Inhaled nitric oxide in preterm infants: a systematic review and individual patient data meta-analysis.

BACKGROUND: 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. METHODS/DESIGN: 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. DISCUSSION: 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.

Cryptococcus neoformans septicemia in an immunocompetent neonate: first case report in Thailand.

Neonatal infection due to Cryptococcus neoformans is extremely rare. We report a case of a 21-day-old neonate diagnosed with cryptococcal septicemia who was successfully treated with amphotericin B. He was born to a human immunodeficiency virus (HIV) seronegative mother. This report alerts general pediatricians and neonatologists to consider Cryptococcus neoformans infection as a possible cause of sepsis in newborn infants.

High-risk neonatal hearing screening program using automated screening device performed by trained nursing personnel at Siriraj Hospital: yield and feasibility.

OBJECTIVES: To determine the prevalence and significant risk factors for pathologic hearing screening test results in high-risk neonates and the feasibility of implementing hearing screening program using automated otoacoustic emission (OAE)/ auditory brain stem response (ABR) device performed by trained nursing staffs. STUDY DESIGN: Single-center prospective, descriptive study. MATERIAL AND METHOD: All neonates admitted to the Division of Neonatology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, who met the high-risk criteria according to Joint Committee of Infant Hearing 1994, American Academy of Pediatrics, were screened with one-step protocol using an automated OAE/ABR device (AccuScreen, GN Otometrics, Denmark). Infants who failed 2 consecutive OAE tests were reconfirmed by ABR prior to discharge. Descriptive analysis was used for the prevalence of pathologic hearing test results, age at screening, duration of procedure, number of risk factors per infant. Univariate analysis using Chi-square test and multiple logistic regression analysis were used for identification of significant risk factors. RESULTS: Five hundred and seven infants were identified to be at-risk in an 18-month study period. The prevalence of pathologic hearing screening test was 6.7% with unilateral and bilateral pathologic results in 13 and 21 infants (2.6% and 4.1%). Only craniofacial anomalies and mechanical ventilation > 5 days were shown to be independent significant risk factors (42-fold and 4-fold increased risk). Median age at screening test performed was 19 days (range 1-149 days) and almost all infants (97.3%) were screened within 3-month postnatal age. The mean time for hearing screening procedure was 10.7 +/- 8.0 minutes (range 2-60 minutes), 98.1% of procedure was accomplished within 30 minutes. CONCLUSION: Hearing screening using automated OAE/ABR devices in high-risk neonates revealed approximately 7% of pathologic results with almost two-thirds having bilateral affected. The significant independent risk factors in this study population were craniofacial anomalies and mechnical ventilation > 5 days. The protocol of having trained nursing staffs to perform the screening yielded good results, i.e., the coverage of screened infants within 3 months of age (97%), feasible duration of procedure.

Inhaled nitric oxide in premature infants with the respiratory distress syndrome.

BACKGROUND: Inhaled nitric oxide improves gas exchange, decreases pulmonary vascular lability, and reduces pulmonary inflammation. We hypothesized that the use of inhaled nitric oxide would decrease the incidence of chronic lung disease and death in premature infants with the respiratory distress syndrome. METHODS: We conducted a randomized, double-blind, placebo-controlled study of the effect of inhaled nitric oxide during the first week of life on the incidence of chronic lung disease and death in premature infants (less than 34 weeks' gestation) who were undergoing mechanical ventilation for the respiratory distress syndrome. Infants were randomly assigned to receive inhaled nitric oxide (10 ppm on day 1, followed by 5 ppm for six days) or inhaled oxygen placebo for seven days. We further randomly assigned the infants in each group to receive intermittent mandatory or high-frequency oscillatory ventilation. RESULTS: A total of 207 premature infants were enrolled. In the group given inhaled nitric oxide, 51 infants (48.6 percent) died or had chronic lung disease, as compared with 65 infants (63.7 percent) in the placebo group (relative risk, 0.76; 95 percent confidence interval, 0.60 to 0.97; P=0.03). There was no significant difference between the nitric oxide and placebo groups in the overall incidence of intraventricular hemorrhage and periventricular leukomalacia (33.3 percent and 38.2 percent, respectively), but the group given inhaled nitric oxide had a lower incidence of severe intraventricular hemorrhage and periventricular leukomalacia (12.4 percent vs. 23.5 percent; relative risk, 0.53; 95 percent confidence interval, 0.28 to 0.98; P=0.04). The type of ventilation had no significant effect on the outcome. CONCLUSIONS: The use of inhaled nitric oxide in premature infants with the respiratory distress syndrome decreases the incidence of chronic lung disease and death.

Predictive power of initial severity of pulmonary disease for subsequent development of bronchopulmonary dysplasia.

Using retrospectively acquired data from 138 mechanically ventilated premature infants, logistic regression was used to determine the relationships between the risk of bronchopulmonary dysplasia (BPD) and indices of initial respiratory disease severity [oxygen index (OI) and alveolar-arterial pO(2) difference (A-a DO(2))]. Indices were calculated from the first arterial blood gas analysis after initial surfactant administration. Infants were also classified as having mild [OI <4 cm H(2)O x mm Hg(-1), A-a DO(2) <150 mm Hg (20 kPa)] or severe [OI >or=10 cm H(2)O x mm Hg(-1), A-a DO(2) >or=300 mm Hg (40 kPa)] respiratory disease, and the ability of this classification to predict subsequent BPD risk was calculated. OI and A-a DO(2) were significantly higher in the BPD group. Logistic regression analysis showed that BPD risk increased linearly with both OI (9%/cm H(2)O x mm Hg(-1)) and A-a DO(2) [16%/50 mm Hg (16%/6.7 kPa)]. However, the predictive power (receiver-operator characteristic) of these models was modest. Unexpectedly, 29% of infants with mild initial disease developed BPD. These data suggest that, while BPD prediction in infants with severe disease is straightforward, the identification of those few infants with mild to moderate disease destined to develop BPD remains problematic.

Inhaled nitric oxide therapy in premature infants with mild to moderate respiratory distress syndrome.

Inhaled nitric oxide (iNO) therapy has been demonstrated to acutely improve oxygenation in preterm infants with severe pulmonary disease. Administration of iNO to the premature infants with less severe pulmonary illness has not yet been studied extensively. Therefore, the authors performed a pilot study enrolling thirty-four premature infants with respiratory distress syndrome (RDS) within 72 hours of age, birth weight between 500-2,000 g, whose oxygenation indexes exceeded our birthweight-specific criteria. Infants were randomly assigned to either treatment with (iNO group; n = 16) or without (control group; n = 18) iNO. Inhaled NO was started at 20 ppm and weaned to 5 ppm over 24-48 hours. Routine cranial ultrasonography was performed and the occurrence of intraventricular hemorrhage (IVH) was interpreted by an attending pediatric radiologist unaware of the treatment group assignment. The study showed that the two groups were of similar birth weight (mean+/-SEM): control 901+/-73 g vs iNO 874+/-70 g; and gestational age: control 27.2+/-0.5 wk vs iNO 26.8+/-0.5 wk. Other baseline parameters between the two groups were also similar. The mean ages of the infants at the time of entry were 11.7+/-2.2 and 8.3+/-0.9 hours in the controls and iNO group. The entry oxygenation index (OI) did not differ between the two groups: control 11.9+/-2.2 vs iNO 10.8+/-1.50. After 30 minutes of iNO therapy, there was a 50 per cent increase in partial pressure of oxygen tension (PaO2) and 15 per cent reduction in OI, (p = 0.02 and p = 0.04 vs baseline, respectively). No statistical difference in the incidence of significant IVH (Grade III and IV) was detected: control 27.8 per cent; iNO 25.0 per cent. The incidence of other acute complications as well as early neonatal death, were comparable between the groups. The mean methemoglobin concentration was 1.2+/-0.5 per cent. In conclusion, these preliminary data suggest that iNO, as used in this protocol, acutely improves oxygenation without increasing significant IVH in premature infants with mild to moderate RDS. These important findings serve to justify further study of the efficacy of iNO on long term pulmonary outcome and mortality in this group of infants.