Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants.

OBJECTIVE: To analyze reasons for low enrollment in a randomized controlled trial (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, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment. RESULTS: Two hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window. CONCLUSION: Despite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives.

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

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

Serial aEEG recordings in a cohort of extremely preterm infants: feasibility and safety.

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.

Inhaled nitric oxide usage in preterm infants in the NICHD Neonatal Research Network: inter-site variation and propensity evaluation.

OBJECTIVE: 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. STUDY DESIGN: 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. RESULT: 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). CONCLUSION: 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.

Technical note: Evaluation of an ear-attached movement sensor to record cow feeding behavior and activity.

The ability to monitor dairy cow feeding behavior and activity could improve dairy herd management. A 3-dimensional accelerometer (SensOor; Agis Automatisering BV, Harmelen, the Netherlands) has been developed that can be attached to ear identification tags. Based on the principle that behavior can be identified by ear movements, a proprietary model classifies sensor data as "ruminating," "eating," "resting," or "active." The objective of the study was to evaluate this sensor on accuracy and precision. First, a pilot evaluation of agreement between 2 independent observers, recording behavior from 3 cows for a period of approximately 9h each, was performed. Second, to evaluate the sensor, the behavior of 15 cows was monitored both visually (VIS) and with the sensor (SENS), with approximately 20 h of registration per cow, evenly distributed over a 24-h period, excluding milking. Cows were chosen from groups of animals in different lactation stages and parities. Each minute of SENS and VIS data was classified into 1 of 9 categories (8 behaviors and 1 transition behavior) and summarized into 4 behavioral groups, namely ruminating, eating, resting, or active, which were analyzed by calculating kappa (κ) values. For the pilot evaluation, a high level of agreement between observers was obtained, with κ values of ≥ 0.96 for all behavioral categories, indicating that visual observation provides a good standard. For the second trial, relationships between SENS and VIS were studied by κ values on a minute basis and Pearson correlation and concordance correlation coefficient analysis on behavior expressed as percentage of total registration time. Times spent ruminating, eating, resting, and active were 42.6, 15.9, 31.6, and 9.9% (SENS) respectively, and 42.1, 13.0, 30.0, and 14.9% (VIS), respectively. Overall κ for the comparison of SENS and VIS was substantial (0.78), with κ values of 0.85, 0.77, 0.86, and 0.47 for "ruminating," "eating," "resting," and "active," respectively. Pearson correlation and concordance correlation coefficients between SENS and VIS for "ruminating," "eating," "resting," and "active" were 0.93, 0.88, 0.98, and 0.73, and 0.93, 0.75, 0.97, and 0.35, respectively. In conclusion, the results provide strong evidence that the present ear sensor technology can be used to monitor ruminating and resting behavior of freestall-housed dairy cattle. Our results also suggest that this technology shows promise for monitoring eating behavior, whereas more work is needed to determine its suitability to monitor activity of dairy cattle.

Impact of early surfactant and inhaled nitric oxide therapies on outcomes in term/late preterm neonates with moderate hypoxic respiratory failure.

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.

Blood stream infection is associated with altered heptavalent pneumococcal conjugate vaccine immune responses in very low birth weight infants.

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.

Efficacy of phototherapy devices and outcomes among extremely low birth weight infants: multi-center observational study.

OBJECTIVE: Evaluate the efficacy of phototherapy (PT) devices and the outcomes of extremely premature infants treated with those devices. STUDY DESIGN: 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. RESULT: 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. CONCLUSION: 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.

Therapeutic hypothermia during neonatal transport: data from the California Perinatal Quality Care Collaborative (CPQCC) and California Perinatal Transport System (CPeTS) for 2010.

OBJECTIVE: 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. STUDY DESIGN: Database analysis to determine the perinatal and neonatal demographics and outcomes of neonates cooled in transport or after admission to a cooling center. RESULT: 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%). CONCLUSION: 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.

Does aggressive phototherapy increase mortality while decreasing profound impairment among the smallest and sickest newborns?

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 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. RESULT: 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. CONCLUSION: 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.

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.

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. METHOD: 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. RESULTS: 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.

Predictors of death or bronchopulmonary dysplasia in preterm infants with respiratory failure.

OBJECTIVES: To identify the variables that predict death/physiologic bronchopulmonary dysplasia (BPD) in preterm infants with severe respiratory failure. STUDY DESIGN: 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). RESULT: 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. CONCLUSIONS: 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 in infants >1500 g and <34 weeks gestation with severe respiratory failure.

OBJECTIVE: 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). STUDY DESIGN: Infants born at <34 weeks gestation with a birth weight >1500 g with respiratory failure were randomly assigned to receive placebo or iNO. RESULTS: 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). CONCLUSIONS: 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.

The use of inhaled nitric oxide in the premature infant with respiratory distress syndrome.

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.

Secondary infection presenting as recurrent pulmonary hypertension.

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.

Decreased use of neonatal extracorporeal membrane oxygenation (ECMO): how new treatment modalities have affected ECMO utilization.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Nitrogen dioxide formation during inhaled nitric oxide therapy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Hemopericardium from coronary artery laceration complicating extracorporeal membrane oxygenation.

OBJECTIVE: 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. STUDY DESIGN: Retrospective case review. RESULTS: 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. CONCLUSIONS: 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.

Response of premature infants with severe respiratory failure to inhaled nitric oxide. Preemie NO Collaborative Group.

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.