurodevelopmental impairment at 18 to 22 months was significantly lower for infants who had been exposed to antenatal corticosteroids and were born at 23 weeks' gestation (83.4% with exposure to antenatal corticosteroids vs 90.5% without exposure; AOR, 0.58 [95% CI, 0.42-0.80]), at 24 weeks' gestation (68.4% with exposure to antenatal corticosteroids vs 80.3% without exposure; AOR, 0.62 [95% CI, 0.49-0.78]), and at 25 weeks' gestation (52.7% with exposure to antenatal corticosteroids vs 67.9% without exposure; AOR, 0.61 [95% CI, 0.50-0.74]) but not in those infants born at 22 weeks' gestation (90.2% with exposure to antenatal corticosteroids vs 93.1% without exposure; AOR, 0.80 [95% CI, 0.29-2.21]). If the mothers had received antenatal corticosteroids, the following events occurred significantly less in infants born at 23, 24, and 25 weeks' gestation: death by 18 to 22 months; hospital death; death, intraventricular hemorrhage, or periventricular leukomalacia; and death or necrotizing enterocolitis. For infants born at 22 weeks' gestation, the only outcome that occurred significantly less was death or necrotizing enterocolitis (73.5% with exposure to antenatal corticosteroids vs 84.5% without exposure; AOR, 0.54 [95% CI, 0.30-0.97]).Among infants born at 23 to 25 weeks' gestation, antenatal exposure to corticosteroids compared with nonexposure was associated with a lower rate of death or neurodevelopmental impairment at 18 to 22 months.

  View details for Web of Science ID 000297680300020

  View details for PubMedID 22147379

• Inhaled Nitric Oxide in Preterm Infants: An Individual-Patient Data Meta-analysis of Randomized Trials PEDIATRICS Askie, L. M., Ballard, R. A., Cutter, G. R., Dani, C., Elbourne, D., Field, D., Hascoet, J., Hibbs, A. M., Kinsella, J. P., Mercier, J., Rich, W., Schreiber, M. D., Wongsiridej, P. (., Subhedar, N. V., Van Meurs, K. P., Voysey, M., Barrington, K., Ehrenkranz, R. A., Finer, N. N. 2011; 128 (4): 729-739

  Abstract

  Inhaled nitric oxide (iNO) is an effective therapy for pulmonary hypertension and hypoxic respiratory failure in term infants. Fourteen randomized controlled trials (n = 3430 infants) have been conducted on preterm infants at risk for chronic lung disease (CLD). The study results seem contradictory.Individual-patient data meta-analysis included randomized controlled trials of preterm infants (<37 weeks' gestation). Outcomes were adjusted for trial differences and correlation between siblings.Data from 3298 infants in 12 trials (96%) were analyzed. There was no statistically significant effect of iNO on death or CLD (59% vs 61%: relative risk [RR]: 0.96 [95% confidence interval (CI): 0.92-1.01]; P = .11) or severe neurologic events on imaging (25% vs 23%: RR: 1.12 [95% CI: 0.98-1.28]; P = .09). There were no statistically significant differences in iNO effect according to any of the patient-level characteristics tested. In trials that used a starting iNO dose of >5 vs ≤ 5 ppm there was evidence of improved outcome (interaction P = .02); however, these differences were not observed at other levels of exposure to iNO. This result was driven primarily by 1 trial, which also differed according to overall dose, duration, timing, and indication for treatment; a significant reduction in death or CLD (RR: 0.85 [95% CI: 0.74-0.98]) was found.Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended. The use of a higher starting dose might be associated with improved outcome, but because there were differences in the designs of these trials, it requires further examination.

  View details for DOI 10.1542/peds.2010-2725

  View details for Web of Science ID 000295406800050

  View details for PubMedID 21930540

• Is phototherapy exposure associated with better or worse outcomes in 501-to 1000-g-birth-weight infants? ACTA PAEDIATRICA Hintz, S. R., Stevenson, D. K., Yao, Q., Wong, R. J., Das, A., Van Meurs, K. P., Morris, B. H., Tyson, J. E., Oh, W., Poole, W. K., Phelps, D. L., McDavid, G. E., Grisby, C., Higgins, R. D. 2011; 100 (7): 960-965

  Abstract

   To compare risk-adjusted outcomes at 18- to 22-month-corrected age for extremely low birth weight (ELBW) infants who never received phototherapy (NoPTx) to those who received any phototherapy (PTx) in the NICHD Neonatal Research Network randomized trial of Aggressive vs. Conservative Phototherapy.Outcomes at 18 to 22-month-corrected age included death, neurodevelopmental impairment (NDI) and Bayley Scales Mental Developmental Index (MDI). Regression models evaluated the independent association of PTx with adverse outcomes controlling for centre and other potentially confounding variables.Of 1972 infants, 216 were NoPTx and 1756 were PTx. For the entire 501- to 1000-g-BW cohort, PTx was not independently associated with death or NDI (OR 0.85, 95% CI: 0.60-1.20), death or adverse neurodevelopmental endpoints. However, among infants 501-750 g BW, the rate of significant developmental impairment with MDI < 50 was significantly higher for NoPTx (29%) than PTx (12%) (p = 0.004).Phototherapy did not appear to be independently associated with death or NDI for the overall ELBW group. Whether PTx increases mortality could not be excluded because of bias from deaths before reaching conservative treatment threshold. The higher rate of MDI < 50 in the 501- to 750-g-BW NoPTx group is concerning and consistent with NRN Trial results.

  View details for DOI 10.1111/j.1651-2227.2011.02175.x

  View details for Web of Science ID 000291224200021

  View details for PubMedID 21272067

• Prediction of Bronchopulmonary Dysplasia by Postnatal Age in Extremely Premature Infants AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Laughon, M. M., Langer, J. C., Bose, C. L., Smith, P. B., Ambalavanan, N., Kennedy, K. A., Stoll, B. J., Buchter, S., Laptook, A. R., Ehrenkranz, R. A., Cotten, C. M., Wilson-Costello, D. E., Shankaran, S., Van Meurs, K. P., Davis, A. S., Gantz, M. G., Finer, N. N., Yoder, B. A., Faix, R. G., Carlo, W. A., Schibler, K. R., Newman, N. S., Rich, W., Das, A., Higgins, R. D., Walsh, M. C. 2011; 183 (12): 1715-1722

  Abstract

  Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment.To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death.We assessed infants of 23-30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000-2004.Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and Fi(O(2)), and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at https://neonatal.rti.org.The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.

  View details for DOI 10.1164/rccm.201101-0055OC

  View details for Web of Science ID 000292305600024

  View details for PubMedID 21471086

  View details for PubMedCentralID PMC3136997

• Early Onset Neonatal Sepsis: The Burden of Group B Streptococcal and E. coli Disease Continues PEDIATRICS Stoll, B. J., Hansen, N. I., Sanchez, P. J., Faix, R. G., Poindexter, B. B., Van Meurs, K. P., Bizzarro, M. J., Goldberg, R. N., Frantz, I. D., Hale, E. C., Shankaran, S., Kennedy, K., Carlo, W. A., Watterberg, K. L., Bell, E. F., Walsh, M. C., Schibler, K., Laptook, A. R., Shane, A. L., Schrag, S. J., Das, A., Higgins, R. D. 2011; 127 (5): 817-826

  Abstract

  Guidelines for prevention of group B streptococcal (GBS) infection have successfully reduced early onset (EO) GBS disease. Study results suggest that Escherichia coli is an important EO pathogen.To determine EO infection rates, pathogens, morbidity, and mortality in a national network of neonatal centers.Infants with EO infection were identified by prospective surveillance at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Network centers. Infection was defined by positive culture results for blood and cerebrospinal fluid obtained from infants aged ≤72 hours plus treatment with antibiotic therapy for ≥5 days. Mother and infant characteristics, treatments, and outcomes were studied. Numbers of cases and total live births (LBs) were used to calculate incidence.Among 396 586 LBs (2006-2009), 389 infants developed EO infection (0.98 cases per 1000 LBs). Infection rates increased with decreasing birth weight. GBS (43%, 0.41 per 1000 LBs) and E coli (29%, 0.28 per 1000 LBs) were most frequently isolated. Most infants with GBS were term (73%); 81% with E coli were preterm. Mothers of 67% of infected term and 58% of infected preterm infants were screened for GBS, and results were positive for 25% of those mothers. Only 76% of mothers with GBS colonization received intrapartum chemoprophylaxis. Although 77% of infected infants required intensive care, 20% of term infants were treated in the normal newborn nursery. Sixteen percent of infected infants died, most commonly with E coli infection (33%).In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease. GBS remains the most frequent pathogen in term infants, and E coli the most significant pathogen in preterm infants. Missed opportunities for GBS prevention continue. Prevention of E coli sepsis, especially among preterm infants, remains a challenge.

  View details for DOI 10.1542/peds.2010-2217

  View details for Web of Science ID 000290097800040

  View details for PubMedID 21518717

• Cerebral Oxygenation during Different Treatment Strategies for a Patent Ductus Arteriosus NEONATOLOGY Chock, V. Y., Ramamoorthy, C., Van Meurs, K. P. 2011; 100 (3): 233-240

  Abstract

  Preterm infants with a hemodynamically significant patent ductus arteriosus (hsPDA) are at risk for fluctuations in cerebral blood flow, but it is unclear how different hsPDA treatment strategies may affect cerebral oxygenation.To compare regional cerebral oxygen saturation (rSO(2)) as measured by near-infrared spectroscopy (NIRS) in very low birth weight (VLBW) infants with a hsPDA treated with conservative management, indomethacin, or surgical ligation.This prospective observational study enrolled 33 VLBW infants with a hsPDA diagnosed by echocardiogram and 12 control VLBW infants without a hsPDA. Infants had NIRS cerebral monitoring applied prior to conservative treatment, indomethacin, or surgical ligation. Cranial ultrasound and magnetic resonance imaging data were also collected.Infants undergoing surgical ligation had a greater time period with >20% change in rSO(2) from baseline (30%) compared to those receiving indomethacin (7.4%, p = 0.001) or control infants without a hsPDA (2.6%, p = 0.0004). NIRS measures were not associated with abnormal neuroimaging in this small cohort.These findings suggest that infants requiring surgical ligation for a hsPDA are at high risk for significant changes in cerebral oxygenation, whereas those receiving either indomethacin or conservative management maintain relatively stable cerebral oxygenation levels. Additional research is necessary to determine if NIRS monitoring identifies infants with a hsPDA at highest risk for brain injury.

  View details for DOI 10.1159/000325149

  View details for Web of Science ID 000295588200004

  View details for PubMedID 21701212

• Seizures in Extremely Low Birth Weight Infants Are Associated with Adverse Outcome JOURNAL OF PEDIATRICS Davis, A. S., Hintz, S. R., Van Meurs, K. P., Li, L., Das, A., Stoll, B. J., Walsh, M. C., Pappas, A., Bell, E. F., Laptook, A. R., Higgins, R. D. 2010; 157 (5): 720-U47

  Abstract

  To examine risk factors for neonatal clinical seizures and to determine the independent association with death or neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants.A total of 6499 ELBW infants (401-1000 g) surviving to 36 weeks postmenstrual age (PMA) were included in this retrospective study. Unadjusted comparisons were performed between infants with (n = 414) and without (n = 6085) clinical seizures during the initial hospitalization. Using multivariate logistic regression modeling, we examined the independent association of seizures with late death (after 36 weeks PMA) or NDI after controlling for multiple demographic, perinatal, and neonatal variables.Infants with clinical seizures had a greater proportion of neonatal morbidities associated with poor outcome, including severe intraventricular hemorrhage, sepsis, meningitis, and cystic periventricular leukomalacia (all P < .01). Survivors were more likely to have NDI or moderate-severe cerebral palsy at 18 to 22 months corrected age (both P < .01). After adjusting for multiple confounders, clinical seizures remained significantly associated with late death or NDI (odds ratio, 3.15; 95% CI, 2.37-4.19).ELBW infants with clinical seizures are at increased risk for adverse neurodevelopmental outcome, independent of multiple confounding factors.

  View details for DOI 10.1016/j.jpeds.2010.04.065

  View details for Web of Science ID 000283045900008

  View details for PubMedID 20542294

• Neonatal Candidiasis: Epidemiology, Risk Factors, and Clinical Judgment PEDIATRICS Benjamin, D. K., Stoll, B. J., Gantz, M. G., Walsh, M. C., Sanchez, P. J., Das, A., Shankaran, S., Higgins, R. D., Auten, K. J., Miller, N. A., Walsh, T. J., Laptook, A. R., Carlo, W. A., Kennedy, K. A., Finer, N. N., Duara, S., Schibler, K., Chapman, R. L., Van Meurs, K. P., Frantz, I. D., Phelps, D. L., Poindexter, B. B., Bell, E. F., O'Shea, T. M., Watterberg, K. L., Goldberg, R. N. 2010; 126 (4): E865-E873

  Abstract

  Invasive candidiasis is a leading cause of infection-related morbidity and mortality in extremely low birth weight (<1000-g) infants. We quantified risk factors that predict infection in premature infants at high risk and compared clinical judgment with a prediction model of invasive candidiasis.The study involved a prospective observational cohort of infants≤1000 g birth weight at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. At each sepsis evaluation, clinical information was recorded, cultures were obtained, and clinicians prospectively recorded their estimate of the probability of invasive candidiasis. Two models were generated with invasive candidiasis as their outcome: (1) potentially modifiable risk factors; and (2) a clinical model at time of blood culture to predict candidiasis.Invasive candidiasis occurred in 137 of 1515 (9.0%) infants and was documented by positive culture from ≥1 of these sources: blood (n=96); cerebrospinal fluid (n=9); urine obtained by catheterization (n=52); or other sterile body fluid (n=10). Mortality rate was not different for infants who had positive blood culture compared with those with isolated positive urine culture. Incidence of candida varied from 2% to 28% at the 13 centers that enrolled≥50 infants. Potentially modifiable risk factors included central catheter, broad-spectrum antibiotics (eg, third-generation cephalosporins), intravenous lipid emulsion, endotracheal tube, and antenatal antibiotics. The clinical prediction model had an area under the receiver operating characteristic curve of 0.79 and was superior to clinician judgment (0.70) in predicting subsequent invasive candidiasis.Previous antibiotics, presence of a central catheter or endotracheal tube, and center were strongly associated with invasive candidiasis. Modeling was more accurate in predicting invasive candidiasis than clinical judgment.

  View details for DOI 10.1542/peds.2009-3412

  View details for Web of Science ID 000282526100014

  View details for PubMedID 20876174

  View details for PubMedCentralID PMC3045840

• Neonatal Outcomes of Extremely Preterm Infants From the NICHD Neonatal Research Network PEDIATRICS Stoll, B. J., Hansen, N. I., Bell, E. F., Shankaran, S., Laptook, A. R., Walsh, M. C., Hale, E. C., Newman, N. S., Schibler, K., Carlo, W. A., Kennedy, K. A., Poindexter, B. B., Finer, N. N., Ehrenkranz, R. A., Duara, S., Sanchez, P. J., O'Shea, T. M., Goldberg, R. N., Van Meurs, K. P., Faix, R. G., Phelps, D. L., Frantz, I. D., Watterberg, K. L., Saha, S., Das, A., Higgins, R. D. 2010; 126 (3): 443-456

  Abstract

  This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA).Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22-28 weeks) and very low birth weight (401-1500 g) who were born at network centers between January 1, 2003, and December 31, 2007.Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at or=24 weeks survive, high rates of morbidity among survivors continue to be observed.

  View details for DOI 10.1542/peds.2009-2959

  View details for Web of Science ID 000281535700006

  View details for PubMedID 20732945

• Heptavalent Pneumococcal Conjugate Vaccine Immunogenicity in Very-Low-Birth-Weight, Premature Infants PEDIATRIC INFECTIOUS DISEASE JOURNAL D'Angio, C. T., Heyne, R. J., O'Shea, T. M., Schelonka, R. L., Shankaran, S., Duara, S., Goldberg, R. N., Stoll, B. J., Van Meurs, K. P., Vohr, B. R., Das, A., Li, L., Burton, R. L., Hastings, B., Phelps, D. L., Sanchez, P. J., Carlo, W. A., Stevenson, D. K., Higgins, R. D. 2010; 29 (7): 600-606

  Abstract

  The heptavalent pneumococcal CRM197 conjugate vaccine (PCV-7) has been incompletely studied in very-low-birth-weight (< or =1500 g) infants.To assess PCV-7 immunogenicity in very-low-birth-weight, premature infants. We hypothesized that the frequency of postvaccine antibody concentrations > or =0.15 microg/mL would vary directly with birth weight.This was a multicenter observational study. Infants 401 to 1500 g birth weight and <32 0/7 weeks gestation, stratified by birth weight, were enrolled from 9 National Institute of Child Health and Human Development Neonatal Research Network centers. Infants received PCV-7 at 2, 4, and 6 months after birth and had blood drawn 4 to 6 weeks following the third dose. Antibodies against the 7 vaccine serotypes were measured by enzyme-linked immunosorbent assay.Of 369 enrolled infants, 244 completed their primary vaccine series by 8 months and had serum obtained. Subjects were 27.8 +/- 2.2 (mean +/- standard deviation) weeks gestation and 1008 +/- 282 g birth weight. Twenty-six percent had bronchopulmonary dysplasia and 16% had received postnatal glucocorticoids. Infants 1001 to 1500 g birth weight were more likely than those 401 to 1000 g to achieve antibody concentrations > or =0.15 microg/mL against the least 2 immunogenic serotypes (6B: 96% vs. 85%, P = 0.003 and 23F: 97% vs. 88%, P = 0.009). In multiple logistic regression analysis, lower birth weight, postnatal glucocorticoid use, lower weight at blood draw, and Caucasian race were each independently associated with antibody concentrations <0.35 microg/mL against serotypes 6B and/or 23F.When compared with larger premature infants, infants weighing < or =1000 g at birth have similar antibody responses to most, but not all, PCV-7 vaccine serotypes.

  View details for DOI 10.1097/INF.0b013e3181d264a6

  View details for Web of Science ID 000279348900004

  View details for PubMedID 20234331

  View details for PubMedCentralID PMC2949965

• Target Ranges of Oxygen Saturation in Extremely Preterm Infants. NEW ENGLAND JOURNAL OF MEDICINE Carlo, W. A., Finer, N. N., Walsh, M. C., Rich, W., Gantz, M. G., Laptook, A. R., Yoder, B. A., Faix, R. G., Das, A., Poole, W. K., Schibler, K., Newman, N. S., Ambalavanan, N., Frantz, I. D., Piazza, A. J., Sanchez, P. J., Morris, B. H., Laroia, N., Phelps, D. L., Poindexter, B. B., Cotten, C. M., Van Meurs, K. P., Duara, S., Narendran, V., Sood, B. G., O'Shea, T. M., Bell, E. F., Ehrenkranz, R. A., Watterberg, K. L., Higgins, R. D., Jobe, A. H., Caplan, M. S., Oh, W., Hensman, A. M., Gingras, D., Barnett, S., LILLIE, S., Francis, K., Andrews, D., Angela, K., Fanaroff, A. A., SINER, B. S., Zadell, A., DiFiore, J., Donovan, E. F., Bridges, K., Alexander, B., Grisby, C., Mersmann, M. W., Mincey, H. L., Hessling, J., Goldberg, R. N., Auten, K. J., Fisher, K. A., Foy, K. A., Siaw, G., Stoll, B. J., Buchter, S., Carlton, D. P., HALE, E. C., Hutchinson, A. K., Archer, S. W., Lemons, J. A., HAMER, F., Herron, D. E., Miller, L. C., Wilson, L. D., Berberich, M. A., Blaisdell, C. J., Gail, D. B., Kiley, J. P., Cunningham, M., Hastings, B. K., Irene, A. R., Auman, J. O., Huitema, C. P., Pickett, J. W., Wallace, D., Zaterka-Baxter, K. M., Stevenson, D. K., Ball, M. B., Proud, M. S., Fiascone, J. M., Furey, A., MacKinnon, B. L., Nylen, E., Collins, M. V., Cosby, S. S., Phillips, V. A., Rasmussen, M. R., Wozniak, P. R., Arnell, K., Bridge, R., Demetrio, C., Widness, J. A., Klein, J. M., Johnson, K. J., Everett-Thomas, R., Ohls, R. K., Rohr, J., Lacy, C. B., Markowitz, G. D., Reubens, L. J., BURNELL, E., Rosenfeld, C. R., Salhab, W. A., Guzman, A., Hensley, G., Lepps, M. H., Miller, N. A., Allen, J., Grau, L., Martin, M., Solis, A., Vasil, D. M., Wilder, K., Kennedy, K. A., TYSON, J. E., HARRIS, B. F., Lis, A. E., Martin, S., MCDAVID, G. E., Tate, P. L., Wright, S. L., Burnett, J., Jensen, J. J., Osborne, K. A., Spencer, C., Weaver-Lewis, K., Peters, N. J., Shankaran, S., Bara, R., Billian, E., Johnson, M., Bhandari, V., Jacobs, H. C., Cervone, P., Gettner, P., Konstantino, M., Poulsen, J., Taft, J., Avery, G., Gleason, C. A., Allen, M. C., Bangdiwala, S. I., Blaisdell, C. J., Boyle, R. J., Clemons, T., D'Alton, M. E., Das, A., Gail, D. B., Hunt, C., Keszler, M., Poole, W. K., Redmond, C. K., Ross, M. G., Thomson, M. A., WEINER, S. J., Willinger, M., Markowitz, G. D., Hutchinson, A. K., Wallace, D. K., Freedman, S. F. 2010; 362 (21): 1959-1969

  Abstract

  Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes.We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant.The rates of severe retinopathy or death did not differ significantly between the lower-oxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P=0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P<0.001). There were no significant differences in the rates of other adverse events.A lower target range of oxygenation (85 to 89%), as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors. The increase in mortality is a major concern, since a lower target range of oxygen saturation is increasingly being advocated to prevent retinopathy of prematurity. (ClinicalTrials.gov number, NCT00233324.)

  View details for DOI 10.1056/NEJMoa0911781

  View details for Web of Science ID 000278054000004

  View details for PubMedID 20472937

  View details for PubMedCentralID PMC2891970

• Early CPAP versus Surfactant in Extremely Preterm Infants. NEW ENGLAND JOURNAL OF MEDICINE Finer, N. N., Carlo, W. A., Walsh, M. C., Rich, W., Gantz, M. G., Laptook, A. R., Yoder, B. A., Faix, R. G., Das, A., Poole, W. K., Donovan, E. F., Newman, N. S., Ambalavanan, N., Frantz, I. D., Buchter, S., Sanchez, P. J., Kennedy, K. A., Laroia, N., Poindexter, B. B., Cotten, C. M., Van Meurs, K. P., Duara, S., Narendran, V., Sood, B. G., O'Shea, T. M., Bell, E. F., Bhandari, V., Watterberg, K. L., Higgins, R. D. 2010; 362 (21): 1970-1979

  Abstract

  There are limited data to inform the choice between early treatment with continuous positive airway pressure (CPAP) and early surfactant treatment as the initial support for extremely-low-birth-weight infants.We performed a randomized, multicenter trial, with a 2-by-2 factorial design, involving infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to CPAP treatment initiated in the delivery room, with subsequent use of a protocol-driven limited ventilation strategy. Infants were also randomly assigned to one of two target ranges of oxygen saturation. The primary outcome was death or bronchopulmonary dysplasia as defined by the requirement for supplemental oxygen at 36 weeks (with an attempt at withdrawal of supplemental oxygen in neonates who were receiving less than 30% oxygen).A total of 1316 infants were enrolled in the study. The rates of the primary outcome did not differ significantly between the CPAP group and the surfactant group (47.8% and 51.0%, respectively; relative risk with CPAP, 0.95; 95% confidence interval [CI], 0.85 to 1.05) after adjustment for gestational age, center, and familial clustering. The results were similar when bronchopulmonary dysplasia was defined according to the need for any supplemental oxygen at 36 weeks (rates of primary outcome, 48.7% and 54.1%, respectively; relative risk with CPAP, 0.91; 95% CI, 0.83 to 1.01). Infants who received CPAP treatment, as compared with infants who received surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P<0.001), required fewer days of mechanical ventilation (P=0.03), and were more likely to be alive and free from the need for mechanical ventilation by day 7 (P=0.01). The rates of other adverse neonatal outcomes did not differ significantly between the two groups.The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants. (ClinicalTrials.gov number, NCT00233324.)

  View details for Web of Science ID 000278054000005

  View details for PubMedID 20472939

  View details for PubMedCentralID PMC3071534

• Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants ACTA PAEDIATRICA Oh, W., Stevenson, D. K., TYSON, J. E., Morris, B. H., Ahlfors, C. E., Bender, G. J., Wong, R. J., Perritt, R., Vohr, B. R., Van Meurs, K. P., Vreman, H. J., Das, A., Phelps, D. L., O'Shea, T. M., Higgins, R. D. 2010; 99 (5): 673-678

  Abstract

  To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18-22 months corrected age in extremely low birth weight infants.Total plasma bilirubin and unbound bilirubin were measured in 1101 extremely low birth weight infants at 5 +/- 1 days of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18-22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors.Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. CONCLUSIONs: In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma bilirubin and death or adverse neurodevelopmental outcomes at 18-22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.

  View details for DOI 10.1111/j.1651-2227.2010.01688.x

  View details for Web of Science ID 000276034800011

  View details for PubMedID 20105142

• Inhaled Nitric Oxide in preterm infants: a systematic review and individual patient data meta-analysis BMC PEDIATRICS Askie, L. M., Ballard, R. A., Cutter, G., Dani, C., Elbourne, D., Field, D., Hascoet, J., Hibbs, A. M., Kinsella, J. P., Mercier, J., Rich, W., Schreiber, M. D., Srisuparp, P., Subhedar, N. V., Van Meurs, K. P., Voysey, M., Barrington, K., Ehrenkranz, R. A., Finer, N. 2010; 10

  Abstract

  Preterm infants requiring assisted ventilation are at significant risk of both pulmonary and cerebral injury. Inhaled Nitric Oxide, an effective therapy for pulmonary hypertension and hypoxic respiratory failure in the full term infant, has also been studied in preterm infants. The most recent Cochrane review of preterm infants includes 11 studies and 3,370 participants. The results show a statistically significant reduction in the combined outcome of death or chronic lung disease (CLD) in two studies with routine use of iNO in intubated preterm infants. However, uncertainty remains as a larger study (Kinsella 2006) showed no significant benefit for iNO for this combined outcome. Also, trials that included very ill infants do not demonstrate significant benefit. One trial of iNO treatment at a later postnatal age reported a decrease in the incidence of CLD. The aim of this individual patient meta-analysis is to confirm or refute these potentially conflicting results and to determine the extent to which patient or treatment characteristics may explain the results and/or may predict benefit from inhaled Nitric Oxide in preterm infants.The Meta-Analysis of Preterm Patients on inhaled Nitric Oxide (MAPPiNO) Collaboration will perform an individual patient data meta-analysis to answer these important clinical questions. Studies will be included if preterm infants receiving assisted ventilation are randomized to receive inhaled Nitric Oxide or to a control group. The individual patient data provided by the Collaborators will be analyzed on an intention-to-treat basis where possible. Binary outcomes will be analyzed using log-binomial regression models and continuous outcomes will be analyzed using linear fixed effects models. Adjustments for trial differences will be made by including the trial variable in the model specification.Thirteen (13) trials, with a total of 3567 infants are eligible for inclusion in the MAPPiNO systematic review. To date 11 trials (n = 3298, 92% of available patients) have agreed to participate. Funding was successfully granted from Ikaria Inc as an unrestricted grant. A collaborative group was formed in 2006 with data collection commencing in 2007. It is anticipated that data analysis will commence in late 2009 with results being publicly available in 2010.

  View details for DOI 10.1186/1471-2431-10-15

  View details for Web of Science ID 000277088200001

  View details for PubMedID 20331899

• Synchronized Nasal Intermittent Positive-Pressure Ventilation and Neonatal Outcomes PEDIATRICS Bhandari, V., Finer, N. N., Ehrenkranz, R. A., Saha, S., Das, A., Walsh, M. C., Engle, W. A., Van Meurs, K. P. 2009; 124 (2): 517-526

  Abstract

  Synchronized nasal intermittent positive-pressure ventilation (SNIPPV) use reduces reintubation rates compared with nasal continuous positive airway pressure (NCPAP). Limited information is available on the outcomes of infants managed with SNIPPV.To compare the outcomes of infants managed with SNIPPV (postextubation or for apnea) to infants not treated with SNIPPV at 2 sites.Clinical retrospective data was used to evaluate the use of SNIPPV in infants

  View details for DOI 10.1542/peds.2008-1302

  View details for Web of Science ID 000268377000011

  View details for PubMedID 19651577

  View details for PubMedCentralID PMC2924622

• Inhaled Nitric Oxide for Preterm Premature Rupture of Membranes, Oligohydramnios, and Pulmonary Hypoplasia AMERICAN JOURNAL OF PERINATOLOGY Chock, V. Y., Van Meurs, K. P., Hintz, S. R., Ehrenkranz, R. A., Lemons, J. A., Kendrick, D. E., Stevenson, D. K. 2009; 26 (4): 317-322

  Abstract

  We sought to determine if inhaled nitric oxide (iNO) administered to preterm infants with premature rupture of membranes (PPROM), oligohydramnios, and pulmonary hypoplasia improved oxygenation, survival, or other clinical outcomes. Data were analyzed from infants with suspected pulmonary hypoplasia, oligohydramnios, and PPROM enrolled in the National Institute of Child Health and Development Neonatal Research Network Preemie Inhaled Nitric Oxide (PiNO) trial, where patients were randomized to receive placebo (oxygen) or iNO at 5 to 10 ppm. Outcome variables assessed were PaO (2) response, mortality, bronchopulmonary dysplasia (BPD), and severe intraventricular hemorrhage (IVH) or periventricular leukomalacia (PVL). Twelve of 449 infants in the PiNO trial met criteria. Six infants received iNO and six received placebo. The iNO group had a mean increase in PaO (2) of 39 +/- 50 mm Hg versus a mean decrease of 11 +/- 15 mm Hg in the control group. Mortality was 33% versus 67%, BPD (2/5) 40% versus (2/2) 100%, and severe IVH or PVL (1/5) 20% versus (1/2) 50% in the iNO and control groups, respectively. None of these changes were statistically significant. Review of a limited number of cases from a large multicenter trial suggests that iNO use in the setting of PPROM, oligohydramnios, and suspected pulmonary hypoplasia improves oxygenation and may decrease the rate of BPD and death without increasing severe IVH or PVL. However, the small sample size precludes definitive conclusions. Further studies are required to determine if iNO is of benefit in this specific patient population.

  View details for DOI 10.1055/s-0028-1104743

  View details for Web of Science ID 000264506400012

  View details for PubMedID 19067285

• Impact of Postnatal Corticosteroid Use on Neurodevelopment at 18 to 22 Months' Adjusted Age: Effects of Dose, Timing, and Risk of Bronchopulmonary Dysplasia in Extremely Low Birth Weight Infants PEDIATRICS Wilson-Costello, D., Walsh, M. C., Langer, J. C., Guillet, R., Laptook, A. R., Stoll, B. J., Shankaran, S., Finer, N. N., Van Meurs, K. P., Engle, W. A., Das, A. 2009; 123 (3): e430-e437

  Abstract

  Postnatal steroid use decreases lung inflammation but increases impairment. We hypothesized that increased dose is associated with increased neurodevelopmental impairment, lower postmenstrual age at exposure increases impairment, and risk of bronchopulmonary dysplasia modifies the effect of postnatal corticosteroid.Steroid dose and timing of exposure beyond 7 days was assessed among 2358 extremely low birth weight infants nested in a prospective trial, with 1667 (84%) survivors examined at 18 to 22 months' postmenstrual age. Logistic regression tested the relationship between impairment (Bayley Mental Developmental Index/Psychomotor Developmental Index of <70, disabling cerebral palsy, or sensory impairment), total dose (tertiles: <0.9, 0.9-1.9, and >/=1.9 mg/kg), and postmenstrual age at first dose. Separate logistic regression tested effect modification according to bronchopulmonary dysplasia severity (Romagnoli risk > 0.5 as high risk, n = 2336 (99%) for days of life 4-7).Three hundred sixty-six (16%) neonates were steroid-treated (94% dexamethasone). Treated neonates were smaller and less mature; 72% of those treated were at high risk for bronchopulmonary dysplasia. Exposure was associated with neurodevelopmental impairment/death. Impairment increased with higher dose; 71% dead or impaired at highest dose tertile. Each 1 mg/kg dose was associated with a 2.0-point reduction on the Mental Developmental Index and a 40% risk increase for disabling cerebral palsy. Older age did not mitigate the harm. Treatment after 33 weeks' postmenstrual age was associated with greatest harm despite not receiving the highest dose. The relationship between steroid exposure and impairment was modified by the bronchopulmonary dysplasia risk, with those at highest risk experiencing less harm.Higher steroid dose was associated with increased neurodevelopmental impairment. There is no "safe" window for steroid use in extremely low birth weight infants. Neonates with low bronchopulmonary dysplasia risk should not be exposed. A randomized trial of steroid use in infants at highest risk is warranted.

  View details for DOI 10.1542/peds.2008-1928

  View details for Web of Science ID 000263825500057

  View details for PubMedID 19204058

• Aggressive vs. conservative phototherapy for infants with extremely low birth weight NEW ENGLAND JOURNAL OF MEDICINE Morris, B. H., Oh, W., Tyson, J. E., Stevenson, D. K., Phelps, D. L., O'Shea, T. M., McDavid, G. E., Perritt, R. L., Van Meurs, K. P., Vohr, B. R., Grisby, C., Yao, Q., Pedroza, C., Das, A., Poole, W. K., Carlo, W. A., Duara, S., Laptook, A. R., Salhab, W. A., Shankaran, S., Poindexter, B. B., Fanaroff, A. A., Walsh, M. C., Rasmussen, M. R., Stoll, B. J., Cotten, C. M., Donovan, E. F., Ehrenkranz, R. A., Guillet, R., Higgins, R. D. 2008; 359 (18): 1885-1896

  Abstract

  It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less).We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments.Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 micromol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P=0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g.Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials.gov number, NCT00114543.)

  View details for Web of Science ID 000260454500005

  View details for PubMedID 18971491

  View details for PubMedCentralID PMC2821221

• Predictors of death or bronchopulmonary dysplasia in preterm infants with respiratory failure JOURNAL OF PERINATOLOGY Ambalavanan, N., Van Meurs, K. P., Perritt, R., Carlo, W. A., Ehrenkranz, R. A., Stevenson, D. K., Lemons, J. A., Poole, W. K., Higgins, R. D. 2008; 28 (6): 420-426

  Abstract

  To identify the variables that predict death/physiologic bronchopulmonary dysplasia (BPD) in preterm infants with severe respiratory failure.The study was a secondary analysis of data from the NICHD Neonatal Research Network trial of inhaled nitric oxide (iNO) in preterm infants. Stepwise logistic regression models and Classification and Regression Tree (CART) models were developed for the outcome of death or physiologic BPD (O(2) at 36 weeks post-menstrual age).Death and/or BPD was associated with lower birth weight, higher oxygen requirement, male gender, additional surfactant doses, higher oxygenation index and outborn status, but not the magnitude of response in PaO(2) to iNO. The positive predictive value of the CART model was 82% at 95% sensitivity.The major factors associated with death/BPD were an increased severity of respiratory failure, lower birth weight, male gender and outborn status, but not the magnitude of initial response to iNO.

  View details for DOI 10.1038/jp.2008.18

  View details for Web of Science ID 000256437600007

  View details for PubMedID 18337740

• Defect size determines survival in infants with congenital diaphragmatic hernia PEDIATRICS Lally, K. P., Lally, P. A., Lasky, R. E., Tibboel, D., Jaksic, T., Wilson, J. M., Frenckner, B., Van Meurs, K. P., Bohn, D. J., Davis, C. F., Hirschl, R. B. 2007; 120 (3): E651-E657

  Abstract

  Congenital diaphragmatic hernia is a significant cause of neonatal mortality. The objective of this study was to evaluate the clinical factors associated with death in infants with congenital diaphragmatic hernia by using a large multicenter data set.This was a prospective cohort study of all liveborn infants with congenital diaphragmatic hernia who were cared for at tertiary referral centers belonging to the Congenital Diaphragmatic Hernia Study Group between 1995 and 2004. Factors thought to influence death included birth weight, Apgar scores, size of defect, and associated anomalies. Survival to hospital discharge, duration of mechanical ventilation, and length of hospital stay were evaluated as end points.A total of 51 centers in 8 countries contributed data on 3062 liveborn infants. The overall survival rate was 69%. Five hundred thirty-eight (18%) patients did not undergo an operation and died. The defect size was the most significant factor that affected outcome; infants with a near absence of the diaphragm had a survival rate of 57% compared with infants having a primary repair with a survival rate of 95%. Infants without agenesis but who required a patch for repair had a survival rate of 79% compared with primary repair.The size of the diaphragmatic defect seems to be the major factor influencing outcome in infants with congenital diaphragmatic hernia. It is likely that the defect size is a surrogate marker for the degree of pulmonary hypoplasia. Future research efforts should be directed to accurately quantitate the degree of pulmonary hypoplasia or defect size antenatally. Experimental therapies can then be targeted to prospectively identify high-risk patients who are more likely to benefit.

  View details for DOI 10.1542/peds.2006-3040

  View details for Web of Science ID 000249232000072

  View details for PubMedID 17766505

• Neurodevelopmental outcomes of premature infants with severe respiratory failure enrolled in a randomized controlled trial of inhaled nitric oxide JOURNAL OF PEDIATRICS Hintz, S. R., Van Meurs, K. P., Perritt, R., Poole, W. K., Das, A., Stevenson, D. K., Ehrenkranz, R. A., Lemons, J. A., Vohr, B. R., Heyne, R., Childers, D. O., Peralta-Carcelen, M., Dusick, A., Johnson, Y. R., Morris, B., Dillard, R., Vaucher, Y., Steichen, J., Adams-Chapman, I., Konduri, G., Myers, G. J., De Ungria, M., Tyson, J. E., Higgins, R. D. 2007; 151 (1): 16-22

  Abstract

  We hypothesized that inhaled nitric oxide (iNO) would not decrease death or neurodevelopmental impairment (NDI) in infants enrolled in the National Institute of Child Health and Human Development Preemie iNO Trial (PiNO) trial, nor improve neurodevelopmental outcomes in the follow-up group.Infants <34 weeks of age, weighing <1500 g, with severe respiratory failure were enrolled in the multicenter, randomized, controlled trial. NDI at 18 to 22 months corrected age was defined as: moderate to severe cerebral palsy (CP; Mental Developmental Index or Psychomotor score Developmental Index <70), blindness, or deafness.Of 420 patients enrolled, 109 who received iNO (52%) and 98 who received placebo (47%) died. The follow-up rate in survivors was 90%. iNO did not reduce death or NDI (78% versus 73%; relative risk [RR], 1.07; 95% CI, 0.95-1.19), or NDI or Mental Developmental Index <70 in the follow-up group. Moderate-severe CP was slightly higher with iNO (RR, 2.41; 95% CI, 1.01-5.75), as was death or CP in infants weighing <1000 g (RR, 1.22; 95% CI, 1.05-1.43).In this extremely ill cohort, iNO did not reduce death or NDI or improve neurodevelopmental outcomes. Routine iNO use in premature infants should be limited to research settings until further data are available.

  View details for DOI 10.1016/j.jpeds.2007.03.017

  View details for Web of Science ID 000247851900007

  View details for PubMedID 17586184

  View details for PubMedCentralID PMC2770191

• Interobserver reliability and accuracy of cranial ultrasound scanning interpretation in premature infants JOURNAL OF PEDIATRICS Hintz, S. R., Slovis, T., Bulas, D., Van Meurs, K. P., Perritt, R., Stevenson, D. K., Poole, W. K., Das, A., Higgins, R. D. 2007; 150 (6): 592-596

  Abstract

  To assess interobserver reliability between 2 central readers of cranial ultrasound scanning (CUS) and accuracy of local, compared with central, interpretations.The study was a retrospective analysis of CUS data from the National Institute of Child Health and Human Development (NICHD) trial of inhaled nitric oxide for premature infants. Interobserver reliability of 2 central readers was assessed with kappa or weighted kappa. Accuracy of local, compared with central, interpretations was assessed by using sensitivity and specificity.CUS from 326 infants had both central reader and local interpretations. Central reader agreement for grade 3/4 intraventricular hemorrhage (IVH), grade 3/4 IVH or periventricular leukomalacia (PVL), grade of IVH, and degree of ventriculomegaly was very good (kappa = 0.84, 0.81, 0.79, and 0.75, respectively). Agreement was poor for lower grade IVH and for PVL alone. Local interpretations were highly accurate for grade 3/4 IVH or PVL (sensitivity, 87%-90%; specificity, 92%-93%), but sensitivity was poor-to-fair for grade 1/2 IVH (48%-68%) and PVL (20%-44%).Our findings demonstrate reliability and accuracy of highly unfavorable CUS findings, but suggest caution when interpreting mild to moderate IVH or white matter injury.

  View details for DOI 10.1016/j.jpeds.2007.02.012

  View details for Web of Science ID 000246939700011

  View details for PubMedID 17517240

  View details for PubMedCentralID PMC2757063

• Inhaled nitric oxide in infants > 1500 g and < 34 weeks gestation with severe respiratory failure JOURNAL OF PERINATOLOGY Van Meurs, K. P., Hintz, S. R., Ehrenkranz, R. A., Lemons, J. A., Ball, M. B., Poole, W. K., Perritt, R., Das, A., Higgins, R. D., Stevenson, D. K. 2007; 27 (6): 347-352

  Abstract

  Inhaled nitric oxide (iNO) use in infants >1500 g, but <34 weeks gestation with severe respiratory failure will reduce the incidence of death and/or bronchopulmonary dysplasia (BPD).Infants born at <34 weeks gestation with a birth weight >1500 g with respiratory failure were randomly assigned to receive placebo or iNO.Twenty-nine infants were randomized. There were no differences in baseline characteristics, but the status at randomization showed a statistically significant difference in the use of high-frequency ventilation (P=0.03). After adjustment for oxygenation index entry strata, there was no difference in death and/or BPD (adjusted relative risk (RR) 0.80, 95% confidence interval (CI) 0.43 to 1.48; P=0.50), death (adjusted RR 1.26, 95% CI 0.47 to 3.41; P=0.65) or BPD (adjusted RR 0.40, 95% CI 0.47 to 3.41; P=0.21).Although sample size limits our ability to make definitive conclusions, this small pilot trial of iNO use in premature infants >1500 g and <34 weeks with severe respiratory failure suggests that iNO does not affect the rate of BPD and/or death.

  View details for DOI 10.1038/sj.jp.7211690

  View details for Web of Science ID 000246905800005

  View details for PubMedID 17443204

• Early inhaled nitric oxide therapy for term and near-term newborn infants with hypoxic respiratory failure: Neurodevelopmental follow-up JOURNAL OF PEDIATRICS Konduri, G. G., Vohr, B., Robertson, C., Sokol, G. M., Solimano, A., Singer, J., Ehrenkranz, R. A., Singhal, N., Wright, L. L., Van Meurs, K., Stork, E., Kirpalani, H., Peliowski, A., Johnson, Y. 2007; 150 (3): 235-240

  Abstract

  To report the neurodevelopmental outcome of infants enrolled in a randomized multicenter trial of early inhaled nitric oxide (iNO) in term and near-term neonates with hypoxic respiratory failure and pulmonary hypertension.Neonates born at > or = 34 weeks gestation who required assisted ventilation and had an oxygenation index > or = 15 and < 25 were randomized to an early iNO group or a control group. A comprehensive neurodevelopmental assessment of survivors was performed at age 18 to 24 months.The trial enrolled 299 infants, of which 266 (89%) survived to age 18 to 24 months (136 in the early iNO group and 130 in the control group). Follow-up evaluations were done on 234 (88%) of surviving infants. There were no differences between the 2 groups in the incidence of neurodevelopmental impairment (early iNO, 27%; control, 25%) and hearing impairment (early iNO, 23%; control, 24%). Mental development index scores were similar in the 2 groups; however, psychomotor developmental index scores were significantly higher in the control group (early iNO, 89 +/- 17.7; control, 93.5 +/- 18.4).Early iNO therapy for hypoxic respiratory failure in term and near-term infants is not associated with an increase in neurodevelopmental impairment or hearing loss at 18 to 24 months postnatal age.

  View details for DOI 10.1016/j.jpeds.2006.11.065

  View details for Web of Science ID 000244629700009

  View details for PubMedID 17307536

• The use of inhaled nitric oxide in the premature infant with respiratory distress syndrome. Minerva pediatrica Van Meurs, K., Hintz, S., Rhine, W., Benitz, W. 2006; 58 (5): 403-422

  Abstract

  The identification of the biologic properties of nitric oxide (NO) is one of the key scientific discoveries of the century, but its potential for treating human disease is yet to be fully realized. NO has a basic role in regulating vascular tone of the pulmonary circulation, and recent animal models have suggested a more wide reaching influence on perinatal lung development. In animal models, NO has effects on lung growth, angiogenesis, airway smooth muscle proliferation, vascular remodeling, surfactant function, inflammation, and pulmonary mechanics. However, despite extensive basic science investigation and completion of several large clinical trials, the role of NO in the treatment of the premature infant with respiratory distress syndrome remains unclear. One must conclude that the interaction of lung immaturity, ventilator and oxygen-induced lung injury, and NO biology in the premature newborn is incompletely understood. Clinical trial results of inhaled NO therapy in the premature infant are accumulating, but the results do not suggest a clear-cut advantage for the population at greatest risk for death and disability. Whether trial design, dose, duration of therapy, or other factors are responsible has not been determined. Further research is needed to answer these questions and more clearly define the population of premature infants who may derive benefit from this new therapy.

  View details for PubMedID 17008853

• Treatment evolution in high-risk congenital diaphragmatic hernia - Ten years experience with diaphragmatic agenesis 126th Annual Meeting of the American-Surgical-Association Lally, K. P., Lally, P. A., Van Meurs, K. P., Bohn, D. J., Davis, C. F., Rodgers, B., Bhatia, J., Dudell, G. LIPPINCOTT WILLIAMS & WILKINS. 2006: 505–13

  Abstract

  The objective of this study was to evaluate the impact of newer therapies on the highest risk patients with congenital diaphragmatic hernia (CDH), those with agenesis of the diaphragm.CDH remains a significant cause of neonatal mortality. Many novel therapeutic interventions have been used in these infants. Those children with large defects or agenesis of the diaphragm have the highest mortality and morbidity.Twenty centers from 5 countries collected data prospectively on all liveborn infants with CDH over a 10-year period. The treatment and outcomes in these patients were examined. Patients were followed until death or hospital discharge.A total of 1,569 patients with CDH were seen between January 1995 and December 2004 in 20 centers. A total of 218 patients (14%) had diaphragmatic agenesis and underwent repair. The overall survival for all patients was 68%, while survival was 54% in patients with agenesis. When patients with diaphragmatic agenesis from the first 2 years were compared with similar patients from the last 2 years, there was significantly less use of ECMO (75% vs. 52%) and an increased use of inhaled nitric oxide (iNO) (30% vs. 80%). There was a trend toward improved survival in patients with agenesis from 47% in the first 2 years to 59% in the last 2 years. The survivors with diaphragmatic agenesis had prolonged hospital stays compared with patients without agenesis (median, 68 vs. 30 days). For the last 2 years of the study, 36% of the patients with agenesis were discharged on tube feedings and 22% on oxygen therapy.There has been a change in the management of infants with CDH with less frequent use of ECMO and a greater use of iNO in high-risk patients with a potential improvement in survival. However, the mortality, hospital length of stay, and morbidity in agenesis patients remain significant.

  View details for DOI 10.1097/01.sla.0000239027.61651.fa

  View details for Web of Science ID 000241254900004

  View details for PubMedID 16998359

• Cardiovascular support in preterm infants Newborn Drug Development Initiative Workshop Evans, J. R., Short, B. L., Van Meurs, K., Sachs, H. C. ELSEVIER. 2006: 1366–84

  Abstract

  Despite increasing investigation in the area of cardiovascular instability in preterm infants, huge gaps in knowledge remain. None of the current treatments for hypotension, including the use of inotropic agents, have been well studied in the preterm population, and data regarding safety and efficacy are lacking. Thus, the labeling information regarding the use of inotropes as therapeutic agents in this population is inadequate.This article reviews the current deficiencies in knowledge with respect to measuring and achieving normal organ perfusion; summarizes the clinical, methodological, and ethical issues to consider when designing trials to evaluate medications for hemodynamic instability in the preterm neonate; and proposes 2 possible trial designs. Unanswered questions and potential obstacles for the systematic study of drugs to treat cardiovascular instability in preterm neonates are discussed.The neonatal Cardiology Group was established in 2003 by the US Food and Drug Administration (FDA) and the National Institute of Child Health and Human Development (NICHD) as part of the Newborn Drug Development Initiative. The Cardiology Group conducted a number of teleconferences and one meeting to develop a document addressing gaps in knowledge regarding cardiovascular drugs commonly used in low-birth-weight neonates and possible approaches to investigate these drugs. This work was presented at a workshop cosponsored by the NICHD and the FDA held in March 2004 in Baltimore, Maryland. Information for this article was gathered during this initiative.To develop rational, evidence-based guidelines corroborated by robust scientific data for cardiovascular support in newborns, well-designed and adequately powered pharmacologic studies and clinical trials are needed to evaluate the safety and efficacy of inotropic agents and to determine the short- and long-term effects of these drugs. Trials investigating the currently available and novel therapies for cardiovascular instability in neonates will provide information that can be incorporated into product labeling and a scientific framework for cardiovascular management in critically ill neonates. The Cardiology Group identified and prioritized 2 conditions for investigation of therapeutic options for the management of neonatal cardiovascular instability: (1) cardiovascular instability in preterm neonates; and (2) cardiac dysfunction in neonates after cardiopulmonary bypass surgery. Key research questions in the area of cardiovascular instability in the preterm infant include determining optimal blood pressure (BP) in preterm infants; identifying better measures than BP to determine organ perfusion; optimizing hemodynamic treatments; and clarifying any associations between BP or therapy for low BP and mortality, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, retinopathy of prematurity, and neurodevelopmental outcome. The Cardiology Group concluded that the study of inotropic agents in neonates using outcomes of importance to patients will require a complicated trial design to address the elements discussed. The group proposed 2 clinical trial designs: (1) a placebo-controlled trial with rescue therapy for symptomatic infants; and (2) a targeted BP trial.This summary is intended to stimulate and assist future research in the area of cardiovascular support for preterm infants.

  View details for DOI 10.1016/j.clinthera.2006.09.006

  View details for Web of Science ID 000241685600012

  View details for PubMedID 17062310

• Corticosteroids for fetuses with congenital diaphragmatic hernia: can we show benefit? 57th Annual Meeting of the American-Academy-of-Pediatrics Lally, K. P., Bagolan, P., Hosie, S., Lally, P. A., Stewart, M., Cotten, C. M., Van Meurs, K. P., Alexander, G. W B SAUNDERS CO-ELSEVIER INC. 2006: 668–74

  Abstract

  Prenatal corticosteroids have been used in fetuses with congenital diaphragmatic hernia (CDH). We tested the utility of steroids by 2 methods.Mothers carrying fetuses with CDH were randomized to 3 weekly doses of betamethasone or placebo starting at 34 weeks. Patients were followed until death or discharge. In a separate cohort study, the CDH Registry was used to compare infants who received prenatal steroids to those who had not.Thirty-four patients were enrolled at 7 centers, with 32 completing the trial. There were 15 placebo and 17 steroid patients. There was no difference in survival, length of stay, duration of ventilation, or oxygen use at 30 days. For the cohort study, we looked at infants older than 34 weeks who were born after October 2000 when data on prenatal steroids were collected. There were 1093 patients; 390 were evaluable, with 56 receiving steroids. There was no difference in survival, length of stay, ventilator days, or oxygen use at 30 days.Neither the trial nor the CDH Registry suggest that late prenatal corticosteroids benefit fetuses with CDH. More than 1700 mothers and fetuses would need to be enrolled in a trial to show a 10% improvement in survival. It is unlikely that late steroids offer benefit to most fetuses with CDH.

  View details for DOI 10.1016/j.jpedsurg.2005.12.007

  View details for Web of Science ID 000237015800014

  View details for PubMedID 16567174

• Summary proceedings from the cardiology group on cardiovascular instability in preterm infants Newborn Drug Development Initiative Workshop Short, B. L., Van Meurs, K., EVANS, J. R. AMER ACAD PEDIATRICS. 2006: S34–S39

  Abstract

  The appropriate determination of adequate tissue perfusion and the best approach to treatment of perceived abnormalities in blood pressure in the neonate remain controversial. There is no consensus regarding the actual definition of hypotension in the neonate or how best to raise perceived low blood pressure. In addition, there is no direct and prospectively collected information available on the result of treatment of a "low" blood pressure on neonatal morbidity and mortality. It also has not been clearly demonstrated that bringing systemic blood pressure to a "normal" range improve outcomes. However, it is widely accepted by clinicians that early and aggressive treatment of hypotension leads to improved neurologic outcome and survival in the neonate. Commonly used therapeutic maneuvers to correct systemic hypotension in the neonate include volume expansion, inotropic agents, and corticosteroids. Although there is a paucity of research on the cardiovascular response to these commonly used agents in neonates, among the commonly used inotropic drugs dopamine has been shown to be more effective than dobutamine in raising blood pressure in the neonate. The cardiology group focused on the use of inotropes, particularly dopamine and dobutamine, to treat very low birth weight infants with cardiac instability and neonatal postoperative cardiac patients. The cardiology group identified key issues that must be considered when designing studies of inotropic agents in preterm infants and proposed 2 clinical-trial designs: (1) a placebo-controlled trial with rescue for symptomatic infants; and (2) a targeted-blood pressure study. The first trial design would answer questions concerning efficacy of treatment with inotropic agents in this population. The second trial design would address concerns related to the lack of knowledge on normal blood pressure ranges in this population. The group identified specific design elements that would need to be addressed for the complicated trial design to study inotropic agents in neonates.

  View details for DOI 10.1542/peda.2005-0620F

  View details for Web of Science ID 000235727300005

  View details for PubMedID 16777820

• The Newborn Drug Development Initiative (NDDI) Workshop: Summary proceedings from the Cardiology Group on Cardiovascular Instability in Preterm Infants. Pediatrics Short BL, Van Meurs K, Evans JR, the Cardiology Working Group. 2006; 117: S34-39
• Inhaled nitric oxide for the premature infant with respiratory distress syndrome: Animal models and clinical trials. Tufts University/Floating Hospital Reports on Neonatal Respiratory Diseases Van Meurs K, Benitz We 2006; 16 (1): 1-8
• Inhaled nitric oxide for premature infants with severe respiratory failure NEW ENGLAND JOURNAL OF MEDICINE Van Meurs, K. P., Wright, L. L., Ehrenkranz, R. A., Lemons, J. A., Ball, M. B., Poole, W. K., Perritt, R., Higgins, R. D., Oh, W., Hudak, M. L., Laptook, A. R., Shankaran, S., Finer, N. N., Carlo, W. A., Kennedy, K. A., Fridriksson, J. H., Steinhorn, R. H., Sokol, G. M., Konduri, G. G., Aschner, J. L., Stoll, B. J., D'Angio, C. T., Stevenson, D. K., Oh, W., Hensman, A., Gingras, D., Stoll, B. J., Jain, L., Hale, E., Seabrook, I., Sokol, G., Lorant, D., Appel, D. D., Miller, L., Chriscinske, D., Attwood, J., Steinhorn, R., Sautel, M., Van Meurs, K., Ball, B., Proud, D., Carlo, W. A., Cosby, S. S., Johnson, R. B., Fridriksson, J., Warner, B., Mersmann, M., Alexander, B., Shively, J., Mincey, H., Hoover, M., Sapienz, S., Stephenson, E., Finer, N. N., Rasmussen, M. R., Henderson, C., Demetrio, C., Rich, W., Joseph, C., Hudak, M., Osbeck, S., Case, E., Kellum, A., Hogans, L., D'Angio, C. T., Reubens, L., Hutton, G., Laptook, A., Madison, S., Hensley, G., Miller, N., Metoyer, G., Kennedy, K., McDavid, G., Emerson, D., Konduri, G., Paquette, M., Wong, S., Aschner, J., O'Shea, T. M., Peters, N., Hansell, B. J., Griffin, J., Adams, C., Shankaran, S., Bara, R. A., Muran, G., Weekfall, W., Ehrenkranz, R. A., Gettner, P., Caldwell, A., Oh, W., Fanaroff, A. A., Goldberg, R. N., Stoll, B. J., Lemons, J. A., Stevenson, D. K., Carlo, W. A., Donovan, E. F., Finer, N. N., Duara, S., Phelps, D. L., Laptook, A. R., TYSON, J. E., O'Shea, T. M., Shankaran, S., Ehrenkranz, R. A., Jobe, A., Poole, W. K., Hastings, B., Petrie, C., Higgins, R. D., Wright, L. L., McClure, E., BULAS, D., Mertens, D., Slovis, T., Avery, G., D'Alton, M., Poole, W. K., Fletcher, J. C., Gleason, C. A., Redmond, C. 2005; 353 (1): 13-22

  Abstract

  Inhaled nitric oxide is a controversial treatment for premature infants with severe respiratory failure. We conducted a multicenter, randomized, blinded, controlled trial to determine whether inhaled nitric oxide reduced the rate of death or bronchopulmonary dysplasia in such infants.We randomly assigned 420 neonates, born at less than 34 weeks of gestation, with a birth weight of 401 to 1500 g, and with respiratory failure more than four hours after treatment with surfactant to receive placebo (simulated flow) or inhaled nitric oxide (5 to 10 ppm). Infants with a response (an increase in the partial pressure of arterial oxygen of more than 10 mm Hg) were weaned according to protocol. Treatment with study gas was discontinued in infants who did not have a response.The rate of death or bronchopulmonary dysplasia was 80 percent in the nitric oxide group, as compared with 82 percent in the placebo group (relative risk, 0.97; 95 percent confidence interval, 0.86 to 1.06; P=0.52), and the rate of bronchopulmonary dysplasia was 60 percent versus 68 percent (relative risk, 0.90; 95 percent confidence interval, 0.75 to 1.08; P=0.26). There were no significant differences in the rates of severe intracranial hemorrhage or periventricular leukomalacia. Post hoc analyses suggest that rates of death and bronchopulmonary dysplasia are reduced for infants with a birth weight greater than 1000 g, whereas infants weighing 1000 g or less who are treated with inhaled nitric oxide have higher mortality and increased rates of severe intracranial hemorrhage.The use of inhaled nitric oxide in critically ill premature infants weighing less than 1500 g does not decrease the rates of death or bronchopulmonary dysplasia. Further trials are required to determine whether inhaled nitric oxide benefits infants with a birth weight of 1000 g or more.

  View details for Web of Science ID 000230267300004

  View details for PubMedID 16000352

• Inhaled NO and markers of oxidant injury in infants with respiratory failure. Journal of perinatology Van Meurs, K. P., Cohen, T. L., Yang, G., Somaschini, M., Kuruma, P., Dennery, P. a. 2005; 25 (7): 463-469

  Abstract

  Inhaled nitric oxide (iNO) is an effective adjunct in the treatment of infants with respiratory failure. Although there are clear benefits to this therapy, potential toxicity could result from reactive nitrosylated species.To evaluate whether iNO therapy is associated with increased serum markers of oxidative stress.Multiple markers were prospectively evaluated in the serum of term infants with severe respiratory failure treated with iNO for 1 to 72 hours. These were compared to those of patients exposed to greater than 80% oxygen for more than 6 hours and room air controls.After 24 hours of exposure, the iNO-treated infants had increased serum lipid hydroperoxides (LPO), protein carbonyls and nitrotyrosine residues as well as increased serum total glutathione (GSH) content. The increase in LPO peaked at 24 hours and correlated with the cumulative dose of iNO whereas other markers did not. The presence of chronic lung disease (CLD) did not correlate with serum markers of oxidative injury.In term infants with respiratory failure, prolonged iNO exposure is associated with a transient increase in markers of oxidative stress, but this finding does not appear to predict the development of CLD.

  View details for PubMedID 15889132

• ECMO for neonatal respiratory failure SEMINARS IN PERINATOLOGY Bahrami, K. R., Van Meurs, K. P. 2005; 29 (1): 15-23

  Abstract

  Extracorporeal membrane oxygenation (ECMO) has been offered as a life-saving technology to newborns with respiratory and cardiac failure refractory to maximal medical therapy. ECMO has been used in treatment of neonates with a variety of cardio-respiratory problems, including meconium aspiration syndrome (MAS), persistent pulmonary hypertension of the neonate (PPHN), congenital diaphragmatic hernia (CDH), sepsis/pneumonia, respiratory distress syndrome (RDS), air leak syndrome, and cardiac anomalies. For this group of high-risk neonates with an anticipated mortality rate of 80% to 85%, ECMO has an overall survival rate of 84%, with recent data showing nearly 100% survival in many diagnostic groups. This article reviews the current selection criteria for ECMO and the clinical management of neonates on ECMO, and discusses the long-term outcome of neonates treated with ECMO.

  View details for DOI 10.1053/j.semperi.2005.02.004

  View details for Web of Science ID 000228783700004

  View details for PubMedID 15921148

• Utilization and outcomes of neonatal cardiac extracorporeal life support: 1996-2000. Pediatric critical care medicine Hintz, S. R., Benitz, W. E., Colby, C. E., Sheehan, A. M., Rycus, P., Van Meurs, K. P. 2005; 6 (1): 33-38

  Abstract

  Extracorporeal life support for neonatal respiratory failure has decreased, but utilization and outcome of cardiac extracorporeal life support are not well characterized. Among neonates born 1996-2000, our objects were to evaluate changes in utilization and outcome of cardiac extracorporeal life support and characterize correlates of survival.Retrospective analysis of Extracorporeal Life Support Organization Registry data.Intensive care units participating in the ELSO registry.Patients placed on extracorporeal life support for center-specified "cardiac support" at 15 days was associated with improved survival among hypoplastic left heart syndrome patients (p = .03), and survivors had fewer mean extracorporeal life support hours (89.3 +/- 52.3 vs. 147.5 +/- 129.7, p = .015). Logistic regression showed that only greater number of hours on extracorporeal life support was independently associated with nonsurvival.Neonatal cardiac extracorporeal life support use increased substantially from 1996 to 2000, with survival to discharge or transfer in more than one third of patients. Hypoplastic left heart syndrome was not associated with nonsurvival. Fewer hours on extracorporeal life support, diagnoses of persistent pulmonary hypertension of the neonate and transposition of the great arteries, and extracorporeal life support at <3 days were associated with survival.

  View details for PubMedID 15636656

• Inhaled nitric oxide therapy in the premature infant with respiratory distress syndrome NeoReviews Van Meurs KP 2005; 6 (6): e268-277
• Surfactant replacement therapy on ECMO does not improve outcome in neonates with congenital diaphragmatic hernia JOURNAL OF PEDIATRIC SURGERY Colby, C. E. 2004; 39 (11): 1632-1637

  Abstract

  Respiratory failure in neonates with congenital diaphragmatic hernia (CDH) may in part be caused by a primary or secondary surfactant deficiency. Knowledge of the optimal approach to surfactant replacement in neonates with CDH and respiratory failure is limited. The aim of this study was to determine if surfactant replacement on extracorporeal membrane oxygenation (ECMO) results in improved outcomes in neonates > or =35 weeks' gestation with unrepaired CDH.Using the CDH Study Group Registry, the authors identified 448 neonates with CDH who were > or =35 weeks' gestation, had no major anomalies, were treated with ECMO within the first 7 days of life, and underwent repair on or after ECMO therapy. Patients in 2 groups were compared: group 1 (- Surf, n = 334) consisted of patients who received no surfactant and group 2 (+ Surf, n = 114) consisted of patients who received at least 1 dose of surfactant while on ECMO. An analysis of all patients in both groups was performed. Additionally, subgroup analyses stratified by gestational age were performed for patients 351/7 to 366/7 weeks' gestation and for patients > or =37 weeks' gestation. Primary end-points for the study were survival and length of ECMO run. Secondary end-points were length of intubation, need for supplemental oxygen at 30 days of life, and at discharge to home. Demographic, clinical, and outcome variables were examined using Fisher's Exact tests for categorical variables and using unpaired t tests for continuous variables. Odds ratios were calculated for categorical end-point variables.Demographic and clinical variables were similar between groups. Analyses of aggregate data showed no significant differences between groups in length of ECMO run, survival, number of days intubated, and percent of patients requiring supplemental oxygen at 30 days or discharge. Subgroup stratification by gestational age did not show significant differences between groups in any of the outcome variables.The data from this study suggest that surfactant replacement on ECMO for neonates with congenital diaphragmatic hernia does not provide significant benefit in the infant's clinical course with respect to survival, length of ECMO course, length of intubation, or subsequent need for supplemental oxygen.

  View details for DOI 10.1016/j.pedsurg.2004.07.005

  View details for Web of Science ID 000225445100005

  View details for PubMedID 15547824

• Is surfactant therapy beneficial in the treatment of the term newborn infant with congenital diaphragmatic hernia? JOURNAL OF PEDIATRICS Van Meurs, K. 2004; 145 (3): 312-316

  Abstract

  To determine the impact of surfactant replacement on survival, need for extracorporeal membrane oxygenation (ECMO), and chronic lung disease in term infants with prenatally diagnosed congenital diaphragmatic hernia (CDH).Prenatally diagnosed infants born at > or =37 weeks' gestation with immediate distress at delivery and no other major congenital anomalies, who were enrolled in the CDH Registry, were analyzed. For univariate analysis, chi 2 tests were used for categoric variables and unpaired t tests for nominal variables. Multiple logistic regression was used to calculate adjusted odds ratios.Eligible infants (n = 522) were identified. Demographic variables were similar between the surfactant-treated (n = 192) and nonsurfactant-treated (n = 330) groups, with the exception of race (white, 88.0% vs 71.2%; P =.0007). The use of ECMO and incidence of chronic lung disease were higher (59.8 vs 50.6, P =.04; 59.9 vs 47.6, P =.0066) and survival lower in the surfactant-treated cohort (57.3 vs 70.0, P =.0033). Adjusted logistic regression for use of ECMO, survival, and chronic lung disease resulted in odds ratios inconsistent with an improved outcome associated with surfactant use.This analysis shows no benefit associated with surfactant therapy for term infants with a prenatal diagnosis of isolated CDH.

  View details for DOI 10.1016/j.jpeds.2004.04.056

  View details for Web of Science ID 000223857400011

  View details for PubMedID 15343181

• Surfactant does not improve survival rate in preterm infants with congenital diaphragmatic hernia 56th Annual Meeting of the American-Academy-of-Pediatrics Lally, K. P., Lally, P. A., Langham, M. R., Hirschl, R., Moya, F. R., Tibboel, D., Van Mears, K. W B SAUNDERS CO-ELSEVIER INC. 2004: 829–33

  Abstract

  Use of exogenous surfactant in congenital diaphragmatic hernia (CDH) patients is routine in many centers. The authors sought to determine the impact of surfactant use in the premature infant with CDH.Data on liveborn infants with CDH from participating institutions were collected prospectively. Surfactant use and timing and outcome data were analyzed retrospectively. The authors evaluated the prenatal diagnosis patients as well. The outcome variable was survival to discharge. Odds ratios with confidence intervals were calculated.Five hundred ten infants less than 37 weeks' gestation were entered in the CDH registry. Infants with severe anomalies (n = 80) were excluded. Information on surfactant use was available for 424 patients. Infants receiving surfactant (n = 209) had a greater odds of death than infants not receiving surfactant (n = 215, odds ratio, 2.17, 95% CI: 1.5 to 3.2; P <.01). In prenatally diagnosed infants with immediate distress, there was a trend toward worse survival rates among those receiving surfactant at 1 hour (52 patients) versus those that did not (93 patients; odds ratio, 1.93, 95% CI: 0.96 to 3.9; P <.07).Surfactant, as currently used, is associated with a lower survival rate in preterm infants with CDH. The use of surfactant replacement in premature infants with CDH can be recommended only within the context of a randomized clinical trial.

  View details for DOI 10.1016/j.jpedsurg.2004.02.011

  View details for Web of Science ID 000222262900014

  View details for PubMedID 15185206

• A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure PEDIATRICS Konduri, G. G., Solimano, A., Sokol, G. M., Singer, J., Ehrenkranz, R. A., Singhal, N., Wright, L. L., Van Meurs, K., Stork, E., Kirpalani, H., Peliowski, A. 2004; 113 (3): 559-564

  Abstract

  Inhaled nitric oxide (iNO) reduces the use of extracorporeal membrane oxygenation (ECMO)/incidence of death in term and near-term neonates with severe hypoxic respiratory failure. We conducted a randomized, double masked, multicenter trial to determine whether administration of iNO earlier in respiratory failure results in additional reduction in the incidence of these outcomes.Neonates who were born at > or =34 weeks' gestation were enrolled when they required assisted ventilation and had an oxygenation index (OI) > or =15 and <25 on any 2 measurements in a 12-hour interval. Infants were randomized to early iNO or to simulated initiation of iNO (control). Infants who had an increase in OI to 25 or more were given iNO as standard therapy.The trial enrollment was halted after 75% of target sample size was reached because of decreasing availability of eligible patients. The 150 infants who were given early iNO and 149 control infants had similar baseline characteristics. Arterial oxygen tension increased by >20 mm Hg in 73% of early iNO and 37% of control infants after study gas initiation. Control infants received standard iNO and deteriorated to OI >40 more often than infants who were given early iNO. The incidence of death (early iNO, 6.7% vs control, 9.4%), ECMO (10.7% vs 12.1%), and their combined incidence (16.7% vs 19.5%) were similar in both groups.iNO improves oxygenation but does not reduce the incidence of ECMO/mortality when initiated at an OI of 15 to 25 compared with initiation at >25 in term and near-term neonates with respiratory failure.

  View details for Web of Science ID 000189344400020

  View details for PubMedID 14993550

• Neonatal Inhaled Nitric Oxide Study Group. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics Konduri GG, Solimano A, Sokol GM, Singer J, Ehrenkranz RA, Singal N, Wright LL, Van Meurs K, Stork E, Kirpalani H, Peliowski A. 2004; 113: 559-564
• Maintaining adequate anticoagulation on extracorporeal membrane oxygenation therapy: Hemochron Junior Low Range versus Hemochron 400. The Journal of extra-corporeal technology Colby, C. E., Sheehan, A., Benitz, W., Van Meurs, K., Halamek, L. P., Moss, R. L. 2003; 35 (1): 35-38

  Abstract

  Extracorporeal membrane oxygenation (ECMO) therapy requires that patients be anticoagulated to prevent clotting and thrombotic complications. There are several bedside whole blood microcoagulation systems available to determine activated clotting time (ACT) levels. Many ECMO centers use Hemochron (International Technidyne, Edison, NJ) products to determine ACT levels. During the study period, we used the Hemochron 400 and then changed to the Hemochron Junior Low Range. There were two specific aims of this study. First, to determine if there was a difference in ACT levels measured by these two distinct Hemochron products both marketed for the use in ECMO therapy. Second, to determine if the differing ACT levels produced by these two devices affected clinical outcomes. We compared ACT levels between two devices on 70 paired blood specimens obtained from four neonatal ECMO patients receiving heparin. A retrospective review of 77 ECMO patients was performed to analyze frequency of circuit emergencies and length of ECMO circuit life while using the two products. In lower ACT ranges, the Hemochron Jr. LR consistently yielded higher ACT values than the Hemochron 400. In higher ACT ranges, the Hemochron Jr. LR consistently yielded lower ACT values than the Hemochron 400. Without calibration, after changing devices, this discrepancy led to shorter circuit life and more circuit clotting complications. After calibration and adjustment in target ACT values, there was a trend toward longer circuit life, and there were fewer clotting complications. There is a difference in the ACT values produced by Hemochron 400 and Hemochron Jr. LR. Failure to calibrate target ACT levels after changing machines may lead to shorter circuit life and more clotting complications.

  View details for PubMedID 12680494

• Use of bronchoscopy for conenital diaphragmatic hernia patients on extracorporeal membrane oxygenation. Clin Intens Care Hintz SR, Sheehan AM, Halamek LP, Rhine WD, Van Meurs KP, Benitz WE, Frankel LR. 2002; 13 (2-3): 101-106
• Venoarterial versus venovenous extracorporeal membrane oxygenation in congenital diaphragmatic hernia: The Extracorporeal Life Support Organization Registry, 1990-1999 31st Annual Meeting of the Section-on-Surgery of the American-Academy-of-Pediatrics Dimmitt, R. A., Moss, R. L., Rhine, W. D., Benitz, W. E., Henry, M. C., VanMeurs, K. P. W B SAUNDERS CO-ELSEVIER INC. 2001: 1199–1204

  Abstract

  Venoarterial (VA) extracorporeal membrane oxygenation (ECMO) traditionally has been the mode of support used in congenital diaphragmatic hernia (CDH). A few studies report success using venovenous (VV) ECMO. The purpose of this study is to compare outcomes in CDH patients treated with VA and VV.The authors queried the Extracorporeal Life Support Organization Registry for newborns with CDH treated with ECMO from January 1, 1990 through December 31, 1999. They analyzed the pre-ECMO data, ECMO course, and complications.VA was utilized in 2,257 (86%) and VV in 371 (14%) patients. The pre-ECMO status was similar, with greater use of nitric oxide, surfactant, and pressors in VV. Survival rate was similar (58.4% for VV and 52.2% for VA, P =.057). VA was associated with more seizures (12.3% v 6.7%, P =.0024) and cerebral infarction (10.5% v 6.7%, P =.03). Sixty-four treatments were converted from VV to VA (VV-->VA). Survival rate in VV-->VA was not significantly different than VA (43.8% v 52.2%, respectively; P =.23). VV-->VA and VA patients had similar neurologic complications.CDH patients treated with VV and VA have similar survival rates. VA had more neurologic complications. The authors identified no disadvantage to the use of VV as an initial mode of ECMO for CDH, although some infants may need conversion to VA.

  View details for DOI 10.1053/jpsu.2001.25762

  View details for Web of Science ID 000170120300021

  View details for PubMedID 11479856

• Early high-frequency oscillatory ventilation versus synchronized intermittent mandatory ventilation in very low birth weight infants: a pilot study of two ventilation protocols. Journal of perinatology Durand, D. J., Asselin, J. M., Hudak, M. L., Aschner, J. L., MCARTOR, R. D., Cleary, J. P., VanMeurs, K. P., Stewart, D. L., Shoemaker, C. T., WISWELL, T. E., Courtney, S. E. 2001; 21 (4): 221-229

  Abstract

  To evaluate the feasibility of conducting a prospective, randomized trial comparing early high-frequency oscillatory ventilation (HFOV) to synchronized intermittent mandatory ventilation (SIMV) in very low birth weight (VLBW) premature infants. This pilot study evaluated two ventilator management protocols to determine how well they could be implemented in a multicenter clinical trial. Although this pilot study was not powered to detect differences in outcome, we also collected outcome data.Prospective, multicenter, randomized pilot study.Seven tertiary-level intensive care nurseries with previous experience with both HFOV and flow-triggered SIMV.Fifty infants weighing 501 to 1200 g, less than 4 hours of age, who had received one dose of surfactant and required ventilation with mean airway pressure > or =6 cm H2O and F(I)O2 > or =0.25, and had an anticipated duration of ventilation greater than 24 hours.Patients were stratified by birth weight and prenatal steroid status, then randomized to either HFOV or SIMV with tidal volume monitoring. Ventilator management for patients in both study arms was strictly governed by protocols that included optimizing lung inflation and blood gases, weaning strategies, and extubation criteria.Data were collected using the tools planned for the larger collaborative study. Protocol compliance was closely monitored, with successive changes in the protocol made as necessary to improve clarity and increase compliance. The incidence of major neonatal adverse outcomes was recorded.Data are presented for 24 HFOV and 24 SIMV infants (two infants, twins, were withdrawn from the study at parent's request). Nineteen of the 24 HFOV infants and 20 of the 24 SIMV infants survived to 36 weeks corrected age. Age at final extubation for survivors was 16+/-16 (mean+/-SD) days for HFOV infants and 24+/-24 days for SIMV infants. At 36 weeks corrected age, 14 of the 19 HFOV survivors were extubated and in room air, whereas 5 required supplemental oxygen. In comparison, 6 of the 20 SIMV survivors were extubated and in room air, whereas 14 required supplemental oxygen. Grade III/IV IVH and/or periventricular leukomalacia occurred in 2 HFOV and 2 SIMV patients. Overall compliance with the ventilator protocols was 82% for the SIMV protocol, and 88% for the HFOV protocol.The preliminary outcome data supports conducting the large randomized trial, which began in July of 1998. The protocols for the ventilator management of VLBW infants, both with HFOV and with SIMV were easily implemented and consistently followed, and are presented here.

  View details for PubMedID 11533838

• Decreased use of neonatal extracorporeal membrane oxygenation (ECMO): How new treatment modalities have affected ECMO utilization PEDIATRICS Hintz, S. R., Suttner, D. M., Sheehan, A. M., Rhine, W. D., Van Meurs, K. P. 2000; 106 (6): 1339-1343

  Abstract

  Over the last decade, several new therapies, including high-frequency oscillatory ventilation (HFOV), exogenous surfactant therapy, and inhaled nitric oxide (iNO), have become available for the treatment of neonatal hypoxemic respiratory failure. The purpose of this retrospective study was to ascertain to what extent these modalities have impacted the use of neonatal extracorporeal membrane oxygenation (ECMO) at our institution.Patients from 2 time periods were evaluated: May 1, 1993 to November 1, 1994 (group 1) and May 1, 1996 to November 1, 1997 (group 2). During the first time period (group 1), HFOV was not consistently used; beractant (Survanta) use for meconium aspiration syndrome (MAS), persistent pulmonary hypertension of the newborn (PPHN), and pneumonia was under investigation; and iNO was not yet available. During the second time period (group 2), HFOV and beractant treatment were considered to be standard therapies, and iNO was available to patients with oxygenation index (OI) >/=25 x 2 at least 30 minutes apart, or on compassionate use basis. Patients were included in the data collection if they met the following entry criteria: 1) OI >15 x 1 within the first 72 hours of admission; 2) EGA >/=35 weeks; 3) diagnosis of MAS, PPHN or sepsis/pneumonia; 4) <5 days of age on admission; and 5) no congenital heart disease, diaphragmatic hernia, or lethal congenital anomaly.Of the 49 patient in group 1, 21 (42.8%) required ECMO therapy. Of these ECMO patients, 14 (66.6%) had received diagnoses of MAS or PPHN. Only 3 of the patients that went on to ECMO received beractant before the initiation of bypass (14.3%). All ECMO patients in group 1 would have met criteria for iNO had it been available. Of all patients in group 1, 18 (36.7%) were treated with HFOV, and 13 (26.5%) received beractant. Of the 47 patients in group 2, only 13 (27.7%) required ECMO therapy (compared with group 1). Of these ECMO patients, only 5 (38.5%) had diagnoses of MAS or PPHN, with the majority of patients (61.5%) requiring ECMO for sepsis/pneumonia, with significant cardiovascular compromise. Only 5 of these ECMO patients, all outborn, did not receive iNO before cannulation because of the severity of their clinical status on admission. Of all patients in group 2, 41 (87.2%) were treated with HFOV (compared with group 1), 42 (89.3%) received beractant (compared with group 1), and 18 (44.7%) received iNO.The results indicate that ECMO was used less frequently when HFOV, beractant and iNO was more commonly used. The differences in treatment modalities used and subsequent use of ECMO were statistically significant. We speculate that, in this patient population, the diagnostic composition of neonatal ECMO patients has changed over time.

  View details for Web of Science ID 000165914800020

  View details for PubMedID 11099586

• Secondary infection presenting as recurrent pulmonary hypertension. Journal of perinatology Hintz, S. R., Benitz, W. E., Halamek, L. P., Van Meurs, K. P., Rhine, W. D. 2000; 20 (4): 262-264

  Abstract

  Primary infection in the neonate, especially group B streptococcal infection, has long been recognized as a cause of persistent pulmonary hypertension of the newborn (PPHN), sometimes requiring treatment with inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO). However, secondary nosocomial infections in the neonatal period have not been widely reported as a cause of severe recurrent pulmonary hypertension (PHTN). We now present two cases of secondary infection in the neonate leading to significant PHTN. In both cases, the infants presented with PPHN soon after birth, requiring transfer to a level 3 neonatal intensive care unit and treatment with high-frequency oscillatory ventilation and iNO. After successful resolution of the initial PPHN, including extubation to nasal cannula, both infants developed signs of severe recurrent PHTN, leading to reintubation, high-frequency oscillatory ventilation and iNO therapy, and consideration of ECMO. In both cases, blood cultures taken at the time of recurrence of PHTN returned positive, one for Staphylococcus epidermidis, the other for methicillin-resistant Staphylococcus aureus. These unusual cases present the possibility of severe recurrent PHTN requiring iNO or ECMO in the setting of secondary infection. We speculate that these infants, although extubated after their first episodes of PHTN, were at risk for recurrence of PHTN due to continued pulmonary vascular reactivity.

  View details for PubMedID 10879342

• Inhaled nitric oxide in term and near-term infants: Neurodevelopmental follow-up of The Neonatal Inhaled Nitric Oxide Study Group (NINOS) JOURNAL OF PEDIATRICS Finer, N. N., Vohr, B. R., Robertson, C. M., Ehrenkranz, R. A., Verter, J., Wright, L. L., Hoffman, H. J., Walsh-Sukys, M. C., Dusick, A. M., Fleisher, B. E., Steichen, J., Laadt, G., Yolton, K., Delaney-Black, V., Vohr, B. R., Whitfield, M. F., Blayney, M. P., Sauve, R. S., Casiro, O. G., Saigal, S., Riley, S. P., Robertson, C. M., Sankaran, K., Gosselin, R., Reynolds, A., Stork, E., Gorjanc, E., Verter, J., Powers, T., Sokol, G. M., Appel, D., Wright, L. L., Van Meurs, K., Rhine, W., Ball, B., Brilli, R., Moles, L., Crowley, M., Backstrom, C., Crouse, D., Hudson, T., Konduri, G. G., Bara, R., Kleinman, M., Hensmann, A., Rothstein, R. W., Ehrenkranz, R. A., Solimano, A., Germain, F., Walker, R., Ramirez, A. M., Singhal, N., Bourcier, L., Fajardo, C., Cook, V., Kirpalani, H., Monkman, S., Johnston, A., Mullahoo, K., Finer, N. N., Peliowski, A., Etches, P., Kamstra, B., Sankaran, K., Riehl, A., Blanchard, P., Gouin, R., Wearden, M. E., Gomez, M. R., Moon, Y. S., Avery, G. B., D'Alton, M. E., Bracken, M. B., Catz, C., Gleason, C. A., Maguire, M., Redmond, C. K., Sinclair, J. C., Verter, J. 2000; 136 (5): 611-617

  Abstract

  Inhaled nitric oxide (INO) improved oxygenation and reduced the occurrence of death or extracorporeal membrane oxygenation in term and near-term hypoxic neonates. We report the results of neurodevelopmental follow-up of infants enrolled in the NINOS trial.Hypoxic infants >/=34 weeks' gestation and <14 days of age were randomized to 20 ppm INO or 100% oxygen as control. Comprehensive neurodevelopmental assessment of survivors occurred at 18 to 24 months of age.A total of 235 infants were enrolled in the original trial. There were 36 deaths, 20 of 121 infants in the control group and 16 of 114 infants in the INO-treated group. Of the 199 surviving infants, 173 (86.9%) were seen for follow-up (88 members of the control group and 85 members of the INO-treated group), and 135 infants were normal (69 [79.3%] members of the control group and 66 [77.6%] members of the INO-treated group). Twenty-two infants had sensorineural hearing loss (12 members of the control group and 10 members of the INO-treated group). Moderate to severe cerebral palsy occurred in 13 infants (7 infants in the control group and 6 infants in the INO-treated group). Mental developmental index scores (87 +/- 18.7 in the control group vs 85 +/- 21.7 in the INO-treated group) and psychomotor developmental index scores (93.6 +/- 17.5 in the control group vs 85.7 +/- 21.2 in the INO-treated group) were not different. A total of 29.6% of the control group compared with 34.5% of the INO-treated group had at least one disability. Infants with congenital diaphragmatic hernia, enrolled in a separate but parallel trial, had similar outcomes with a higher incidence of sensorineural hearing loss.Inhaled nitric oxide is not associated with an increase in neurodevelopmental, behavioral, or medical abnormalities at 2 years of age.

  View details for Web of Science ID 000086985900011

  View details for PubMedID 10802492

• Inhaled nitric oxide in term and near-term infants: Neurodevelopmental follow-up of the Neonatal Inhaled Nitric Oxide Study Group (NINOS). J Pediatr The Neonatal Inhaled Nitric Oxide Study Group (NINOS). 2000; 136 (5): 611-617
• Congenital diaphragmatic hernia: the neonatologist's perspective. Pediatrics in review Van Meurs, K., Lou Short, B. 1999; 20 (10): e79-87

  View details for PubMedID 10512896

• Nitrogen dioxide formation during inhaled nitric oxide therapy CLINICAL CHEMISTRY Sokol, G. M., Van Meurs, K. P., Wright, L. L., Rivera, O., Thorn, W. J., Chu, P. M., Sams, R. L. 1999; 45 (3): 382-387

  Abstract

  Nitrogen dioxide (NO2) is a toxic by-product of inhalation therapy with nitric oxide (NO). The rate of NO2 formation during NO therapy is controversial.The formation of NO2 was studied under dynamic flows emulating a base case NO ventilator mixture containing 80 ppm NO in a 90% oxygen matrix. The difficulty in measuring NO2 concentrations below 2 ppm accurately was overcome by the use of tunable diode laser absorption spectroscopy.Using a second-order model, the rate constant, k, for NO2 formation was determined to be (1.19 +/- 0.11) x 10(-11) ppm-2s-1, which is in basic agreement with evaluated data from atmospheric literature.Inhaled NO can be delivered safely in a well-designed, continuous flow neonatal ventilatory circuit, and NO2 formation can be calculated reliably using the rate constant and circuit dwell time.

  View details for Web of Science ID 000078979100009

  View details for PubMedID 10053039

• Cigarette smoking, pregnancy, and the developing fetus. Stanford Medical Review Van Meurs KP 1999; 1 (1): 14-16
• Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. J Pediatr Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH, the Survanta Term Infants Study Group. 1998; 132: 40-47
• Response of premature infants with severe respiratory failure to inhaled nitric oxide. Preemie NO Collaborative Group. Pediatric pulmonology Van Meurs, K. P., Rhine, W. D., Asselin, J. M., Durand, D. J. 1997; 24 (5): 319-323

  Abstract

  Elevated pulmonary vascular resistance is seen in premature infants with severe respiratory distress syndrome (RDS). Inhaled nitric oxide (NO) has been shown to decrease pulmonary vascular resistance and to improve oxygenation in some patients with respiratory failure. The purpose of this study was to determine whether premature infants with severe RDS would respond to inhaled NO with an improvement in oxygenation. Eleven premature infants (mean gestational age 29.8 weeks) with severe respiratory failure caused by RDS were treated with NO in four concentrations [1, 5, 10, 20 parts per million (ppm) NO] and with placebo (0 ppm NO). Arterial blood gas measurements were drawn immediately before and at the end of each of the 15-minute treatments and were used to determine the arterial/alveolar oxygen ratio (PaO2/PAO2). Ten of the 11 infants had a greater than 25% increase in PaO2/PAO2. Five of the 11 had a greater than 50% increase in PaO2/PAO2. Despite normal cranial ultrasound imaging prior to NO, 3 infants had intracranial hemorrhage (ICH) noted on their first ultrasound scan after this brief period of NO treatment, and 4 additional infants developed ICH later during their hospitalization. No infant had significant elevations of methemoglobin concentrations after the total 60-minute exposure to NO. NO may be an effective method of improving oxygenation in infants with severe RDS. The disturbing incidence of ICH in this small group of infants needs to be carefully evaluated before considering routine use or NO for preterm infants.

  View details for PubMedID 9407564

• Response of premature infants with severe respiratory failure to inhaled nitric oxide 66th Annual Meeting of the Society-for-Pediatric-Research VanMeurs, K. P., Rhine, W. D., Asselin, J. M., Durand, D. J., Peverini, R., Dudell, G., Butler, S., Durand, D., Asselin, J., VANMEURS, K., Rhine, W. WILEY-LISS. 1997: 319–23

  View details for Web of Science ID A1997YJ50900003

• Hemopericardium from coronary artery laceration complicating extracorporeal membrane oxygenation. Journal of perinatology Rhine, W. D., Hartman, G. E., Shochat, S. J., Benitz, W. E., Van Meurs, K. P. 1997; 17 (3): 189-192

  Abstract

  We report the clinical course and successful surgical treatment of hemopericardium resulting from coronary artery (CA) laceration in two patients with congenital diaphragmatic hernia (CDH) undergoing extracorporeal membrane oxygenation (ECMO) bypass.Retrospective case review.Two neonates with CDH had needle aspiration for either pneumothorax or pericardial effusion before initiation of ECMO. While on bypass, progressive hemopericardium led to narrow pulse pressure and decreased venous return that limited bypass flow. Widened cardiac silhouette on chest radiographs suggested hemopericardium; echocardiography was confirmatory in one case. The underlying diagnosis of CA laceration was made during pericardiotomy and treated with surgical patching.Pre-ECMO history of cardiothoracic needle aspiration is important because complications such as hemothorax or hemopericardium may arise once ECMO bypass is initiated. Inadvertent CA laceration may lead to acute hemopericardium, compromising venous drainage. However, CA laceration can be successfully repaired while the patient is on bypass.

  View details for PubMedID 9210072

• Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure NEW ENGLAND JOURNAL OF MEDICINE Stork, E., Gorjanc, E., Verter, J., Younes, N., Stenzel, B. A., Powers, T., Sokol, G., Wright, L. L., Yaffe, S. J., Catz, C., VANMEURS, K., Rhine, W., Ball, B., Brilli, R., Moles, L., Crowley, M., Backstrom, C., Crouse, D., Hudson, T., Konduri, G., Bara, R., Kleinman, M., Hensman, A., Rothstein, R. W., Ehrenkranz, R. A., Solimano, A., Germain, F., Walker, R., Ramirez, A. M., Singhal, N., Bourcier, L., Fajardo, C., Cook, V., Kirpalani, H., Monkman, S., Johnston, A., Mullahoo, K., Finer, N. N., Peliowski, A., Etches, P., Kamstra, B., Sankarhan, K., Riehl, A., Blanchard, P., Gouin, R., Wearden, M., Gomez, M., Moon, Y., Bauer, C. R., Donovan, E. F., Fanaroff, A. A., Korones, S. B., Lemons, J. A., Oh, W., Papile, L. A., Shankaran, S., Stoll, B. J., TYSON, J. E., Avery, G., DALTON, M., Bracken, M. B., Gleason, C. A., Maguire, M., Redmond, C., Silverman, W., Sinclair, J. 1997; 336 (9): 597-604

  View details for Web of Science ID A1997WK02800001

• Inhaled nitric oxide in full term and nearly full term infants with hypoxic respiratory failure. N Engl J Med The Neonatal Inhaled Nitric Oxide Study Group (NINOS) 1997; 336: 597-604
• Nitrovasodilator therapy for severe respiratory distress syndrome. Journal of perinatology Benitz, W. E., Rhine, W. D., Van Meurs, K. P., Stevenson, D. K. 1996; 16 (6): 443-448

  Abstract

  Improved gas exchange in infants with severe respiratory distress syndrome has been reported in association with infusion of nitroprusside and during inhalation of nitric oxide. To evaluate the association between nitrovasodilator therapy and clinical improvement in premature neonates with severe respiratory distress syndrome, we reviewed the courses of 22 infants with severe respiratory distress syndrome who were treated with sodium nitroprusside for at least 24 hours. These infants had birth weights of 2049 +/- 828 gm (range 720 to 3430 gm), gestational ages of 32.5 +/- 3.5 weeks (range 25 to 38 weeks), high ventilator settings before treatment (FIO2 of 100%, peak inspiratory pressures of 37.8 +/- 6.1 cm H2O [range 30 to 50 cm H2O], and mean airway pressures of 18.0 +/- 3.3 cm H2O [range 12.3 to 26 cm H2O]), and low pretreatment PaO2 of 49.3 +/- 9.4 mm Hg (range 27 to 69 mm Hg). Baseline oxygenation indexes were 39.4 +/- 12.1 (range 18.6 to 66.7). Nitroprusside infusion was temporally associated with increased PaO2, decreased PaCO2, and reduced oxygenation index. Potentially beneficial changes were inconsistent in infants with pulmonary interstitial emphysema and were greatest in infants treated with end-expiratory pressures of at least 4 cm H2O. These observations provide a basis for the hypothesis that nitrovasodilator therapy produces improvement in gas exchange in premature infants with severe respiratory distress syndrome.

  View details for PubMedID 8979182

• CARDIAC TRANSPLANTATION FOR HYPERTROPHIC CARDIOMYOPATHY ASSOCIATED WITH SENGERS-SYNDROME ANNALS OF THORACIC SURGERY Robbins, R. C., Bernstein, D., Berry, G. J., VanMeurs, K. P., Frankel, L. R., Reitz, B. A. 1995; 60 (5): 1425-1427

  Abstract

  Sengers' syndrome is a rare condition consisting of congenital cataracts, mitochondrial myopathy, and hypertrophic cardiomyopathy. The syndrome is transmitted in an autosomal recessive pattern. Progressive cardiac failure is the cause of death in most patients. This report describes cardiac transplantation for the treatment of the cardiomyopathy associated with Sengers' syndrome.

  View details for Web of Science ID A1995TE95600056

  View details for PubMedID 8526648

• INHALED NITRIC-OXIDE DOES NOT ALTER THE LONGITUDINAL DISTRIBUTION OF PULMONARY VASCULAR-RESISTANCE JOURNAL OF APPLIED PHYSIOLOGY LINDEBORG, D. M., Kavanagh, B. P., VANMEURS, K., Pearl, R. G. 1995; 78 (1): 341-348

  Abstract

  Because the effects of inhaled nitric oxide (NO) may be localized to its site of delivery, we studied the effects of inhaled NO on the longitudinal distribution of pulmonary vascular resistance during pulmonary hypertension in perfused rabbit lungs. Before NO administration, pulmonary hypertension was produced by infusion of the thromboxane A2 mimetic U-46619 in all lungs. Pulmonary vascular resistance was divided into arterial, microvascular, and venous components by arterial and venous occlusion techniques. In the buffer-perfused lung, all doses of inhaled NO (5, 20, and 80 ppm) produced small decreases (approximately 3 mmHg) in pulmonary arterial pressure (Ppa), with equivalent proportional reductions in all segmental vascular resistances. Similar results were obtained after an extended inhaled NO dose range of 20, 80, and 240 ppm. In the buffer-perfused lung, inhibition of endogenous NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME) potentiated the effects of U-46619. Subsequent inhaled NO administration produced larger decreases (approximately 7 mmHg) in Ppa with equivalent proportional reductions in all segmental vascular resistances. In the blood-perfused lung, L-NAME did not alter baseline pulmonary pressures. Administration of inhaled NO during U-46619-induced pulmonary hypertension produced dose-related decreases in Ppa. The highest dose (80 ppm) of inhaled NO decreased Ppa by 3.5 mmHg, with equivalent proportional reductions in all segmental vascular resistances.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1995QC30100049

  View details for PubMedID 7713835

• LOBAR LUNG TRANSPLANTATION AS A TREATMENT FOR CONGENITAL DIAPHRAGMATIC-HERNIA JOURNAL OF PEDIATRIC SURGERY VanMeurs, K. P., Rhine, W. D., Benitz, W. E., Shochat, S. J., Hartman, G. E., Sheehan, A. M., Starnes, V. A. 1994; 29 (12): 1557-1560

  Abstract

  The mortality rate for infants severely affected with congenital diaphragmatic hernia (CDH) remains high despite significant advances in surgical and neonatal intensive care including delayed repair and extracorporeal membrane oxygenation (ECMO). Because of the increasingly successful experience with single-lung transplantation in adults; this approach has been suggested as a potential treatment for CDH infants with unsalvageable pulmonary hypoplasia. The authors report on a newborn female infant who was the product of a pregnancy complicated by polyhydramnios. At birth, she was found to have a right-sided CDH and initially was treated with preoperative ECMO, followed by delayed surgical repair. Despite the CDH repair and apparent resolution of pulmonary hypertension, the infant's condition deteriorated gradually after decannulation, and escalating ventilator settings were required as well as neuromuscular paralysis and pressor support because of progressive hypoxemia and hypercarbia. A lung transplant was performed 8 days after decannulation, using the right lung obtained from a 6-week-old donor. The right middle lobe was excised because of the size discrepancy between the donor and recipient. After transplantation, the patient was found to have duodenal stenosis and gastroesophageal reflux, which required duodenoduodenostomy and fundoplication. The patient was discharged from the hospital 90 days posttransplantation, at 3 1/2 months of age. Currently she is 24 months old and doing well except for poor growth. This case shows the feasibility of single-lung transplantation for infants with CDH, and the potential use of ECMO as a temporary bridge to transplantation. Lobar lung transplantation allowed for less stringent size constraints for the donor lung.

  View details for Web of Science ID A1994PW61200018

  View details for PubMedID 7877027

• INTRACRANIAL ABNORMALITIES AND NEURODEVELOPMENTAL STATUS AFTER VENOVENOUS EXTRACORPOREAL MEMBRANE-OXYGENATION JOURNAL OF PEDIATRICS VanMeurs, K. P., Nguyen, H. T., Rhine, W. D., Marks, M. P., Fleisher, B. E., Benitz, W. E. 1994; 125 (2): 304-307

  Abstract

  Computed tomography scans of the head and early neurodevelopmental assessment (Bayley Scales of Infant development) were recorded for 24 surviving infants who received venovenous extracorporeal membrane oxygenation and were compared with those of infants treated with venoarterial bypass matched by diagnosis and oxygenation index before extracorporeal membrane oxygenation. A comparable neuroradiographic and early neurodevelopmental outcome was documented for survivors of venoarterial and venovenous extracorporeal membrane oxygenation.

  View details for Web of Science ID A1994PA95200025

  View details for PubMedID 8040782

• CONGENITAL DIAPHRAGMATIC-HERNIA - LONG-TERM OUTCOME IN NEONATES TREATED WITH EXTRACORPOREAL MEMBRANE-OXYGENATION JOURNAL OF PEDIATRICS VanMeurs, K. P., ROBBINS, S. T., Reed, V. L., Karr, S. S., Wagner, A. E., Glass, P., Anderson, K. D., Short, B. L. 1993; 122 (6): 893-899

  Abstract

  As more infants with congenital diaphragmatic hernia (CDH) survive with extracorporeal membrane oxygenation (ECMO), it seems prudent to detail the longterm outcome in these medically complex infants. Eighteen children with CDH-treated with postoperative ECMO were recruited for participation in this study. The mean duration of ECMO was 193 hours (range 82 to 493 hours), mean time to extubation after ECMO was 142 hours (range 34 to 312 hours), and median duration of hospitalization was 46 days (range 30 to 181 days). Of the 18 infants, 4 (22%) were discharged home requiring oxygen therapy. At follow-up the notable findings were a high incidence of gastroesophageal reflux and failure to thrive. At both 1 and 2 years of age, 50% of infants were at less than the 5th percentile for weight. At 1 and 2 years of age, 39% and 21%, respectively, were at less than the 5th percentile for weight/length ratio. A total of 16 children (89%) had clinical evidence of reflux, and 8 (44%) were discharged home on a regimen of nasogastric feedings. Reherniation occurred in 4 children (22%) and was more frequent when a patch was used. An electrocardiogram showed right ventricular hypertrophy in 6 (43%); oxygen saturation by pulse oximetry was > 95% in all children, and pulmonary artery pressure was estimated by Doppler echocardiography to be normal in 12 of 14 children examined. The neurodevelopmental outcome (Bayley Scales or Stanford-Binet scale) at 1 to 4 years of age was not dissimilar from that of other ECMO-treated children. Given the severity of illness in the neonatal period, the general health and development of children with CDH surviving after ECMO are good. Surprisingly few children have long-term respiratory complications related to pulmonary hypoplasia. Follow-up in the first few years should be aimed at aggressive nutritional intervention to prevent the growth failure that appears to be prevalent in these children.

  View details for Web of Science ID A1993LF55200009

  View details for PubMedID 8501565

• EXTRACORPOREAL LIFE-SUPPORT - ISSUES OF WHO, WHEN, WHY, AND HOW CRITICAL CARE MEDICINE VanMeurs, K. P., Frankel, L. R., Pearl, R. G. 1992; 20 (9): 1200-1202

  View details for Web of Science ID A1992JN86900003

  View details for PubMedID 1521433

• In vitro testing of the 0.6 M2 SciMed membrane oxygenator J Extra Corpor Technol Van Meurs KP, Mikesell GT, Hearty JP III, Seale WR, Rivera O, Short BL. 1992; 23 (2): 49-53
• A FLOW CYTOMETRIC ANALYSIS OF LYMPHOCYTE SUBPOPULATIONS IN NEONATES UNDERGOING EXTRACORPOREAL MEMBRANE-OXYGENATION JOURNAL OF PEDIATRICS DePalma, L., Short, B. L., VANMEURS, K., LUBAN, N. L. 1991; 118 (1): 117-120

  View details for Web of Science ID A1991EU22200026

  View details for PubMedID 1986078

• EFFECT OF EXTRACORPOREAL MEMBRANE-OXYGENATION ON SURVIVAL OF INFANTS WITH CONGENITAL DIAPHRAGMATIC-HERNIA JOURNAL OF PEDIATRICS VanMeurs, K. P., Newman, K. D., Anderson, K. D., Short, B. L. 1990; 117 (6): 954-960

  Abstract

  To determine the effect of extracorporeal membrane oxygenation (ECMO) on the survival of infants with congenital diaphragmatic hernia, we undertook a retrospective review of 31 infants with congenital diaphragmatic hernia treated at Children's National Medical Center. Infants were categorized by means of the Bohn quadrant analysis to determine the impact of ECMO on infants with congenital diaphragmatic hernia and a "poor prognosis." All infants assigned to the Bohn 100% mortality quadrant required ECMO. The survival rate in this group was 86% (6/7) when assessed preoperatively and 67% (6/9) when assessed postoperatively. Comparison of the change occurring in ventilation index and arterial carbon dioxide pressure demonstrated that after repair the clinical condition of 48% of infants deteriorated, 40% improved, and 12% remained unchanged. Of the 12 infants whose condition was worse after surgery, 11 eventually required ECMO. Our review demonstrates that ECMO improved survival significantly in infants with congenital diaphragmatic hernia who had a "poor prognosis" by the criteria of Bohn et al. We recommend consideration of ECMO for all infants with congenital diaphragmatic hernia for whom maximal medical therapy has failed.

  View details for Web of Science ID A1990EM11600025

  View details for PubMedID 2246699

• EXTRACORPOREAL MEMBRANE-OXYGENATION AND CONGENITAL DIAPHRAGMATIC-HERNIA - SHOULD ANY INFANT BE EXCLUDED 38TH ANNUAL MEETING OF THE SURGICAL SECTION OF THE AMERICAN ACADEMY OF PEDIATRICS Newman, K. D., Anderson, K. D., VANMEURS, K., Parson, S., Loe, W., Short, B. W B SAUNDERS CO. 1990: 1048–53

  Abstract

  Mortality in infants with congenital diaphragmatic hernia (CDH) remains high despite improvements in neonatal and surgical care because many infants develop persistent pulmonary hypertension of the newborn (PPHN) following repair. Since 1984, extracorporeal membrane oxygenation (ECMO) has been used as rescue therapy in all infants (n = 25) with PPHN following CDH repair when conventional management failed, with an overall survival of 60%. Repair was performed in this hospital on 12 infants and in other hospitals in 13 infants transferred for consideration of ECMO after repair. Mortality was the same in the group repaired here and those transferred for ECMO. Although complications were frequent in the surviving group, they were successfully managed with nonoperative or operative therapy. Selective use of ECMO has been advocated in CDH patients based on various predictors of high mortality such as "best" PO2 postrepair less than 100 mm Hg, oxygenation index greater than 40, and ventilation index greater than 1,000 with PCO2 greater than 40. Seven surviving infants following ECMO would have been classified as unsalvageable by at least one parameter if selection criteria based on these parameters had been used. We conclude from this series that current predictors of high mortality in CDH patients are unreliable when ECMO is used. Surgeons caring for infants with CDH should consider the use of ECMO in all infants.

  View details for Web of Science ID A1990EC27000008

  View details for PubMedID 2262856

• Maximum blood flow rates for arterial cannulae used in neonatal ECMO. ASAIO transactions / American Society for Artificial Internal Organs Van Meurs, K. P., Mikesell, G. T., Seale, W. R., Short, B. L., Rivera, O. 1990; 36 (3): M679-81

  Abstract

  The arterial cannulae used in neonatal ECMO cause hemolysis and red blood cell damage at elevated blood flows. Hemolysis in extracorporeal circuits has been found to occur with shear stress greater than 132 dynes/cm2, turbulence as measured by Reynold's number greater than 1,000, and velocity greater than 120 to 200 cm/sec. These parameters need to be considered when sizing the proper arterial cannula for a required flow rate. In-vitro measurements of the pressure drop across six arterial cannulae at varying flow rates were performed using human blood with a hematocrit of 43%. Shear stress, Reynold's number, velocity, and pressure drop were calculated for each catheter at flow rates from 50 to 1,000 cc/min. The maximum mean flow rate to maintain the shear stress, Reynold's number, velocity, and pressure drop within the accepted range, was determined for each cannula. Recommended maximum blood flow rates for each of the six cannulae are given. Internal diameter, length, and cannula geometry appear to be the factors most affecting the flow achievable without causing red blood cell damage and hemolysis. Ten French Biomedicus, 10 French Cook, and 10 French Elecath arterial cannulae appear best suited to deliver the range of blood flow rates used in neonatal ECMO.

  View details for PubMedID 2252781

• MULTIPLE FORMS OF G0-ALPHA MESSENGER-RNA - ANALYSIS OF THE 3'-UNTRANSLATED REGIONS BIOCHEMISTRY Price, S. R., Murtagh, J. J., Tsuchiya, M., SERVENTI, I. M., VanMeurs, K. P., Angus, C. W., Moss, J., Vaughan, M. 1990; 29 (21): 5069-5076

  Abstract

  Go, a guanine nucleotide binding protein found predominantly in neural tissues, interacts in vitro with rhodopsin, muscarinic, and other receptors and has been implicated in the regulation of ion channels. Despite the virtual identity of reported cDNA sequences for the alpha subunit of Go (Go alpha), multiple molecular weight forms of mRNA have been identified in tissues from all species examined. To investigate the molecular basis for the size heterogeneity of Go alpha mRNAs, four cDNA clones were isolated from the same retinal lambda gt10 cDNA library that was used earlier to isolate lambda GO9, a clone encompassing the complete coding region of Go alpha. These clones were identified as Go alpha clones based on nucleotide sequence identity with lambda GO9 in the coding region; they diverge, however, from lambda GO9 in the 3'-untranslated region 28 nucleotides past the stop codon. An oligonucleotide probe complementary to a portion of the 3'-untranslated region of lambda GO9 that differs from the newly isolated clones hybridized with 3.0- and 4.0-kb mRNAs present in bovine brain and retina whereas a similar probe for the unique region of the new clones hybridized with a 4.0-kb mRNA in both tissues and with a 2.0-kb mRNA found predominantly in retina. A similar hybridization pattern was observed when brain poly(A+) RNA from other species was hybridized with the different 3'-untranslated region probes. It appears that differences in the 3'-untranslated regions could, in part, be the basis for the observed heterogeneity in Go alpha mRNAs.

  View details for Web of Science ID A1990DF84300011

  View details for PubMedID 2116165

• Signal transduction by guanine nucleotide-binding proteins: possible molecular basis for multiple forms of Go alpha mRNA. Transactions of the Association of American Physicians Murtagh, J. J., Price, S. R., Van Meurs, K. P., Angus, C. W., Moss, J., Vaughan, M. 1988; 101: 235-241

  View details for PubMedID 3152020

• DEDUCED AMINO-ACID-SEQUENCE OF BOVINE RETINAL GO-ALPHA - SIMILARITIES TO OTHER GUANINE NUCLEOTIDE-BINDING PROTEINS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA VanMeurs, K. P., Angus, C. W., Lavu, S., Kung, H. F., Czarnecki, S. K., Moss, J., Vaughan, M. 1987; 84 (10): 3107-3111

  Abstract

  A bovine retinal cDNA clone encoding the complete sequence (354 amino acids) of Go alpha, a guanine nucleotide-binding protein (G protein), was isolated by using oligonucleotide probes complementary to published sequences in two putative clones for the alpha subunit of bovine transducin (T alpha). The deduced amino acid sequence contained sequences identical to those in seven tryptic peptides (total 63 amino acids) from bovine brain Go alpha. The cDNA for bovine retinal Go alpha exhibits greater than 90% identity in both coding and 3' untranslated regions with a recently described partial cDNA clone for Go alpha from rat brain [Itoh, H., Kozasa, T., Nagata, S., Nakamura, S., Katada, T., Ui, M., Iwai, S., Ohtsuka, E., Kawasaki, H., Suzuki, K. & Kaziro, Y. (1986) Proc. Natl. Acad. Sci. USA 83, 3776-3780]. Comparison of the nucleotide and deduced amino acid sequences of the bovine Go alpha clone with those previously reported for other G proteins of bovine origin (Gs alpha, Gi alpha, and T alpha) reveals extensive regions identical to those surrounding the amino acids modified by cholera toxin and pertussis toxin. There are also marked similarities of sequence in regions of the G proteins, elongation factors, and the ras p21 gene products that are believed to be involved in guanine nucleotide binding and GTP hydrolysis.

  View details for Web of Science ID A1987H388200007

  View details for PubMedID 3106961

• IDENTIFICATION OF THE PROBABLE SITE OF CHOLERAGEN-CATALYZED ADP-RIBOSYLATION IN A GO-ALPHA-LIKE PROTEIN BASED ON CDNA SEQUENCE PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Angus, C. W., VanMeurs, K. P., Tsai, S. C., Adamik, R., MIEDEL, M. C., Pan, Y. C., Kung, H. F., Moss, J., Vaughan, M. 1986; 83 (16): 5813-5816

  Abstract

  Go alpha, a 39-kDa guanyl nucleotide-binding protein, is functionally and structurally similar to the alpha subunits of the stimulatory and inhibitory guanyl nucleotide-binding proteins (Gs alpha, Gi alpha) of adenylate cyclase and to the alpha subunit of transducin (T alpha), the guanyl nucleotide-binding protein of the retinal photon reception system. A cDNA clone was isolated from a bovine retinal lambda gt10 library by using oligonucleotide probes complementary to sequences in two putative T alpha clones. Partial sequence analysis revealed a deduced amino acid sequence identical to sequences of four tryptic peptides from bovine brain Go alpha. Gs alpha and T alpha are known to serve as substrates for ADP-ribosylation by choleragen. Other workers have established the sequence of the tetrapeptide in T alpha containing the arginine that is ADP-ribosylated and its location in the amino acid sequence deduced from T alpha cDNA. The Go alpha cDNA described here includes a region encoding an amino acid sequence very similar to that surrounding the ADP-ribosylation site in T alpha, consistent with observations that Go alpha can also be a substrate for choleragen. A corresponding sequence in the recently identified Gs alpha cDNA is less homologous to that in T alpha or Go alpha. The reported differences in conditions that promote choleragen-catalyzed ADP-ribosylation of Gs alpha vs. Go alpha could be related to differences in amino acid sequence in the region of the acceptor arginine.

  View details for Web of Science ID A1986D754900014

  View details for PubMedID 3090546