The Provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory distress syndrome. Respiratory disease in very-low-birthweight infants after prenatal thyrotropin-releasing hormone and glucocorticoid. TRH Study Group. Long term follow-up of very low birthweight infants from a neonatal volume versus pressure mechanical ventilation trial. Improved outcome at 28 days of age for very low birth weight infants treated with a single dose of a synthetic surfactant. Failure of early postnatal dexamethasone to prevent chronic lung disease in infants with respiratory distress syndrome. Effects of early dexamethasone therapy on pulmonary mechanics and chronic lung disease in very low birth weight infants: a randomized, controlled trial. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. Prophylaxis against early adrenal insufficiency to prevent chronic lung disease in premature infants. Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. The Neonatal Inhaled Nitric Oxide Study Group (NINOS).
To compare the hospital course and clinical outcome of preterm infants with respiratory distress syndrome treated with surfactant and managed with high-frequency oscillatory ventilation (HFOV) or conventional mechanical ventilation (CV) as their primary mode of ventilator support.
                A prospective randomized clinical trial.
                Three community-based level III neonatal intensive care units.
                A total of 125 neonates who were 35 weeks or less estimated gestation requiring intubation and assisted ventilation for respiratory distress syndrome with arterial to alveolar oxygen ratio less than .50.
                Patients were randomized to continue CV (61 patients) or be changed to HFOV (64 patients) after exogenous surfactant administration (100 mg/kg). HFOV was used in a strategy to promote lung recruitment and maintain lung volume. Protocol respiratory care guidelines were followed; otherwise routine care was provided by each neonatal intensive care unit.
                No differences were noted in demographic features between the two study groups. The study population birth weight was 1.51 +/- .47 kg (mean +/- SD), gestational age was 30.9 +/- 2.5 weeks, and study entry age was 2 to 3 hours. Patients randomized to HFOV demonstrated the following significant findings compared with CV-treated patients: vasopressor support was less intensive; surfactant redosing was not as frequent; oxygenation improved more rapidly and remained higher during the first 7 days; fewer infants required prolonged supplemental oxygen or ventilator support; treatment failure was reduced; more patients survived without chronic lung disease at 30 days; need for continuous supplemental oxygen at discharge was less; frequency of necrotizing enterocolitis illness was lower; there were fewer abnormal hearing tests; and hospital costs were decreased. No differences were seen between the two study groups in the frequency or severity of patent ductus arteriosus, air leak, retinopathy of prematurity, or intraventricular hemorrhage. Length of hospital stay and survival to discharge were similar for HFOV- and CV-treated infants.
                When used early with a lung recruitment strategy, HFOV after surfactant replacement resulted in clinical outcomes consistent with a reduction in both acute and chronic lung injury. Benefit was evident for preterm infants both less than or equal to 1 kg and more than 1 kg. In addition, early HFOV treatment may have had a more global effect on patient health throughout the hospitalization, resulting in reduced morbidity and decreased health care cost. Although prenatal glucocorticoid treatment reduces neonatal respiratory morbidity, respiratory distress syndrome and chronic lung disease (CLD) develop in many very-low-birthweight infants despite therapy. To investigate the effect of additional prenatal treatment with thyrotropin-releasing hormone (TRH), we did a multicentre, blinded, randomised trial. 404 women with threatened preterm delivery at less than 32 weeks' gestation received betamethasone plus TRH (4 doses of 400 micrograms 8-hourly) or betamethasone plus placebo. 103 infants who were fully treated and of less than 1500 g birthweight were evaluated during the neonatal period. TRH treatment (55 infants) did not affect the total incidence of respiratory distress syndrome (47% vs 58% in controls) or of severe respiratory distress syndrome (13% vs 25% in controls, p = 0.11). CLD (defined as requirement for supplemental oxygen at 28 days after birth) developed in significantly fewer TRH-treated infants (18% vs 44% of controls, p less than 0.01). The unadjusted relative risk of CLD with TRH therapy was 0.40 (95% CI 0.26-0.80, p less than 0.05), and this was not materially changed after adjustment for potentially modifying variables. There were significantly fewer adverse outcomes, defined as death or continuing oxygen requirement, in the TRH group than in the steroid-alone group both at 28 days and when infants reached 36 weeks' postconceptional age. The incidence of other complications of prematurity was similar in the two groups. Prenatal TRH reduces the incidence of chronic lung disease among betamethasone-treated infants. A previous randomised trial showed volume controlled ventilation (VCV) was efficacious in ventilating very preterm and extremely low birthweight babies.
                To compare long term survival, pulmonary morbidities and gross neurodevelopmental outcomes of babies randomised to either VCV or pressure limited ventilation (PLV) for treatment of respiratory distress syndrome.
                Masked evaluation of health status, including frequency of respiratory illness, use of medications, hospital admissions, and gross neurodevelopmental status were obtained using a structured parental questionnaire and verification from medical records.
                94 of 109 children (86%) survived to discharge. Three died after discharge (2 VCV, 1 PLV). Modality of ventilation did not affect overall mortality; seven VCV children died (12%) versus 11 PLV (21%) (OR 0.5 (95% CI 0.1 to 1.4), p = 0.13). Respiratory abnormalities were present in 32 (37%), and 26 (30%) required hospital readmission. There was no significant difference in readmission rates between the two groups: VC 13/45 (29%) and PLV 19/40 (47%) (OR 0.4 (0.1 to 1.1), p = 0.07). Modality of ventilation did not affect frequency of respiratory illness: VC 12 (27%) and PLV 14 (35%) (OR 0.46 (0.1 to 1.1), p = 0.09). However, significantly fewer VCV children (13%, n = 6) compared to PLV children (32%, n = 13) required treatment with inhaled steroids/bronchodilators (OR 0.3 (0.1 to 0.9), p = 0.04). Nine children had severe neurodevelopmental disability (cerebral palsy, blindness, deafness) (9.8%; 3 VCV, 6 PLV 6) (OR 0.4 (0.09 to 1.7)).
                The efficacy of VCV in very preterm and low birth babies appears to be maintained on longer term evaluation. Two identical double-blind, controlled, randomized trials were initiated to determine whether the administration of a single 5 ml/kg dose of a synthetic surfactant (Exosurf Neonatal), soon after the delivery of infants with birth weights 700 to 1350 gm, would improve rates of survival without bronchopulmonary dysplasia. Both trials were terminated before enrolling their planned sample sizes because of the availability of Exosurf under the provisions of a Treatment Investigational New Drug program. We report the combined results of these trials. Study infants were stratified according to birth weight and gender before random assignment to a treatment regimen. One hundred ninety-two infants received Exosurf and 193 received an air placebo. The study groups were similar when a variety of demographic features describing the mothers, their pregnancies, the circumstances of the births, and the infants were compared. Exosurf-treated infants required significantly less oxygen and respiratory support during the first 3 days of life in comparison with the air-treated infants. Fewer infants in the Exosurf group had pulmonary interstitial emphysema (26 vs 13; p = 0.028). In the Exosurf group, there was a significant reduction in the combined outcome, neonatal death or survival with bronchopulmonary dysplasia (57 vs 39; p = 0.042), and there was a significant increase in rates of survival without this disease (128 vs 137; p = 0.042). There were no differences between treatment groups in the incidences of a variety of complications of prematurity, including apnea, patent ductus arteriosus, intraventricular hemorrhage, and necrotizing enterocolitis. We conclude that improvements in respiratory physiology after a single prophylactic dose of Exosurf result in an increased likelihood of neonatal survival without bronchopulmonary dysplasia. To study the effect of early postnatal dexamethasone (days 1-3) on the incidence and severity of chronic lung disease in preterm infants with respiratory distress syndrome.
                A multicentre, randomised, placebo controlled, blinded study was carried out in 18 neonatal intensive care units in Israel. The primary outcome measure was survival to discharge without requirement for supplemental oxygen therapy beyond 28 days of life. The secondary outcome measures were requirement for mechanical ventilation at 3 and 7 days, duration of ventilation or oxygen therapy, need for subsequent steroids for established chronic lung disease and incidence of major morbidities.
                The study consisted of 248 infants (dexamethasone n = 132; placebo n = 116). No differences were found in the outcome variables except for a reduction in requirement for mechanical ventilation at age 3 days in treated infants (dexamethasone 44%, placebo 67%; P = 0.001). Gastrointestinal haemorrhage, hypertension, and hyperglycaemia were more common in treated infants, but no life threatening complications, such as gastrointestinal perforation, were encountered.
                These data do no support the routine use of early postnatal steroids, but may justify further study in a selected, high risk group of infants. To determine the changes in pulmonary mechanics before and during early dexamethasone therapy, and to evaluate the effect of dexamethasone on the duration of mechanical ventilation in very low birth weight (VLBW) ventilator-dependent infants at risk for chronic lung disease (CLD).
                A prospective randomized trial was conducted. Forty-three patients (birth weight 600 to 1500 g, gestational age 24 to 32 weeks) who failed to be weaned from the respirator at 7 to 14 days of age were enrolled; 23 infants received a 7-day course of dexamethasone (0.5 mg/kg/day intravenously for 3 days, 0.25 mg/kg/day for 3 days, and 0.1 mg/kg/day for 1 day), and 20 patients were in the control group. At similar mean airway pressure (MAP) and fractional inspired oxygen concentration (FiO2), respiratory system mechanics were measured before and on days 2, 5, and 7 of the study. Airway pressure, flow and tidal volume (VT) were recorded and only mechanical breaths were analyzed. Respiratory compliance (Crs) and respiratory resistance (Rrs) were calculated by two factor least mean square analysis.
                Eighty-three percent of infants in the dexamethasone group and 90% in the control group received surfactant in the first 24 hours of life. There was a significant increase in Crs and VT in the dexamethasone group as compared with the control group (P < .001). No major changes in Rrs were observed. Dexamethasone therapy significantly decreased FiO2 and MAP P < .001) and facilitated successful weaning from mechanical ventilation. In addition to a shorter duration of mechanical ventilation (P < .01), the occurrence of CLD (FiO2 > 0.21 at 36 weeks of corrected gestational age, chest radiograph changes) was significantly decreased in the dexamethasone group (P < .01). Except for a transient increase in blood pressure and serum glucose, there were no significant differences in infection rates, intraventricular hemorrhage, or retinopathy of prematurity. Thirteen patients in the control group received dexamethasone at a later age.
                Our findings indicate that: 1) early dexamethasone therapy in VLBW infants markedly improves respiratory compliance and tidal volume, reduces FiO2 and MAP requirements, and facilitates extubation in these infants; 2) early dexamethasone therapy reduces the duration of mechanical ventilation and decreases CLD (at 28 days and 36 weeks) in a population of VLBW infants largely treated with surfactant. The safety and efficacy of early, low-dose, prolonged therapy with inhaled nitric oxide in premature newborns with respiratory failure are uncertain.
                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.
                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.
                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].).
                Copyright 2006 Massachusetts Medical Society. BACKGROUND. Many extremely low birth weight infants (<1000 g) show biochemical evidence of adrenal insufficiency in the first week of life, correlating with subsequent development of chronic lung disease (CLD).
                We conducted a randomized, double-masked, placebo-controlled pilot study to test whether early treatment with low-dose hydrocortisone for 12 days (1 mg/kg/day for 9 days followed by.5 mg/kg/day for 3 days), begun before 48 hours of life, would increase the likelihood of survival without CLD.
                Forty patients were enrolled at two centers. Birth weight and gestation were similar for treatment and placebo groups: 732 +/- 135 g versus 770 +/- 135 g and 25.2 +/- 1.3 weeks versus 25.4 +/- 1.5 weeks. More infants treated with hydrocortisone achieved study success, defined as survival without supplemental oxygen at 36 weeks' postconception (12/20 [60%] vs 7/20 [35%]). Lower birth weight, histologic chorioamnionitis, and preeclampsia were significant risk factors, whereas study center, prenatal steroids, sex, and ethnicity were not significant. Hydrocortisone treatment decreased days on >40% oxygen, days on >25% oxygen, days on ventilator, and oxygen at discharge. Among infants exposed to chorioamnionitis, hydrocortisone treatment also was associated with increased enteral intake during the first month of life and with increased weight at 36 weeks' postconception. Five treated infants and 6 placebo infants developed sepsis; 3 in each group died.
                First, early treatment with low-dose hydrocortisone in this population of extremely low birth weight infants increased the likelihood of survival without CLD. Second, the benefit was particularly apparent in infants with chorioamnionitis. Third, a larger multicenter trial is needed to verify the primary outcome and to better evaluate risks and benefits. We designed and conducted a randomized, double-masked, controlled multicenter study to determine whether inhaled nitric oxide (INO) in term and near-term infants with congenital diaphragmatic hernia (CDH) would reduce the occurrence of death and/or the initiation of extracorporeal membrane oxygenation (ECMO).
                Infants of 34 weeks gestation or more, <14 days of age with CDH, without known structural heart disease, requiring assisted ventilation for hypoxemic respiratory failure with two oxygenation indices (OIs) of 25 or more at least 15 minutes apart, were eligible for this trial. Infants were centrally randomized and then received masked treatment with 20 ppm NO or 100% oxygen as control. Infants with less than a full response to 20 ppm NO (increase in PaO2 > 20 Torr) after 30 minutes were evaluated at 80 ppm NO/control study gas.
                The 28 control and 25 treated infants enrolled by the 13 participating centers were not significantly different at randomization for any of the measured variables including prerandomization therapies and initial OIs (45.8 +/- 16.3 for controls, 44.5 +/- 14.5 for INO). Death at <120 days of age or the need for ECMO occurred in 82% of control infants compared with 96% of INO infants (ns). Death occurred in 43% of controls and 48% of the INO group (ns), and ECMO treatment was used for 54% of control and 80% of INO-treated infants. There was no significant improvement in PaO2 (delta PaO2 7.8 +/- 19.8 vs 1.1 +/- 7.6 Torr, ns) nor significant reduction in OI (-2.7 +/- 23.4 vs 4.0 +/- 14.8, ns) associated with INO treatment. Mean peak nitrogen dioxide (NO2) concentration was 1.9 +/- 1.3 ppm and the mean peak methemoglobin was 1.6 +/- 0.8 mg/dL. No infant had study gas discontinued for toxicity. There were no differences between the control and INO groups for the occurrence of intracranial hemorrhage, specific grades of intracranial hemorrhage, periventricular leukomalacia, brain infarction, and pulmonary or gastrointestinal hemorrhages.
                Although the immediate short-term improvements in oxygenation seen in some treated infants may be of benefit in stabilizing responding infants for transport and initiation of ECMO, we conclude that for term and near-term infants with CDH and hypoxemic respiratory failure unresponsive to conventional therapy, inhaled NO therapy as used in this trial did not reduce the need for ECMO or death.
When MV was introduced in the 1960s to treat infants with severe respiratory failure due to pulmonary disease, trials showed an overall reduction in mortality which was most marked in infants born with a birthweight of more than 2 kg. This review does not provide information to evaluate the relative benefits or harms of MV in the setting of modern perinatal care.