The Management of Myelomeningocele Study: Short-Term Neonatal Outcomes.

INTRODUCTION: The Management of Myelomeningocele Study was a multicenter randomized trial to compare prenatal and standard postnatal repair of myelomeningocele (MMC). Neonatal outcome data for 158 of the 183 randomized women were published in The New England Journal of Medicine in 2011. OBJECTIVE: Neonatal outcomes for the complete trial cohort (N = 183) are presented outlining the similarities with the original report and describing the impact of gestational age as a mediator. METHODS: Gestational age, neonatal characteristics at delivery, and outcomes including common complications of prematurity were assessed. RESULTS: Analysis of the complete cohort confirmed the initial findings that prenatal surgery was associated with an increased risk for earlier gestational age at birth. Delivery occurred before 30 weeks of gestation in 11% of neonates that had fetal MMC repair. Adverse pulmonary sequelae were rare in the prenatal surgery group despite an increased rate of oligohydramnios. There was no significant difference in other complications of prematurity including patent ductus arteriosus, sepsis, necrotizing enterocolitis, periventricular leukomalacia, and intraventricular hemorrhage. CONCLUSION: The benefits of prenatal surgery outweigh the complications of prematurity.

Early elective delivery for fetal ventriculomegaly: are neurosurgical and medical complications mitigated by this practice?

PURPOSE: Antenatally diagnosed ventriculomegaly (VM) requires the balance of risks of neurological injury with premature delivery. The purpose of this study was to evaluate outcomes related to early elective delivery due to fetal VM at our institution. METHODS: We retrospectively assessed 120 babies (2008-2012) with antenatally diagnosed fetal VM. Inclusion criteria for ("early") cohort were (1) elective delivery occurred for expedited neurosurgical intervention between 32 and 36 weeks EGA and (2) fetal VM noted on official antenatal ultrasound. The comparative "near term" cohort differed only in that delivery occurred at 37+ weeks EGA. Statistical significance for comparative analyses set a priori at p < 0.05. RESULTS: Babies electively delivered early had a lower birthweight (p < 0.0001), greater ventricle width (p < 0.0001), and underwent initial CSF diversion sooner (p = 0.014). The early cohort (n = 22), compared to near term (n = 50), had a lower birthweight (p < 0.0001), greater ventricle width (p < 0.0001), and underwent initial CSF diversion sooner (p = 0.014). The early cohort required more repeat procedures: (45 vs. 22% p = 0.021), and VPS removals after VPS infections (41 vs. 12%, p = 0.010). Additionally, newborn respiratory failure (32 vs. 6%, p = 0.037) was more common. Finally, of four babies who died in the early cohort, 2/4 died for prematurity-associated pulmonary hypoplasia. CONCLUSIONS: While early elective delivery for fetal VM expedites intervention for rapidly expanding ventricles, few benefits were identified. Our study concluded those infants that were delivered earlier had increased VPS infections, repeat neurosurgical procedures, and medical co-morbidities. A multi-institutional prospective observational study would be needed in order to confirm the clinical implications of such practice.

Endotracheal Intubation in Neonates: A Prospective Study of Adverse Safety Events in 162 Infants.

OBJECTIVE: To determine the rate of adverse events associated with endotracheal intubation in newborns and modifiable factors contributing to these events. STUDY DESIGN: We conducted a prospective, observational study in a 100-bed, academic, level IV neonatal intensive care unit from September 2013 through June 2014. We collected data on intubations using standardized data collection instruments with validation by medical record review. Intubations in the delivery or operating rooms were excluded. The primary outcome was an intubation with any adverse event. Adverse events were defined and tracked prospectively as nonsevere or severe. We measured clinical variables including number of attempts to successful intubation and intubation urgency (elective, urgent, or emergent). We used logistic regression models to estimate the association of these variables with adverse events. RESULTS: During the study period, 304 intubations occurred in 178 infants. Data were available for 273 intubations (90%) in 162 patients. Adverse events occurred in 107 (39%) intubations with nonsevere and severe events in 96 (35%) and 24 (8.8%) intubations, respectively. Increasing number of intubation attempts (OR 2.1, 95% CI, 1.6-2.6) and emergent intubations (OR 4.7, 95% CI, 1.7-13) were predictors of adverse events. The primary cause of emergent intubations was unplanned extubation (62%). CONCLUSIONS: Adverse events are common in the neonatal intensive care unit, occurring in 4 of 10 intubations. The odds of an adverse event doubled with increasing number of attempts and quadrupled in the emergent setting. Quality improvement efforts to address these factors are needed to improve patient safety.

Darbepoetin administration to neonates undergoing cooling for encephalopathy: a safety and pharmacokinetic trial.

BACKGROUND: Despite therapeutic hypothermia, neonates with encephalopathy (NE) have high rates of death or disability. Darbepoetin alfa (Darbe) has comparable biological activity to erythropoietin, but has extended circulating half-life (t(1/2)). Our aim was to determine Darbe safety and pharmacokinetics as adjunctive therapy to hypothermia. STUDY DESIGN: Thirty infants (n = 10/arm) ≥36 wk gestation undergoing therapeutic hypothermia for NE were randomized to receive placebo, Darbe low dose (2 µg/kg), or high dose (10 µg/kg) given intravenously within 12 h of birth (first dose/hypothermia condition) and at 7 d (second dose/normothermia condition). Adverse events were documented for 1 mo. Serum samples were obtained to characterize Darbe pharmacokinetics. RESULTS: Adverse events (hypotension, altered liver and renal function, seizures, and death) were similar to placebo and historical controls. Following the first Darbe dose at 2 and 10 µg/kg, t(1/2) was 24 and 32 h, and the area under the curve (AUC(inf)) was 26,555 and 180,886 h*mU/ml*, respectively. In addition, clearance was not significantly different between the doses (0.05 and 0.04 l/h). At 7 d, t(1/2) was 26 and 35 h, and AUC(inf) was 10,790 and 56,233 h*mU/ml*, respectively (*P < 0.01). CONCLUSION: Darbe combined with hypothermia has similar safety profile to placebo with pharmacokinetics sufficient for weekly administration.

Noninvasive inhaled nitric oxide does not prevent bronchopulmonary dysplasia in premature newborns.

OBJECTIVE: To assess the efficacy and safety of early, noninvasive inhaled nitric oxide (iNO) therapy in premature newborns who do not require mechanical ventilation. STUDY DESIGN: We performed a multicenter randomized trial including 124 premature newborns who required noninvasive supplemental oxygen within the first 72 hours after birth. Newborns were stratified into 3 different groups by birth weight (500-749, 750-999, 1000-1250 g) prior to randomization to iNO (10 ppm) or placebo gas (controls) until 30 weeks postmenstrual age. The primary outcome was a composite of death or bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age. Secondary outcomes included the need for and duration of mechanical ventilation, severity of BPD, and safety outcomes. RESULTS: There was no difference in the incidence of death or BPD in the iNO and placebo groups (42% vs 40%, P = .86, relative risk = 1.06, 0.7-1.6). BPD severity was not different between the treatment groups. There were no differences between the groups in the need for mechanical ventilation (22% vs 23%; P = .89), duration of mechanical ventilation (9.7 vs 8.4 days; P = .27), or safety outcomes including severe intracranial hemorrhage (3.4% vs 6.2%, P = .68). CONCLUSIONS: We found that iNO delivered noninvasively to premature infants who have not progressed to early respiratory failure is a safe treatment, but does not decrease the incidence or severity of BPD, reduce the need for mechanical ventilation, or alter the clinical course.

Evaluating the diagnostic gap: statewide incidence of undiagnosed critical congenital heart disease before newborn screening with pulse oximetry.

Screening for critical congenital heart disease (CCHD) using pulse oximetry has been endorsed by the American Academy of Pediatrics and the American Heart Association. We sought to determine the incidence of undetected CCHD in Tennessee and the diagnostic gap of CCHD in Middle Tennessee prior to screening implementation. The Tennessee Initiative for Perinatal Quality Care (TIPQC) Undetected CCHD Registry is a quality improvement initiative established to identify neonates discharged from the nursery with undetected CCHD. The TIPQC database was queried and a simultaneous review of all neonates with CCHD in the Middle Tennessee region was performed to define the incidence and identify the pre-screen diagnostic gap of undetected CCHD at the time of hospital discharge. In 2011, of 79,462 live births in Tennessee, 12 newborns had undiagnosed CCHD (incidence 15 per 100,000; 95 % CI 9-26 per 100,000). Nine of 12 (75 %) had coarctation of the aorta (CoA). There were no deaths due to undiagnosed CCHD. In the Middle Tennessee region, 6 of 45 neonates with CCHD were missed, for a diagnostic gap of 13 % (95 % CI 6-26 %). Prior to implementation of CCHD screening using pulse oximetry, 12 Tennessee neonates with CCHD were missed by prenatal ultrasound and newborn examination. CoA was the most common lesion missed and is also the CCHD most likely to be missed despite addition of screening using pulse oximetry. Continued evaluation of the diagnostic gap with particular attention to missed diagnoses of CoA should accompany institution of CCHD screening programs.

Is preterm delivery indicated in fetuses with gastroschisis and antenatally detected bowel dilation?

INTRODUCTION: Due to the controversy surrounding diagnostic ultrasound evaluations and elective preterm delivery of fetuses with gastroschisis, we sought to calculate the predictive value of bowel dilation in fetuses with gastroschisis and evaluate the effect of preterm delivery on neonatal outcomes. MATERIALS AND METHODS: Ultrasounds and medical records of 103 mother-infant pairs with fetal gastroschisis were reviewed. Eighty-nine pairs met the criteria. Intestinal complications, gestational age at delivery, birth weight, and number of abdominal surgeries were documented. RESULTS: Forty-eight fetuses (54%) had bowel dilation and 41 (46%) did not. The positive predictive value of bowel dilation for complicated gastroschisis was 21%. There were 50 (56%) preterm and 39 (44%) term deliveries. The mean birth weight was 2,114 g (SD = 507) and 2,659 g (SD = 687), p = 0.001. For infants delivered preterm, the mean number of postnatal abdominal surgeries was 2.1 (SD = 1.1) as compared to 1.3 (SD = 0.5) surgical procedures for those infants delivered at term gestation. This was not statistically significant. With respect to hospital stay for each group, the mean length of neonatal intensive care unit admission was 48 days (SD = 33) in the preterm group and 35 days (SD = 50) in the term group, which was not statistically significant. DISCUSSION: Ultrasound-detected bowel dilation was not predictive of important intestinal complications. Our data did not substantiate any benefit for elective preterm delivery of neonates with gastroschisis.

Improvement in antenatal diagnosis of critical congenital heart disease implications for postnatal care and screening.

OBJECTIVE: This observational study was performed to examine the current timing and mode of diagnosis of critical congenital heart disease (CCHD), since early detection of cardiac lesions can significantly improve morbidity and mortality. METHOD: Ninety cases of CCHD in infants born in Middle Tennessee in 2009 were identified by weekly review of admissions to a single cardiac referral center. CCHD is defined as lesions requiring admission or re-admission for surgical or medical intervention within 1 month of life. RESULTS: Overall, the observed antenatal detection rate of 49% is significantly greater than published values of 25%. Hypoplastic left heart syndrome was detected in 11/11, but only 5/16 coarctations were detected. CONCLUSION: Compared to earlier reports, our study showed a doubling of the antenatal detection rate. Perhaps efforts to improve early diagnosis of CCHD could focus on antenatal ultrasound screening techniques for lesions that are missed most often as well as on postnatal screening.

Early inhaled nitric oxide therapy in premature newborns with respiratory failure.

BACKGROUND: The safety and efficacy of early, low-dose, prolonged therapy with inhaled nitric oxide in premature newborns with respiratory failure are uncertain. METHODS: We performed a multicenter, randomized trial involving 793 newborns who were 34 weeks of gestational age or less and had respiratory failure requiring mechanical ventilation. Newborns were randomly assigned to receive either inhaled nitric oxide (5 ppm) or placebo gas for 21 days or until extubation, with stratification according to birth weight (500 to 749 g, 750 to 999 g, or 1000 to 1250 g). The primary efficacy outcome was a composite of death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age. Secondary safety outcomes included severe intracranial hemorrhage, periventricular leukomalacia, and ventriculomegaly. RESULTS: Overall, there was no significant difference in the incidence of death or bronchopulmonary dysplasia between patients receiving inhaled nitric oxide and those receiving placebo (71.6 percent vs. 75.3 percent, P=0.24). However, for infants with a birth weight between 1000 and 1250 g, as compared with placebo, inhaled nitric oxide therapy reduced the incidence of bronchopulmonary dysplasia (29.8 percent vs. 59.6 percent); for the cohort overall, such treatment reduced the combined end point of intracranial hemorrhage, periventricular leukomalacia, or ventriculomegaly (17.5 percent vs. 23.9 percent, P=0.03) and of periventricular leukomalacia alone (5.2 percent vs. 9.0 percent, P=0.048). Inhaled nitric oxide therapy did not increase the incidence of pulmonary hemorrhage or other adverse events. CONCLUSIONS: Among premature newborns with respiratory failure, low-dose inhaled nitric oxide did not reduce the overall incidence of bronchopulmonary dysplasia, except among infants with a birth weight of at least 1000 g, but it did reduce the overall risk of brain injury. (ClinicalTrials.gov number, NCT00006401 [ClinicalTrials.gov].).

National and regional trends in gastrostomy in very low birth weight infants in the USA: 2000-2012.

OBJECTIVE: To determine rates of gastrostomy (GT) in very low birth weight (VLBW) infants. STUDY DESIGN: Retrospective, cross-sectional analysis of the Kids' Inpatient Database for the years 2000, 2003, 2006, 2009 and 2012. We identified VLBW births and infants undergoing a GT, with and without fundoplication, using ICD-9-CM codes. RESULT: National rates (per 1000 VLBW births) of GT increased from 11.5 GT (95% CI 10-13) in 2000 to 22.9 (95% CI 20-25) in 2012 (p < 0.001). Gastrostomy with and without fundoplication increased during the study period (p < 0.001 in both groups). VLBW survival also increased from 78.5% in 2000 to 81.1% in 2012 (p < 0.001). In all study years, the Northeast census region had the lowest GT rates, while the West had the highest rates in 4 of the 5 study years. CONCLUSION: Between 2000 and 2012, the incidence of GT in VLBW infants doubled, associated with improvements in survival in this population.

Update on Vitamin E and Its Potential Role in Preventing or Treating Bronchopulmonary Dysplasia.

Vitamin E is obtained only through the diet and has a number of important biological activities, including functioning as an antioxidant. Evidence that free radicals may contribute to pathological processes such as bronchopulmonary dysplasia (BPD), a disease of prematurity associated with increased lung injury, inflammation and oxidative stress, led to trials of the antioxidant vitamin E (α-tocopherol) to prevent BPD with variable results. These trials were all conducted at supraphysiologic doses and 2 of these trials utilized a formulation containing a potentially harmful excipient. Since 1991, when the last of these trials was conducted, both neonatal management strategies for minimizing oxygen and ventilator-related lung injury and our understanding of vitamin E isoforms in respiratory health have advanced substantially. It is now known that there are differences between the effects of vitamin E isoforms α-tocopherol and γ-tocopherol on the development of respiratory morbidity and inflammation. What is not known is whether improvements in physiologic concentrations of individual or combinations of vitamin E isoforms during pregnancy or following preterm birth might prevent or reduce BPD development. The answers to these questions require adequately powered studies targeting pregnant women at risk of preterm birth or their premature infants immediately following birth, especially in certain subgroups that are at increased risk of vitamin E deficiency (e.g., smokers). The objective of this review is to compile, update, and interpret what is known about vitamin E isoforms and BPD since these first studies were conducted, and suggest future research directions.

Review of 1,000 consecutive extracorporeal membrane oxygenation runs as a quality initiative.

BACKGROUND: Extracorporeal membrane oxygenation is a resource-intensive mode of life-support potentially applicable when conventional therapies fail. Given the initial success of extracorporeal membrane oxygenation to support neonates and infants in the 1980s, indications have expanded to include adolescents, adults, and selected moribund patients during cardiopulmonary resuscitation. This single-institution analysis was conducted to evaluate programmatic growth, outcomes, and risk for death despite extracorporeal membrane oxygenation across all ages and diseases. METHODS: Beginning in 1989, we registered prospectively all extracorporeal membrane oxygenation patient data with the Extracorporeal Life Support Organization. We queried this registry for our institution-specific data to compare the parameter of "discharge alive" between age groups (neonatal, pediatric, adult), disease groups (respiratory, cardiac, cardiopulmonary resuscitation), and modes of extracorporeal membrane oxygenation (veno-venous; veno-arterial). Extracorporeal membrane oxygenation-specific complications (mechanical, hemorrhagic, neurologic, renal, cardiovascular, pulmonary, infectious, metabolic) were analyzed similarly. Descriptive statistics, Kaplan-Meier, and linear regression analyses were conducted. RESULTS: After 1,052 extracorporeal membrane oxygenation runs, indications have expanded to include adults, to supplement cardiopulmonary resuscitation, to support hemodialysis in neonates and plasmapheresis in children, and to bridge all age patients to heart and lung transplant. Overall survival to discharge was 52% and was better for respiratory diseases (P < .001). Probability of individual survival decreased to <50% if pre-extracorporeal membrane oxygenation mechanical ventilation exceeded respectively 123 hours for cardiac, 166 hours for cardiopulmonary resuscitation, and 183 hours for respiratory diseases (P = .013). Complications occurred most commonly among cardiac and cardiopulmonary resuscitation runs (P < .001), the veno-arterial mode (P < .001), and in adults (P = .044). CONCLUSION: Our extracorporeal membrane oxygenation program, an Extracorporeal Life Support Organization-designated Center of Excellence, has experienced substantial growth in volume and indications, including increasing age and disease severity. Considering the entire cohort, pre-extracorporeal membrane oxygenation ventilation exceeding 7 days was associated with an increased probability of death.

Bladder agenesis, ectopic ureters and a multicystic dysplastic horseshoe kidney in one twin newborn with normal amniotic fluid index in utero.

A monochorionic-diamniotic twin baby presented with intrauterine growth restriction and anuria. The baby was found to have bladder agenesis, a pelvic dysplastic horseshoe kidney, vertebral anomalies, a ventricular septal defect and facial dysmorphisms. It was surprising to find no abnormalities in amniotic fluid indices prenatally, suggesting the possibility of urine output that declined as the pregnancy proceeded. Some degree of twin-to-twin transfusion of amniotic fluid was also possible, which could have rescued the oligohydramnios known to be associated with kidney and urinary tract abnormalities. It was also notable that there was no abnormality in respiratory function, especially since further investigations revealed close to no kidney function. The intrauterine growth restriction (IUGR) along with the multiple anomalies found made the baby unsuitable for dialysis and transplant, and the decision of transition to palliative care was made.

Interventions to Improve Patient Safety During Intubation in the Neonatal Intensive Care Unit.

OBJECTIVE: To improve patient safety in our NICU by decreasing the incidence of intubation-associated adverse events (AEs). METHODS: We sequentially implemented and tested 3 interventions: standardized checklist for intubation, premedication algorithm, and computerized provider order entry set for intubation. We compared baseline data collected over 10 months (period 1) with data collected over a 10-month intervention and sustainment period (period 2). Outcomes were the percentage of intubations containing any prospectively defined AE and intubations with bradycardia or hypoxemia. We followed process measures for each intervention. We used risk ratios (RRs) and statistical process control methods in a times series design to assess differences between the 2 periods. RESULTS: AEs occurred in 126/273 (46%) intubations during period 1 and 85/236 (36%) intubations during period 2 (RR = 0.78; 95% confidence interval [CI], 0.63-0.97). Significantly fewer intubations with bradycardia (24.2% vs 9.3%, RR = 0.39; 95% CI, 0.25-0.61) and hypoxemia (44.3% vs 33.1%, RR = 0.75, 95% CI 0.6-0.93) occurred during period 2. Using statistical process control methods, we identified 2 cases of special cause variation with a sustained decrease in AEs and bradycardia after implementation of our checklist. All process measures increased reflecting sustained improvement throughout data collection. CONCLUSIONS: Our interventions resulted in a 10% absolute reduction in AEs that was sustained. Implementation of a standardized checklist for intubation made the greatest impact, with reductions in both AEs and bradycardia.

Medical and economic impact of a respiratory syncytial virus outbreak in a neonatal intensive care unit.

BACKGROUND: Respiratory syncytial virus (RSV) causes frequent nosocomial outbreaks in general pediatric wards but is less commonly reported in neonatal intensive care units (NICUs). We investigated an outbreak of RSV infection in a NICU and its impact on health care delivery, outcomes and costs. METHODS: Retrospective chart review was performed after an RSV outbreak occurred in the NICU. A case was defined as an infant with a nasopharyngeal aspirate positive for RSV by viral culture. Nucleotide sequencing of the isolates was done to determine relatedness. Hospital bills for all RSV culture-positive infants were reviewed. RESULTS: Nine infants (mean age, 34 days; mean birth weight, 1757 g; and mean estimated gestational age 31 weeks and 5 days) were infected with RSV subgroup B during this outbreak. By nucleotide sequencing, the isolates were identical. Clinical manifestations included cough, congestion, increased oxygen requirement, apnea and respiratory failure. The 5 infants requiring intubation had a significantly lower mean birth weight (1301 g versus 2328 g, P = 0.027), mean estimated gestational age (28 weeks and 5 days versus 35 weeks and 2 days, P = 0.014) and mean weight at onset of symptoms (2093 g versus 2989 g, P = 0.049) than the 4 nonintubated infants. More than 1.15 million dollars in hospital charges were attributable to the outbreak. All infants survived. CONCLUSION: Infants in a NICU who develop cough, congestion or apnea should be tested for RSV and other common respiratory viruses during the winter respiratory season. Even in a closed NICU, nosocomial outbreaks of these viruses can occur and have a major effect on healthcare delivery, costs and outcomes.

A crossover analysis of mandatory minute ventilation compared to synchronized intermittent mandatory ventilation in neonates.

BACKGROUND: Mandatory minute ventilation (MMV) is a novel ventilator mode that combines synchronized intermittent mandatory ventilation (SIMV) breaths with pressure-supported spontaneous breaths to maintain a desired minute volume. The SIMV rate is automatically adjusted to maintain minute ventilation. OBJECTIVE: To evaluate MMV in a cohort of infants without parenchymal lung disease alternately ventilated by MMV and SIMV. DESIGN/METHODS: Neonates >33 weeks' gestational age and electively intubated for medical or surgical procedures were enrolled. Exclusionary criteria included: nonintact respiratory drive or active pulmonary disease. Infants were randomized to receive 2 hours of either SIMV or MMV and then crossed over to the other mode for 2 hours. Ventilator parameters and end-tidal CO(2) (etCO(2)) were measured via inline, mainstream monitoring and recorded every minute. RESULTS: In total, 20 infants were evaluated. No statistically significant differences were found for overall means between etCO(2), minute volumes, peak inspiratory pressure (PIP), or positive end expiratory pressure (PEEP). However, there was a significant difference in the type of ventilator breaths given and in the mean airway pressure. Additionally, there was a statistically significant negative trend in MMV over time compared to SIMV, although this was subtle and could have been due to extreme cases. CONCLUSIONS: Neonates with an intact respiratory drive can be successfully managed with MMV without an increase in etCO(2). While this mode generates similar PIP and PEEP, the decrease in mechanical breaths and the mean airway pressure generated with MMV may reduce the risk of some of the long-term complications associated with mechanical ventilation.

Initial dosing of inhaled nitric oxide in infants with hypoxic respiratory failure.

BACKGROUND: Inhaled nitric oxide (iNO) is a potent and selective pulmonary vasodilator that decreases pulmonary resistance, and improves ventilation-perfusion matching, thereby improving oxygenation and reducing the need for more invasive therapies. Despite the efficacy of iNO at reducing the use of extracorporeal membrane oxygenation, significant concern remains over the potential toxicity from oxidative derivatives and methemoglobinemia. At present, there is no universal agreement on the lowest effective starting dose. Reported initial doses in the neonatal literature have ranged from 1 to 80 ppm. PURPOSE: To determine if the initial dose of iNO altered the incidence of adverse outcome. METHODS: A cohort of neonates who received iNO for treatment of hypoxic respiratory failure and were entered into the Duke Neonatal Nitric Oxide Registry were evaluated. Neonates with congenital anomalies were excluded. This registry collects data from 36 centers that voluntarily report their experiences with iNO. From this database, the starting dose was recorded and the clinical course was followed. Adverse outcomes were prospectively defined and monitored in the database and included: methemoglobinemia, chronic lung disease, treatment with extracorporeal membrane oxygenation, or death. RESULTS: Data on 476 patients were analyzed. Based on starting doses, records were sorted into three groups: a low-dose group (LDG; <18 ppm, n=57), a mid-dose group (MDG; 18 to 22 ppm, n=320), and a high-dose group (HDG; >22 ppm, n=99). ANOVA showed no statistically significant differences among the groups except for PaO(2)/FiO(2) (p<0.05). Neonates in the high starting dose group were more often classified as treatment failures (21% in the LDG, 27% in the MDG, and 38% in the HDG, p=0.04) and treated with extracorporeal membrane oxygenation (19% in the LDG, 23% in the MDG, and 34% in the HDG, p=0.05) compared to the lower dose groups. In addition, survival without the need for oxygen at 30 days or at discharge was higher in the lower dose groups (93% in the LDG, 84% in the MDG, and 76% in the HDG, p=0.03). Logistic regression, however, showed that the starting dose of iNO did not significantly influence these outcomes when corrected for the degree of hypoxemia (PaO(2)/FiO(2)) at the start of therapy (p>0.1). High initial doses of iNO (>22 ppm) were associated with higher levels of methemoglobin (p< 0.05). There were no differences in mortality or length of hospital stay between the groups. CONCLUSIONS: There is significant variation in the starting dose of iNO between centers. Our retrospective study shows no evidence that higher doses improve outcome. A low concentration of iNO (<18 ppm) should be considered to minimize the potential toxicity of methemoglobin. Furthermore, a well-designed, prospective trial should be undertaken to further define the optimal starting dose.