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The Renal Anhydramnios Fetal Therapy (RAFT) trial is a study of serial amnioinfusions to prevent lethal neonatal pulmonary hypoplasia from early renal anhydramnios. Infant neurologic outcomes were not originally evaluated. We describe the high incidence of stroke observed among infants in the treatment arm of the trial at our center., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose. Funding for the Renal Anhydramnios Fetal Therapy (RAFT) Trial is provided by RO1 HD100540 from the National Institutes of Child Health and Development (NICHD; authors JLM and MAA co-PI). The NICHD had no role in the design and conduct of the study. Publication of this data was approved by the Data Safety Monitoring Board (DSMB). Renal Anhydramnios Fetal Therapy (RAFT) is listed on ClinicalTrials.gov, identifier NCT03101891. Deidentified individual participant data will not be made available., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To collect all published cases up to January 2019 of pulmonary alveolar microlithiasis (PAM) in patients age 5 years and under and to compare their characteristics with those of the 1022 cases in the most recent all-age cohort published in 2015., Study Design: We identified 28 cases of PAM worldwide in children age 5 years and under, accounting for only 2%-3% of all cases., Results: Children seem more frequently symptomatic, notably with more cough and severe acute respiratory failure, but had no reported extrapulmonary manifestation. Children with PAM evidenced less typical radiologic findings, with frequent ground glass opacities not reported in adult cases and milder calcifications as less frequent, smaller, and mainly restricted to the lower lobes., Conclusions: PAM remains an uncommon diagnosis in young children, as symptoms and radiologic findings are less specific. Physicians should be aware to look for calcifications in chest computed tomography at mediastinal window and avoid elution of the bronchoalveolar lavage to find microliths. Collecting longitudinal data through an international registry would help in characterizing PAM to predict disease progression and plan lung transplantation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To review the pulmonary findings of the first 51 patients who presented to our interdisciplinary single-ventricle clinic after undergoing the Fontan procedure., Study Design: We performed an Institutional Review Board-approved retrospective review of 51 patients evaluated following the Fontan procedure. Evaluation included history, physical examination, pulmonary function testing, and 6-minute walk. Descriptive statistics were used to describe the population and testing data., Results: Sixty-one percent of the patients had a pulmonary concern raised during the visit. Three patients had plastic bronchitis. Abnormal lung function testing was present in 46% of patients. Two-thirds (66%) of the patients had significant desaturation during the 6-minute walk test. Patients who underwent a fenestrated Fontan procedure and those who underwent unfenestrated Fontan were compared in terms of saturation and 6-minute walk test results. Sleep concerns were present in 45% of the patients., Conclusions: Pulmonary morbidities are common in patients after Fontan surgery and include plastic bronchitis, abnormal lung function, desaturations with walking, and sleep concerns. Abnormal lung function and obstructive sleep apnea may stress the Fontan circuit and may have implications for cognitive and emotional functioning. A pulmonologist involved in the care of patients after Fontan surgery can assist in screening for comorbidities and recommend interventions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To evaluate the incidence of death or neurodevelopmental impairment (NDI) at 18-22 months corrected age in subjects enrolled in a trial of early dexamethasone treatment to prevent death or chronic lung disease in extremely low birth weight infants., Study Design: Evaluation of infants at 18-22 months corrected age included anthropomorphic measurements, a standard neurological examination, and the Bayley Scales of Infant Development-II, including the Mental Developmental Index and the Psychomotor Developmental Index. NDI was defined as moderate or severe cerebral palsy, Mental Developmental Index or Psychomotor Developmental Index <70, blindness, or hearing impairment., Results: Death or NDI at 18-22 months corrected age was similar in the dexamethasone and placebo groups (65% vs 66%, P = .99 among those with known outcome). The proportion of survivors with NDI was also similar, as were mean values for weight, length, and head circumference and the proportion of infants with poor growth (50% vs 41%, P = .42 for weight less than 10th percentile); 49% of infants in the placebo group received treatment with corticosteroid compared with 32% in the dexamethasone group (P = .02)., Conclusion: The risk of death or NDI and rate of poor growth were high but similar in the dexamethasone and placebo groups. The lack of a discernible effect of early dexamethasone on neurodevelopmental outcome may be due to frequent clinical corticosteroid use in the placebo group., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: To measure the changes in whole blood fatty acid levels in premature infants and evaluate associations between these changes and neonatal morbidities., Study Design: This was a retrospective cohort study of 88 infants born at <30 weeks' gestation. Serial fatty acid profiles during the first postnatal month and infant outcomes, including chronic lung disease (CLD), retinopathy of prematurity, and late-onset sepsis, were analyzed. Regression modeling was applied to determine the association between fatty acid levels and neonatal morbidities., Results: Docosahexaenoic acid (DHA) and arachidonic acid levels declined rapidly in the first postnatal week, with a concomitant increase in linoleic acid levels. Decreased DHA level was associated with an increased risk of CLD (OR, 2.5; 95% CI, 1.3-5.0). Decreased arachidonic acid level was associated with an increased risk of late-onset sepsis (hazard ratio, 1.4; 95% CI, 1.1-1.7). The balance of fatty acids was also a predictor of CLD and late-onset sepsis. An increased linoleic acid:DHA ratio was associated with an increased risk of CLD (OR, 8.6; 95% CI, 1.4-53.1) and late-onset sepsis (hazard ratio, 4.6; 95% CI, 1.5-14.1)., Conclusion: Altered postnatal fatty acid levels in premature infants are associated with an increased risk of CLD and late-onset sepsis., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objective: To determine the clinical course and outcomes of children born early preterm (EPT, <32 weeks), late preterm (LPT, 32 to 35 weeks), and full term (FT, >or=36 weeks) who were subsequently admitted to the pediatric intensive care unit (PICU) with respiratory illness., Study Design: Retrospective chart review of patients <2 years old admitted to a tertiary PICU with respiratory illness., Results: Two hundred seventy-one patients met inclusion criteria: 17.3% were EPT, 12.2% were LPT, and 70.5% were FT. Lower respiratory tract infection was the most common diagnosis (55%) for all groups. Median PICU length of stay was longer for EPT (6.3 days) and LPT infants (7.1 days) compared with FT infants (3.7 days; P < .03 for both comparisons). EPT and LPT infants had longer hospital stays (median, 11.7 and 13.8 days, respectively) compared with FT infants (median, 7.1 days; P < .03 and P = .004, respectively). Median hospital charges were also greater for EPT ($85 151) and LPT ($83 576) groups compared with FT group ($55 122; P < .01 and P < .02, respectively)., Conclusions: EPT and LPT infants comprise a considerable proportion of PICU admissions for respiratory illness and have greater resource utilization than FT infants., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Objectives: To determine whether pediatric systemic lupus erythematosus (SLE) is associated with alterations in the vitamin D-parathyroid hormone (PTH) axis and to assess the relation between vitamin D deficiency and SLE activity., Study Design: 25-hydroxy vitamin D [25(OH)D], 1,25-dihydroxy vitamin D [1,25(OH)2D], and intact PTH were measured in subjects with SLE (n = 38) and healthy controls (n = 207), ages 5 to 21 years. Vitamin D status and its relation with disease activity were assessed using multivariable logistic and linear regression., Results: Severe vitamin D deficiency (25(OH)D <10 ng/ml) was observed in a significantly higher proportion of subjects with SLE (36.8% vs 9.2%, P < .001). In SLE, the odds ratio (OR) for severe deficiency was 2.37 (P = .09), adjusting for age, sex, race, and season. However, for each 1 SD greater body mass index (BMI) z-score, 25(OH)D levels were 4.2 ng/mL lower (P = .01) in SLE, compared with controls. Adjusting for 25(OH)D levels, SLE was associated with significantly lower 1,25(OH)2D (P < .001) and intact PTH levels (P = .03). Greater SLE disease activity index scores were observed in those with 25(OH)D <20 ng/mL (P = .01)., Conclusions: SLE was associated with vitamin D deficiency, particularly among those subjects with SLE who were overweight. Future studies should assess the effect of vitamin D supplementation on skeletal and nonskeletal outcomes in SLE.

Objective: To compare the efficacy and safety of bubble continuous positive airway pressure (CPAP) and Infant Flow Driver (IFD) CPAP for the post-extubation management of preterm infants with respiratory distress syndrome (RDS)., Study Design: A total of 140 preterm infants at 24 to 29 weeks' gestation or with a birth weight of 600 to 1500 g who were ventilated at birth for RDS were randomized to receive either IFD CPAP (a variable-flow device) or bubble CPAP (a continuous-flow device). A standardized protocol was used for extubation and CPAP. No crossover was allowed. The primary outcome was successful extubation maintained for at least 72 hours. Secondary outcomes included successful extubation maintained for 7 days, total duration of CPAP support, chronic lung disease, and complications of prematurity., Results: Seventy-one infants were randomized to bubble CPAP, and 69 were randomized to IFD CPAP. Mean gestational age and birth weight were similar in the 2 groups, as were the proportions of infants who achieved successful extubation for 72 hours and for 7 days. However, the median duration of CPAP support was 50% shorter in the infants on bubble CPAP. Moreover, in the subset of infants who were ventilated for less than 14 days, the infants on bubble CPAP had a significantly lower extubation failure rate. There was no difference in the incidence of chronic lung disease or other complications between the 2 study groups., Conclusions: Bubble CPAP is as effective as IFD CPAP in the post-extubation management of infants with RDS; however, in infants ventilated for < or = 14 days, bubble CPAP is associated with a significantly higher rate of successful extubation. Bubble CPAP also is associated with a significantly reduced duration of CPAP support.

Objective: To identify whether inhaled nitric oxide treatment decreased indicators of long-term pulmonary morbidities after discharge from the neonatal intensive care unit., Study Design: The Nitric Oxide (to Prevent) Chronic Lung Disease trial enrolled preterm infants (<1250 g) between 7 to 21 days of age who were ventilated and at high risk for bronchopulmonary dysplasia. Follow-up occurred at 12 +/- 3 months of age adjusted for prematurity; long-term pulmonary morbidity and other outcomes were reported by parents during structured blinded interviews., Results: A total of 456 infants (85%) were seen at 1 year. Compared with control infants, infants randomized to inhaled nitric oxide received significantly less bronchodilators (odds ratio [OR] 0.53 [95% confidence interval 0.36-0.78]), inhaled steroids (OR 0.50 [0.32-0.77]), systemic steroids (OR 0.56 [0.32-0.97]), diuretics (OR 0.54 [0.34-0.85]), and supplemental oxygen (OR 0.65 [0.44-0.95]) after discharge from the neonatal intensive care unit. There were no significant differences between parental report of rehospitalizations (OR 0.83 [0.57-1.21]) or wheezing or whistling in the chest (OR 0.70 [0.48-1.03])., Conclusions: Infants treated with inhaled nitric oxide received fewer outpatient respiratory medications than the control group. However, any decision to institute routine use of this dosing regimen should also take into account the results of the 24-month neurodevelopmental assessment.

Objectives: To characterize the rate of decline of forced expiratory volume in 1 second (FEV(1)) in children and adolescents with cystic fibrosis and to identify and compare risk factors associated with FEV(1) decline., Study Design: The rate of decline in FEV(1)% predicted over 3 to 6 years in 3 different age groups was determined. Risk factors for decline were identified and compared among and within age groups as a function of disease severity with repeated-measures, mixed-model regression., Results: Mean (+/-SD) baseline FEV(1)% predicted was 88.4% +/- 20.5% for 6- to 8-year-olds (n = 1811), 85.3% +/- 20.8% for 9- to 12-year-olds (n = 1696), and 78.4% +/- 22.0% for 13- to 17-year-olds (n = 1359). Decline in FEV(1)% predicted/year was -1.12, -2.39, and -2.34, respectively. High baseline FEV(1) and persistent crackles were significant independent risk factors for decline across all age groups. Female sex, Pseudomonas aeruginosa infection, low weight-for-age, sputum, wheezing, sinusitis, pulmonary exacerbations treated with intravenous antibiotics, elevated liver test results, and pancreatic insufficiency were also identified as independent risk factors in some age groups., Conclusions: This study identifies risk factors for FEV(1) decline in children and adolescents with cystic fibrosis. Clinicians should not be reassured by high lung function, particularly in young children, because this factor, among others, is independently associated with steeper decline in FEV(1).

Objective: Although influenza immunization is recommended for children with high-risk medical conditions, the majority of such children do not receive influenza vaccine. This study was designed to measure the burden of influenza among children with asthma and other chronic medical conditions., Study Design: We performed a retrospective cohort study of children younger than 15 years with medically treated asthma or other chronic medical conditions enrolled in the Tennessee Medicaid program from 1973 to 1993. We determined rates of hospitalization for acute cardiopulmonary disease, outpatient visits, and antibiotic courses throughout the year. Annual differences between event rates when influenza virus was circulating and event rates during winter months when there was no influenza in the community were used to calculate influenza-attributable morbidity., Results: Influenza accounted for an average of 19, 8, and 2 excess hospitalizations for cardiopulmonary disease yearly per 1000 high-risk children aged <1 year, 1 to <3 years, and 3 to <15 years, respectively. For every 1000 children, an estimated 120 to 200 outpatient visits and 65 to 140 antibiotic courses were attributable to influenza annually., Conclusions: Children younger than 15 years with asthma and other chronic medical conditions experience substantial morbidity requiring inpatient and outpatient care during influenza season. More effective targeting of this population for annual influenza immunization is warranted.

Objectives: To determine the value of open lung biopsy (OLB) in terms of diagnosis, morbidity, mortality, and benefits in immunocompromised children with pulmonary involvement., Study Design: We retrospectively reviewed 36 OLBs performed in 32 immunocompromised children between 1985 and 1998. Seventeen biopsies were performed in patients with primary immunodeficiency syndromes and 19 in patients with secondary immunodeficiency syndromes. Twenty-eight biopsies were performed because of a lack of response to ongoing antimicrobial treatments with negative or positive findings on bronchoalveolar lavage (BAL) and a deteriorating clinical or radiologic course, and 8 biopsies were performed because of persistent chest x-ray infiltrates., Results: Diffuse pulmonary infiltrates were observed on chest x-ray in 28 cases, hyperinflation in 3 cases, and nodular infiltrates in 5 cases. A histopathologic diagnosis was possible for all 36 OLBs. Specific diagnosis was obtained in 22 (61%) (12 infectious agents, 6 tumors, 4 bronchiolitis obliterans) and non-specific diagnosis in 14 (39%). Fungi were the main infectious agents (8 of 12). For the diagnosed infections, BAL provided 4 true-positive, 3 false-positive, and 6 false-negative results. Specific treatment was changed in 77% of cases, providing real benefits in 12 (33%) cases. The morbidity and overall mortality rates were 31% and 33%, respectively. The mortality rate was significantly higher in the first 30 days after OLB in patients receiving ventilatory assistance (58%)., Conclusions: OLB in immunocompromised children with deteriorating clinical or radiologic course is a sensitive diagnostic tool.

Criteria in common use for the diagnosis of chronic lung disease of prematurity or bronchopulmonary dysplasia in the neonatal period have not been sufficiently compared and validated against indicators of later respiratory complications. In this study of all 680 infants < or = 1500 gm birth weight admitted to six perinatal centers August 1, 1988, to July 31, 1990, 524 were alive and had no major congenital anomalies at 5 years old. Of 419 who had given permission to release their names and addresses, 272 were located and participated in a follow-up study. The following diagnostic criteria for bronchopulmonary dysplasia and chronic lung disease of prematurity were used during the initial hospitalization: (1) use of supplemental oxygen on day 30 of life, (2) a comprehensive bronchopulmonary dysplasia severity score applied at 25 to 35 days of life developed by a clinician panel to adjust for practice variation in ventilatory support and blood gases, (3) use of supplemental oxygen on day 30 of life with radiographic evidence consistent with bronchopulmonary dysplasia between days 25 and 35 of life, (4) radiographic evidence consistent with bronchopulmonary dysplasia alone, and (5) use of supplemental oxygen at 36 weeks' postconceptional age. These criteria were assessed against use of bronchodilators or steroids during the first 2 years of life, diagnosis of asthma, and hospitalizations for respiratory causes up to age 5. Although all criteria were significantly associated with all the outcomes, radiographic evidence was most predictive. These results indicate that, during a period when 21% of neonates were exposed to antenatal steroids, 24% received surfactant and 9% received postnatal corticosteroids, radiographic evidence was more predictive of long-term respiratory outcome than other commonly used criteria.

Background: Chronic progressive lung disease is the most prominent cause of morbidity and death in patients with cystic fibrosis (CF), but severity of lung disease and rate of lung function decline are widely variable. Accurate estimates of decline have been difficult to define and compare because the timing of measurements and duration of follow-up differ in various patient groups., Patients: Three hundred sixty-six patients with CF, born from 1960 to 1974, were selected from a CF database birth cohort if they had two or more measurements of pulmonary function, at least one of which was performed before the age of 10 years., Methods: Mixed model regression analysis provided estimates of the average rate of decline of spirometry measurements in subgroups on the basis of survival age, sex, pancreatic status, and genotype., Results: Patients who died before the age of 15 years had significantly poorer pulmonary function when first tested and a more rapid decline in pulmonary function thereafter than patients who survived beyond the age of 15 years. In the latter, functional levels at the age of 5 years were normal, but average rates of decline were significantly related to survival age. Female patients had significantly steeper decline than male patients, and those with pancreatic insufficiency had much steeper decline than those with pancreatic sufficiency. In the subset of 197 who survived to 1990 and were subsequently genotyped, rate of decline was greater in those homozygous for the delta F508 mutation, compared with those who were heterozygous for delta F508 or those, who had two other mutations., Discussion: All but the most severely affected patients, who died before age 15, appear to have had normal pulmonary function when first tested in early childhood. Pancreatic sufficiency, male gender, and some non-delta F508 mutations are associated with a slower rate of pulmonary function decline. Mixed model analysis is a valuable tool for describing and comparing pulmonary function decline in groups of patients with CF.

Objective: To examine the spectrum of hospitalization and rehospitalization among very low birth weight (VLBW, <1500 gm) infants with severe chronic lung disease during the first 2 years of life., Population: All 124 VLBW infants admitted to our center from October 1988 to September 1990 who were oxygen and ventilator dependent at 21 days of age. One hundred infants survived to discharge, of whom two subsequently died. The 98 surviving infants are the subject of this report., Methods: The duration of the neonatal stay, the use of a long-term care facility, and rehospitalizations were recorded to a postnatal age of 24 months. The duration of these hospitalizations and the total duration of hospitalization during the first year of life were correlated with demographic and perinatal risk factors and 20-month outcome., Results: The 98 infants spent a median of 125 days (range, 44 to 365) of their first year hospitalized; the neonatal stay accounted for 85% of this time. Forty-nine of the infants (50%) were rehospitalized in their first year (median stay, 14 days), and 36 (37%) were rehospitalized in their second year (median stay, 7 days). Long-term care facility stay and rehospitalizations accounted for 6% and 9% of the first-year hospitalizations, respectively. A median of 9 days (range, 1 to 365) of the second year of life were spent in hospital. The infants rehospitalized during their first year of life did not differ significantly from those not requiring rehospitalization with regard to maternal demographic descriptors, birth data, severity of chronic lung disease, or measures of 20-month outcome. Both duration of neonatal stay and total hospital stay during the first year were significantly associated with all measures of chronic lung disease severity and with 20-month neurodevelopmental outcome measures, whereas the duration of rehospitalization was associated only with duration of oxygen dependence., Conclusion: Among infants with severe chronic lung disease, the total duration of hospitalization during the first year of life provides a better index of morbidity than the number or duration of rehospitalizations alone.

A three-dose prophylactic regimen of synthetic surfactant replacement has been shown to improve neonatal and 1-year survival rates in infants of 700 to 1100 gm birth weight when compared with a single prophylactic dose. The purpose of this study was to evaluate the growth, development, and late morbidity at 1 year adjusted age among the survivors of the 826 patients enrolled in the protocol. Complete follow-up data were obtained for 75% of the survivors in both groups. Chronic lung disease, need for respiratory support, neurologic disease requiring medication, visual or auditory impairments, and the incidence and severity of retinopathy of prematurity were equivalent in the two groups. The frequency of neurodevelopmental impairment was also comparable in the groups that received one dose versus three doses: moderate to severe cerebral palsy was found in 9% versus 6%, mental retardation assessed by Bayley Scales of Infant Development scores less than 69 was found in 16% vs 14%, and moderate to severe impairments of any kind were found in 33% vs 24%, respectively. Furthermore, the absolute number of impaired survivors was 92 in the three-dose group versus 106 in the one-dose group, despite a higher survival rate in the three-dose group. This study demonstrates that developmental outcomes of infants weighing 700 to 1100 gm who received three prophylactic doses of synthetic surfactant are at least as good as those of infants receiving a single dose, and that improving survival rates of very premature infants with synthetic surfactant does not result in increased numbers of infants with impairments.

A single dose of synthetic surfactant was administered prophylactically to premature neonates with birth weights between 700 and 1100 gm. The effects of this treatment on neurodevelopmental, neurologic, and ophthalmologic outcomes, impairments, and general health status were examined during a follow-up evaluation at 1-year adjusted age. The study was a multicenter, parallel, randomized, double-blind comparison of 446 infants who received either air placebo (n = 222) or synthetic surfactant (n = 224). Follow-up evaluations were completed for 82% of surviving infants in both treatment groups. Neurodevelopmental outcome and growth were equivalent in the infants treated with synthetic surfactant and in the infants given air placebo. Impairments occurred in 38% of the infants treated with air placebo compared with 31% of those given synthetic surfactant; the difference was not statistically significant (relative risk 0.809, 95% confidence interval 0.585, 1.119). The incidence of asthma was significantly higher in the group of infants given air placebo (4% vs 10% for surfactant and air placebo, respectively, relative risk 0.391, 95% confidence intervals 0.157, 0.972). Other outcomes, including retinopathy of prematurity, hospital readmissions, surgery, and evidence of chronic lung disease, were not different. Administration of a single prophylactic dose of synthetic surfactant increases survival in infants with birth weights between 700 and 110 gm without increasing the number or proportion of impaired survivors.

In a multicenter, double-blind, placebo-controlled trial that enrolled 215 premature infants with birth weights of 500 to 699 gm, 106 infants were treated prophylactically with a single 5 ml/kg dose of synthetic surfactant and 109 infants were given an equivalent dose of air placebo shortly after birth. In each group, 40 children survived infancy: 36 children in the air placebo group and 30 children in the synthetic surfactant group were available for follow-up. Weight, height, and head circumference measurements were similar for both groups at 1-year adjusted age. Infants who received synthetic surfactant at birth had statistically similar Bayley Scales of Infant Development scores (mental developmental index, 92 vs 83; psychomotor developmental index, 87 vs 82) compared with controls. Mild to moderate impairments in the synthetic surfactant group were 7% versus 29% in the control group; these differences were not statistically significant. The incidence of retinopathy of prematurity, the number of hospital readmissions, the need for surgery after day 28, evidence of chronic lung disease, the need for respiratory support at 1-year adjusted age, and the incidence of allergies were also not different between the two groups. However, the proportion of infants surviving without impairment was modestly higher in the synthetic surfactant group (8%, air placebo group; 23%, synthetic surfactant group). The findings from this small study indicate that infants weighing 500 to 699 gm who receive a single prophylactic dose of synthetic surfactant at birth have neurodevelopmental outcomes at least equivalent to those of infants given air placebo at 1-year follow-up.

In a multicenter, double-blind, placebo-controlled rescue trial conducted at 13 Canadian hospitals, two 5 ml/kg doses of a synthetic surfactant or air placebo were administered to 344 infants with birth weights of 750 to 1249 gm who had established respiratory distress syndrome and an arterial/alveolar oxygen tension ratio less than 0.22. The first dose was given between 2 and 24 hours of age, and the second dose was given 12 hours later to the infants remaining on mechanical ventilation. Infants were stratified at study entry by birth weight and gender. The trial was terminated short of the targeted sample size because significant reductions in mortality were observed in another rescue trial completed in the United States in the same weight class of infants. Despite premature termination of the trial, the rate of survival without bronchopulmonary dysplasia was increased (61% vs 52%; p = 0.046) in infants treated with surfactant. In addition, there was a significant reduction in the incidence of overall pulmonary air leak (46% vs 32%; p = 0.009), pneumothorax (27% vs 17%; p = 0.023), and pulmonary interstitial emphysema (40% vs 28%; p = 0.018) in infants treated with synthetic surfactant. There was no difference in the incidence of bronchopulmonary dysplasia, apnea, or pulmonary hemorrhage. Significant improvements in alveolar-arterial oxygen tension gradient, arterial/alveolar oxygen tension ratio, and oxygen and ventilator requirements through day 7 were present. These findings indicate that rescue therapy with synthetic surfactant can improve outcome for premature infants weighing 750 to 1249 gm with respiratory distress syndrome.

This study determined outcomes at 12-months adjusted age of 957 infants weighing more than 1250 gm at birth who were subjects in a randomized, double-blind, controlled trial of synthetic surfactant or air placebo administered in a rescue trial at 23 hospitals in the United States and 13 hospitals in Canada. Follow-up results were available for 475 of 563 surviving infants who received air placebo (84%) and 482 of 571 infants who received synthetic surfactant (84%). Developmental outcome was equivalent in the two groups. Morbidity was less in the synthetic surfactant group as assessed by the need for medication for chronic lung disease (52 of 475 (11%) for the air placebo group vs 32 of 482 (7%) for the synthetic surfactant group) or respiratory support (10 of 475 (2%) for the air placebo group vs 1 of 482 (< 1%) for the synthetic surfactant group) at 1-year adjusted age. Bayley Scales of Infant Development (mental development Index: 102 for both the air placebo and synthetic surfactant groups; psychomotor development index: 95 for the air placebo group vs 94 for the synthetic surfactant group) and impairment rates (94 of 475 (20%) for the air placebo group vs 86 of 482 (18%) for the synthetic surfactant group) were similar in the two groups. Infants weighing more than 1250 gm who have respiratory distress syndrome have previously been shown to have improved survival rates and lower neonatal morbidity after treatment with synthetic surfactant. These follow-up data confirm that developmental outcome as determined at 12-months adjusted age is at least as good in those receiving synthetic surfactant.

A multicenter, randomized, double-blind, placebo-controlled trial of synthetic surfactant therapy for premature infants with respiratory distress syndrome (RDS) and birth weights of 700 to 1350 gm demonstrated a reduction in severity of RDS, morbidity, and neonatal and 1-year mortality. Of the 419 infants who were entered in the study, 80% of the surviving infants in both the air placebo group (122) and the synthetic surfactant group (138) returned for the follow-up evaluation at 1-year adjusted age. The only significant difference observed at follow-up was a reduction in the incidence of mild cerebral palsy in the synthetic surfactant group (air placebo group, 8 of 122 (7%); synthetic surfactant group, 3 of 138 (2%); relative risk 0.306; 95% confidence interval 0.094, 0.999). No differences were observed between the air placebo and synthetic surfactant treatment groups with respect to health status of the infants, including the incidence of retinopathy of prematurity and neurodevelopmental delays. The difference in the overall incidence of impairment among the 1-year survivors in the air placebo group (43 of 122 (35%)) and in the synthetic surfactant group (40 of 138 (29%)) was not statistically significant. The results of this 1-year follow-up study show that rescue treatment with synthetic surfactant in infants weighing 700 to 1300 gm is not associated with adverse developmental consequences despite the improvement in survival.

We conducted a prospective, randomized, double-blind trial to assess the efficacy and safety of pulse doses of dexamethasone on survival without supplemental oxygen in very low birth weight infants at high risk of having chronic lung disease. Seventy-eight infants with birth weights < or = 1500 gm who were ventilator dependent at 7 days of postnatal age were randomly assigned to receive pulse doses of dexamethasone, 0.5 mg/kg per day, divided twice daily (n = 39), or an equivalent volume of saline solution placebo (n = 39), for 3 days at 10-day intervals until they no longer required supplemental oxygen or assisted ventilation, or reached 36 weeks of postmenstrual age. At study entry, the groups did not differ by birth weight, gestational age, or severity of lung disease. At 36 weeks of postmenstrual age, there was both a significant increase in survival rates without oxygen supplementation (p = 0.03) and a significant decrease in the incidence of chronic lung disease (p = 0.047) in the group that received pulse therapy. Supplemental oxygen requirements were less throughout the study period in the group that received repeated pulse doses of dexamethasone (p = 0.013). The total numbers of deaths and the durations of supplemental oxygen, ventilator support, and hospital stay did not differ between groups. Recorded side effects in the pulse therapy group were minimal and included an increase in the use of insulin therapy for hyperglycemia (p < 0.05). We conclude that in this population of very low birth weight infants, treatment with pulse doses of dexamethasone resulted in improvement in pulmonary outcome without clinically significant side effects.

Objective: To assess the role of specific risk factors that may predispose preterm infants with mild or no initial respiratory distress syndrome to the development of chronic lung disease (CLD)., Study Design: Clinical data were collected prospectively from 119 ventilator-supported preterm infants with birth weights between 500 and 1000 gm, who survived more than 28 days and required fewer than 3 days of treatment with fraction of inspired oxygen > 25% during the first 5 days of life. Logistic regression analysis was used in a multivariate assessment of risk factors for CLD., Results: Chronic lung disease occurred in 44 of the patients (37%). The analysis showed that low birth weight, patent ductus arteriosus (PDA), and sepsis were significant risk factors for CLD. The corresponding odds ratios for CLD and their 95% confidence intervals (CI) were as follows: 2.9 per 100 gm birth weight decrement (CI, 1.7 to 4.8); 6.2 (CI, 2.1 to 18.4) for PDA; and 4.4 (CI, 1.3 to 14.5) for sepsis. When sepsis and PDA occurred simultaneously, the odds ratio for CLD increased to 48.3 (CI, 6.3 to > 100) in comparison with infants without these conditions. Episodes of PDA were categorized as either early (occurring during the first week of life) or late (after the first week), and the respective odds ratios for CLD were 2.8 (CI, 0.8 to 9.4) and 21.1 (CI, 5.6 to 80) in comparison with infants without PDA. For the duration of symptomatic PDA, the odds ratio for CLD was 3.5 per week that the PDA remained open (CI, 1.9 to 6.5)., Conclusion: CLD is a frequent sequela in very low birth weight infants with mild or no respiratory distress syndrome. In this population, the development of late episodes of PDA, usually in association with a nosocomial infection, seems to play a primary role in the pathogenesis of CLD.

We sought to examine the effect of the introduction of dexamethasone therapy on health, growth, and neurodevelopmental outcome in very low birth weight (VLBW) infants at 20 months of age. We compared outcomes in all 86 VLBW infants (mean birth weight 871 gm, mean gestational age 26.4 weeks) who were ventilator dependent on day 21 of life during the 2 years preceding October 1988 (period 1), when dexamethasone therapy became accepted clinical practice in our unit, with outcomes in all 124 infants (mean birth weight 891 gm, mean gestational age 26.9 weeks) with similar ventilator status during the subsequent 2 years (period 2). In addition, we compared outcomes in infants who received dexamethasone during period 2 with those in a concurrent cohort of less ill infants who were not given dexamethasone. There were no significant differences between periods 1 and 2 in mortality rates after 21 days (17% vs 21%), need for home oxygen (23% vs 25%), oxygen dependence at 20 months of corrected age (11% vs 10%), rate of neurosensory impairment (24% vs 25%), and mean Bayley Mental scores (81.5 vs 77.2) or Psychomotor Development Index (81.6 vs 71.1). Infants who received dexamethasone during period 2 had significantly more severe lung disease and poorer respiratory, growth, and developmental outcomes. We conclude that VLBW infants with ventilator-dependent chronic lung disease have very poor outcomes, even when treated with dexamethasone. More information is needed from prospective, randomized trials before dexamethasone can be accepted as routine therapy for chronic lung disease.

A metaanalysis of surfactant clinical trials was carried out to assess whether or not an association exists between exogenous surfactant therapy and pulmonary hemorrhage. Trials that reported the pulmonary hemorrhage occurrence (group 1) and those that did not (group 2) were analyzed. Thirty-three treatment strategies were tested in 29 publications from 1980 through 1992. Eleven of these were group 1 trials, which reported a 3% overall incidence of pulmonary hemorrhage. The rates were significantly higher in both the treated and the control groups of natural surfactant trials than in synthetic surfactant trails (5.87% and 5.36% in the natural surfactant trials vs 2.51% and 1.04% in the synthetic surfactant trials, respectively). The pooled estimate of relative risk for pulmonary hemorrhage with any surfactant therapy was 1.47 (95% confidence interval 1.05, 2.07; p < 0.05). Logistic regression modeling revealed that the nature of surfactant, treatment strategy, and lower mean birth weight had a significant influence on the relative risk of pulmonary hemorrhage; a similar trend was seen with higher mortality rates. Variation in the rates of patent ductus arteriosus did not have an independent effect on the estimated pulmonary hemorrhage risk. Most group 2 trials were published before 1990, and the median total sample size was 73, compared with 402 for the group 1 trials (p < 0.05), most of which were published in the 1990s. In 10 (50%) of 20 group 2 trials, pulmonary hemorrhage data were collected methodically, in comparison with all group 1 trials, most of which collected data prospectively. We conclude that pulmonary hemorrhage is a rare complication of respiratory distress syndrome. An awareness of the possible association of pulmonary hemorrhage with surfactant use in later trials and the differences in definitions and reporting practices probably explain variations in the reported incidence among the trials. The risk of pulmonary hemorrhage increases slightly, on an average of 47%, with any surfactant therapy. This increased risk is small compared with the documented benefits of surfactant therapy in respiratory distress syndrome.

In an across study analysis of five multicenter, placebo-controlled trials of the synthetic surfactant, Exosurf Neonatal in infants weighing at least 700 gm, the incidence of clinical pulmonary hemorrhage was 1.9% in treated infants and 1.0% in control infants. To investigate whether a similar increase was also present histologically at postmortem examination, a blinded retrospective review of all autopsy reports from infants dying during these five trials was conducted. Pulmonary hemorrhage was present in 55% of 159 infants undergoing autopsy; the incidence was not different in infants treated with surfactant or air placebo. Birth weight was inversely related to the incidence of pulmonary hemorrhage in both groups. Pulmonary pathologic findings significantly associated with pulmonary hemorrhage included pulmonary interstitial emphysema and necrotizing laryngotracheitis in both groups. In the surfactant group, patent ductus arteriosus, intraventricular hemorrhage, and pneumothorax were significantly more frequent among those who developed pulmonary hemorrhage. In contrast to clinical diagnosis, pathologic diagnosis of pulmonary hemorrhage at autopsy was not more common in infants treated with Exosurf Neonatal.

All neonates (n = 581) with birth weights less than 1501 gm admitted to seven neonatal intensive care units in Wisconsin and Iowa were candidates for a study aimed at the multivariate assessment of risk factors for chronic lung disease while controlling for baseline severity of respiratory disease. Data from 361 neonates were analyzed for all risk factors except fluids; only neonates weighing less than 1200 gm were included (n = 220). Information on traditional risk factors for chronic lung disease was abstracted. A total of 110 (30%) of the analyzed neonates were oxygen dependent on day 30 of life. The following baseline factors were associated with increased risk of oxygen dependence in a joint multivariate model: lower birth weight (odds ratio 1.4/100 gm), higher baseline severity score (odds ratio 2.7/doubling at 32 weeks gestational age), lower gestational age (odds ratio 2.4/week at severity 0), Apgar score at 1 minute (odds ratio 1.6/2 points), male gender (odds ratio 1.9), and nonblack race (odds ratio 2.2). After adjustment for all baseline factors, patent ductus arteriosus, ventilator pressure at 96 hours, oxygen at 96 hours, and fluid intake were associated with oxygen dependence. Neonates with a low baseline severity score who remained oxygen dependent had a higher intake of fluid relative to output, whereas neonates with a higher baseline severity score had higher fluid intake and output. Lack of weight loss was associated with increased severity but not with oxygen dependence. The results of this study generally confirm the significance of previously reported risk factors for chronic lung disease in a multivariate setting but show that risk factors may not have the same impact in neonates with different baseline severity.

To test the hypothesis that decreased mortality from severe HMD will result in increased morbidity from BPD, chest films of 30-day survivors of severe HMD were reviewed for evidence of Northway's Stage IV BPD. During July, 1970 to June, 1971, 20 survivors of severe HMD were identified; one case of Stage IV BPD was found in this group. During July 1974-June 1975, 80 survivors of severe HMD were identified; five infants had BPD. In spite of more survivors of severe HMD, no increase in the incidence of BPD could be demonstrated.

We did an epidemiologic survey of 30 children in whom idiopathic pulmonary hemosiderosis was diagnosed. Eighteen patients had died; 12 patients were still living. The majority of the cases were diagnosed in between 1962 and 1971, mainly in the spring and fall. Eighty percent of the patient lived in villages, whereas only 30% of the total population resided in the same type of rural area. Only one (5%) of the deceased children lived in the city, whereas four (33%) of the living children were city dwellers. The socioeconomic conditions were poor, and in 50% of the cases continuous exposure to highly toxic insecticides was elicited by history and investigation of housing conditions. The incidence of newly diagnosed cases decreased with the improvement of living conditions and the prohibition of the use of certain insecticides. We believe that environmental factors, perhaps insecticides, may cause idiopathic pulmonary hemosiderosis in genetically predisposed persons. An epidemiologic history and genetic investigation should be included in the evaluation of patients with any disease when the cause is obscure.