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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.

Introduction Amplitude-integrated EEG (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. Methods Inborn infants 230/7 – 286/7 weeks gestation or birth weight 401–1000 grams were eligible. Serial, six-hour 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. Results 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. Conclusions Serial aEEG monitoring is safe in preterm infants, with few adverse events and general acceptance by nursing staff.

Objective To analyze reasons for low enrollment in an RCT of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late-preterm newborns. Study Design The original study was a multicenter RCT. Eligibility: ≥34 weeks’ gestation

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 was35 weeks in 10 (4.5%). For outborn and transported infants, chronologic age at the time of cooling initiation was6 h in 20 (11%). When initiated at the birth hospital, cooling was initiated at6 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.

Objective 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. Study Design ELBW infants (n=1974) were randomized to AgPT or conservative phototherapy at age 12–36 hours. The effect of AgPT on outcomes (death; impairment; profound impairment; death or impairment [primary outcome], and death or profound impairment) at 18–22 months corrected age was related to BW stratum (501–750 g; 751–1000 g) and baseline severity of illness using multilevel regression equations. The probability of benefit and of harm was directly assessed with Bayesian analyses. Results Baseline illness severity was well characterized using mechanical ventilation and FiO2 at 24 hours 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

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

Objectives 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.

Study objectives : We reviewed the use of and indications for therapeutic bronchoscopy in congenital diaphragmatic hernia (CDH) patients requiring ECMO; timing, frequency, and complications of the intervention during ECMO run; and outcome. Design: Retrospective study. Setting: Neonatal intensive care unit (NICU) of a university children’ s hospital. Patients: All CDH patients requiring ECMO from 1/1/1996 to 12/31/2000. Measurements and Results : A total of 17 patients with CDH were placed on ECMO during the period examined, all before repair. Of those, eight received therapeutic bronchoscopy. The major indication for bronchoscopy in all cases was persistent atelectasis or collapse consistent with mucus plugging. The number of bronchoscopy procedures performed in each case ranged from 1 to 4. Temporally-related radiographic improvements were seen in the majority of cases after one or two procedures. Seven of the eight patients underwent first bronchoscopy after CDH repair. Both acetylcysteine (Mucomyst® ) and beractant were used during bronchoscopy in selected cases. Complications were limited to minor bleeding, which was easily controlled. All patients who received therapeutic bronchoscopy survived decannulation, although one infant with neurologic and renal abnormalities died at 4 months. Conclusions : In this small number of patients with CDH requiring ECMO, bronchoscopy appeared to be safe and efficacious. Clearly, the outcome of patients with CDH requiring ECMO is influenced by numerous and complex factors. This preliminary report suggests the need for larger randomized controlled trials of bronchoscopy in this population to assess whether this intervention could result in shorter ECMO runs or improved outcomes.

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%) at28 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% (P0.001) 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.

Objective: The purpose of this study was to determine whether surfactant (beractant) administration to term newborns in respiratory failure and at risk for requiring extracorporeal membrane oxygenation (ECMO) treatment would significantly reduce the incidence of severe complications through 28 days of age and the need for ECMO. Study design: A multicenter ( n = 44), randomized, double-blind, placebo-controlled trial was conducted. Infants weighing 2000 gm or more with gestational ages of 36 weeks or greater were stratified by diagnosis (meconium aspiration syndrome, sepsis, or idiopathic persistent pulmonary hypertension of the newborn) and oxygenation index (15 to 22, 23 to 30, 31 to 39) and then randomly assigned to receive four doses of beractant, 100 mg/kg ( n = 167), or air placebo ( n = 161) before ECMO treatment and four additional doses during ECMO, if ECMO was required. The incidence of untoward effects (including hemorrhagic, neurologic, pulmonary, renal, cardiovascular, infectious, metabolic, and technical complications) occurring before and after randomization and through 28 days of age or discharge were recorded. Results: The two treatment groups were comparable in baseline parameters, including birth weight, sex, gestational age, oxygenation index, and primary diagnosis. There was no difference in the incidence of severe complications. The need for ECMO therapy was significantly less in the surfactant group than in the placebo group ( p = 0.038); this effect was greatest within the lowest oxygenation index stratum (15 to 22; p = 0.013). Conclusions: Use of surfactant, particularly in the early phase of respiratory failure, significantly decreases the need for ECMO in the treatment of term newborns with respiratory failure, without increasing the risk of complications. (J Pediatr 1998;132:40-7)

RESPONSE OF PREMATURE INFANTS WITH SEVERE RESPIRATORY FAILURE TO INHALED NITRIC OXIDE. † 1613

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.Univariate and multivariate logistic regression analyses were used to determine risk factors for the progression of respiratory failure and extracorporeal membrane oxygenation (ECMO)/death.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 (P0.001). Early iNO (OI 15 to 25) decreased the progression of respiratory failure to OI30 (P=0.002) and to composite outcome of OI30 or ECMO/death (P=0.02).This post-hoc analysis suggests that early use of surfactant and iNO in moderate respiratory failure is associated with improved outcomes.

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.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.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).BSI was not associated with reduced odds of World Health Organization-defined protective PCV7 responses in VLBWs.

As more infants with congenital diaphragmatic hernia (CDH) survive with extracorporeal membrane oxygenation (ECMO), it seems prudent to detail the long-term outcome in these medically complex intants. 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 neurodevel-opmental 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.

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.

Inhaled nitric oxide (iNO) use in infants1500 g, but34 weeks gestation with severe respiratory failure will reduce the incidence of death and/or bronchopulmonary dysplasia (BPD).Infants born at34 weeks gestation with a birth weight1500 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 infants1500 g and34 weeks with severe respiratory failure suggests that iNO does not affect the rate of BPD and/or death.

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.

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.

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.

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.

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.

Clincal Measurement of the Oxides of Nitrogen: Comparison of Four Electrochemical and Chemiluminescence Analyzers. † 1614

Introduction: Inhaled nitric oxide (INO) has been shown in several clinical trials in term infants with respiratory failure to acutely increase oxygenation and significantly decrease the incidence of death and/or ECMO. However the potential pulmonary toxicity and long term effects of INO remain largely unknown. Both NO and its metabolites may react to form secondary cytotoxic species which may be linked to the development of chronic lung disease. The purpose of this study was to investigate whether INO causes increased oxidant stress in the serum of newborns when compared to normal controls and infants exposed to hyperoxia.

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.

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.