Late outcomes of a randomized trial of high-frequency oscillation in neonates.

BACKGROUND: Results from an observational study involving neonates suggested that high-frequency oscillatory ventilation (HFOV), as compared with conventional ventilation, was associated with superior small-airway function at follow-up. Data from randomized trials are needed to confirm this finding. METHODS: We studied 319 adolescents who had been born before 29 weeks of gestation and had been enrolled in a multicenter, randomized trial that compared HFOV with conventional ventilation immediately after birth. The trial involved 797 neonates, of whom 592 survived to hospital discharge. We compared follow-up data from adolescents who had been randomly assigned to HFOV with follow-up data from those who had been randomly assigned to conventional ventilation, with respect to lung function and respiratory health, health-related quality of life, and functional status, as assessed with the use of questionnaires completed when the participants were 11 to 14 years of age. The primary outcome was forced expiratory flow at 75% of the expired vital capacity (FEF75). RESULTS: The HFOV group had superior results on a test of small-airway function (z score for FEF75, -0.97 with HFOV vs. -1.19 with conventional therapy; adjusted difference, 0.23 [95% confidence interval, 0.02 to 0.45]). There were significant differences in favor of HFOV in several other measures of respiratory function, including forced expiratory volume in 1 second, forced vital capacity, peak expiratory flow, diffusing capacity, and impulse-oscillometric findings. As compared with the conventional-therapy group, the HFOV group had significantly higher ratings from teachers in three of eight school subjects assessed, but there were no other significant differences in functional outcomes. CONCLUSIONS: In a randomized trial involving children who had been born extremely prematurely, those who had undergone HFOV, as compared with those who had received conventional ventilation, had superior lung function at 11 to 14 years of age, with no evidence of poorer functional outcomes. (Funded by the National Institute for Health Research Health Technology Assessment Programme and others.).

Pulmonary Artery Pressures in School-Age Children Born Prematurely.

OBJECTIVES: To test the hypothesis that pulmonary artery pressures were higher in school aged children born extremely premature than those born at term. We also wanted to assess whether pulmonary artery pressures differed between children born prematurely with or without bronchopulmonary dysplasia (BPD) or between those randomized in the neonatal period to different ventilation modes. STUDY DESIGN: Transthoracic echocardiography was performed on 193 children born extremely premature (106 had BPD) and 110 children born at term when they were 11-14 years of age. Ninety-nine children born extremely premature had been supported by high-frequency oscillation and 94 by conventional ventilation. Tricuspid regurgitation was assessed in the apical 4-chamber and modified parasternal long-axis views. Continuous-wave Doppler of the peak regurgitant jet velocity was used to estimate the right-ventricular-to-right-atrial systolic pressure gradient. RESULTS: Tricuspid regurgitation was measurable in 71% (137/193) of the children born preterm and 75% (83/110) of the children born at term (P .23). The children born prematurely compared with the children born at term had a greater peak tricuspid regurgitation velocity (2.21 vs 1.95 m/s, P < .001) and the children born prematurely who had BPD vs those without BPD had a greater peak tricuspid regurgitation velocity (P = .023). There were no significant differences in pulmonary artery pressures according to neonatal ventilation mode. CONCLUSIONS: Pulmonary artery pressures were estimated to be greater in 11- to 14-year-old children born extremely prematurely compared with those born at term and in those born prematurely who developed BPD compared with those who did not but did not differ significantly by neonatal ventilation mode.

Longitudinal changes in lung function in very prematurely born young people receiving high-frequency oscillation or conventional ventilation from birth.

OBJECTIVE: To examine changes in lung function over time in extremely prematurely born adolescents. WORKING HYPOTHESIS: Changes in lung function during adolescence would vary by ventilation mode immediately after birth. STUDY DESIGN: Longitudinal follow-up study. PATIENT SUBJECT SELECTION: Participants from the United Kingdom Oscillation Study who were randomized at birth to high-frequency oscillation (HFO) or conventional ventilation (CV) were assessed at 11-14 years (n = 319) and at 16-19 years (n = 159). METHODOLOGY: Forced expiratory flow (FEF), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and lung volumes including functional residual capacity (FRC) were reported as z-scores. The diffusion capacity of the lungs for carbon monoxide (DLCO) was measured. Lung function trajectories were compared by mode of ventilation using mixed models. Changes in z-scores were scaled to 5-year average follow-up. RESULTS: There were significant changes in the mean FEF75, FEF50, FEF25, FEV1, FVC, and DLCO z-scores within the CV and HFO cohorts, but no significant differences in the changes between the two groups. The mean FRC z-score increased in both groups, with an average change of greater than one z-score. The mean FEV1/FVC z-score increased significantly in the CV group, but not in the HFO group (difference in slopes: p = 0.02). Across the population, deterioration in lung function was associated with male sex, white ethnicity, lower gestational age at birth, postnatal corticosteroids, oxygen dependency at 36 weeks postmenstrual age, and lower birth weight, but not ventilation mode. CONCLUSIONS: There was little evidence that the mode of ventilation affected changes in lung function over time.

Prevention BINGO: reducing medication and alcohol use risks for older adults.

OBJECTIVES: Older adults are a population vulnerable to the effects of alcohol, medication-to-alcohol interactions, and combining multiple medications. This study examines the effectiveness of a prevention program to increase older adults' knowledge about these risks. METHODS: Older adults (N = 348) were asked to participate in a prevention program and to take a pre- and post-test measuring knowledge about the risks of taking multiple medications and of alcohol use as one ages, before and after participation. A subsample of the group (N = 60) was followed at 30 days after participation in the program and asked to complete a survey on how the program affected their attitudes and choices regarding their medications and alcohol use. RESULTS: Results show a significant increase in knowledge about older adults' risks related to their medication and alcohol use from pre- to post-test. The group sampled at 30 days after program participation showed that the majority either agreed or strongly agreed that their attitudes had changed toward more awareness and increased understanding of the importance of knowing their risks related to medication use, medication interactions, multiple medications or polypharmacy, and alcohol. CONCLUSION: As a result of this intervention, older adults gained knowledge about their own risks related to medication use, medication interactions, multiple medications or polypharmacy, and alcohol use. Further research is needed to replicate these findings and to determine how prevention education can reduce these risks for older adults.

Postnatal dexamethasone exposure and lung function in adolescents born very prematurely.

We previously demonstrated corticosteroid administration on the neonatal intensive care unit was associated with reduced lung function at 11 to 14 years of age in children born very prematurely. The objective of this observational study was to assess if lung function remained impaired at 16 to 19 years of age in those who had received postnatal corticosteroids and whether the trajectory of lung function with increasing age differed between those who had and had not received corticosteroids. One hundred and fifty-nine children born prior to 29 weeks of gestational age had comprehensive lung function measurements; 49 had received postnatal dexamethasone. Lung function outcomes were compared between those who had and had not received postnatal dexamethasone after adjustment for neonatal factors. Forced expiratory flow at 75%, 50%, 25% and 25-75% of the expired vital capacity, forced expiratory volume in one second, peak expiratory flow and forced vital capacity and lung volumes (total lung capacity and residual volume) were assessed. The majority of results were significantly lower in those who received dexamethasone (between 0.61 to 0.78 standard deviations). Lung function reduced as the number of courses of dexamethasone increased. Between 11 and 14 years and 16 to 19 years, lung function improved in the unexposed group, but forced expiratory flow at 75% of the expired vital capacity and forced expiratory volume in one second deteriorated in those who had received postnatal corticosteroids (p = 0.0006). These results suggest that prematurely born young people who received postnatal corticosteroids may be at risk of premature onset of chronic obstructive pulmonary disease.

Lung function and respiratory outcomes in teenage boys and girls born very prematurely.

OBJECTIVES: Male sex in prematurely born infants has been associated with worse respiratory outcomes in early childhood. WORKING HYPOTHESIS: Respiratory outcomes at 11 to 14 years of age in children born very prematurely and routinely exposed to antenatal corticosteroids and postnatal surfactant would differ according to sex. STUDY DESIGN: Analysis of follow-up data. PATIENT-SUBJECT SELECTION: Three hundred and nineteen children born before 29 weeks of gestational age from the United Kingdom Oscillation Study. METHODOLOGY: Spirometry was used to assess forced expiratory flow at 75%, 50%, and 25% of expired vital capacity (FEF75 , FEF50 , and FEF25 ), forced expiratory volume in 1 second (FEV1 ), peak expiratory flow (PEF), and forced vital capacity (FVC). Lung volumes were measured using a helium dilution technique (FRCHe ) and by plethysmography (FRCpleth ). Total lung capacity (TLC) and residual volume (RV) were calculated. Mean lung function measurements were compared using linear mixed models and reported as unadjusted and adjusted for neonatal and age 11 to 14 years factors. The participants also completed health questionnaires and provided a urine sample for assessment of passive or active smoking. RESULTS: Three (FEF25 , FEF25-75 , FEV1 ) lung function measures showed significant differences in favor of females after adjustment. The percentage of children with abnormal lung function (below 5th centile for normal) had adjusted differences between 10 and 30 percentage points, for example, for FEF25 15% females compared with 26% males. CONCLUSIONS: Among extremely prematurely born school children airway function was significantly worse in males.

Effect of dexamethasone exposure on the neonatal unit on the school age lung function of children born very prematurely.

The objective of this study was to determine the impact of postnatal dexamethasone treatment on the neonatal unit on the school age lung function of very prematurely born children. Children born prior to 29 weeks of gestational age had been entered into a randomised trial of two methods of neonatal ventilation (United Kingdom Oscillation Study). They had comprehensive lung function measurements at 11 to 14 years of age. One hundred and seventy-nine children born at a mean gestational age of 26.9 (range 23-28) weeks were assessed at 11 to 14 years; 50 had received postnatal dexamethasone. Forced expiratory flow at 75% (FEF75), 50%, 25% and 25-75% of the expired vital capacity, forced expiratory volume in one second, peak expiratory flow and forced vital capacity and lung volumes including total lung capacity and residual volume were assessed. Lung function outcomes were compared between children who had and had not been exposed to dexamethasone after adjustment for neonatal factors using linear mixed effects regression. After adjustment for confounders all the mean spirometry results were between 0.38 and 0.87 standard deviations lower in those exposed to dexamethasone compared to the unexposed. For example, the mean FEF75 z-score was 0.53 lower (95% CI 0.21 to 0.85). The mean lung function was lower as the number of courses of dexamethasone increased. In conclusion, postnatal dexamethasone exposure was associated with lower mean lung function at school age in children born extremely prematurely. Our results suggest the larger the cumulative dose the greater the adverse effect on lung function at follow-up.

Longitudinal assessment of lung function in extremely prematurely born children.

OBJECTIVES: To assess longitudinally small airway function in children born extremely prematurely and whether there was a correlation between airway function in infancy and at 11-14 years. WORKING HYPOTHESES: There would be tracking of airways obstruction and small airway function would deteriorate during childhood in those born extremely prematurely. STUDY DESIGN: A longitudinal study. PATIENT-SUBJECT SELECTION: Thirty-five children with a mean gestational age of 26 weeks had lung function assessed at 1 year corrected and 11-14 years of age. METHODOLOGY: Lung volumes were measured by helium gas dilution (FRCHe ) and plethysmography (FRCpleth ) and small airway function assessed by calculating the FRCHe :FRCpleth ratio. Airway function was assessed at 1 year corrected by measurement of airway resistance (Raw ) and at 11-14 years by assessment of Raw , forced expiratory flow from 75% of vital capacity (FEF75 ), and forced expiratory volume at one second (FEV1 ). RESULTS: At the first assessment, the children had a mean (SD) FRCHe :FRCpleth of 0.90 (0.13) and at the second, 0.83 (0.12) (P = 0.035). There was a significant 0.54% decrease (95%CI: -1.02%, -0.06%) in FRCHe :FRCpleth for increased age per year after adjusting for birth weight, gestational age, sex, and bronchopulmonary dysplasia (P = 0.027). There were significant correlations between Raw at the first assessment and Raw (P = 0.012), FEF75 (P = 0.034), and FEV1 (P = 0.04) at 11-14 years. CONCLUSIONS: These results demonstrate in those born extremely prematurely there is tracking of airway function during childhood.

Postnatal dexamethasone, respiratory and neurodevelopmental outcomes at two years in babies born extremely preterm.

IMPORTANCE: Postnatal dexamethasone is associated with reduction in bronchopulmonary dysplasia. There remains, however, concern that its short-term benefits are accompanied by long-term adverse effects e.g. poorer neurodevelopmental outcomes. OBJECTIVE: Our aim was to determine the effects of administration of postnatal dexamethasone on respiratory and neurodevelopmental outcome at two years of age after adjusting for neonatal and infant risk factors. MATERIALS AND METHODS: The study included 412 infants born at 23-28 weeks of gestation, 29% had received postnatal dexamethasone. Two outcomes were examined, respiratory hospital admissions in the past 12 months and neurodevelopmental impairment. Logistic regression, adjusted for sex, birthweight z-score, gestation, maternal smoking, oxygen dependency at 36 weeks, airleak, patent ductus arteriosus, pulmonary haemorrhage, major ultrasound abnormality, mode of ventilation and age at assessment, was undertaken. RESULTS: After adjustment, postnatal dexamethasone was associated with significantly increased proportions of both respiratory hospital readmission: (0.35 vs 0.15, difference = 0.20; 95% CI: 0.08, 0.31) and neurodevelopmental impairment (0.59 vs 0.45, difference = 0.14; 95% CI: 0.02, 0.26). CONCLUSIONS: Postnatal dexamethasone use in extremely preterm infants is associated with increased risks of respiratory hospital admissions and neurodevelopmental impairment. These associations were not explained by excess neonatal morbidities.

Prediction of respiratory outcome in extremely low gestational age infants.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a commonly used outcome for randomized neonatal trials. OBJECTIVES: The aim of the present study was to determine whether a diagnosis of BPD or respiratory morbidity (RM1 or RM2) at 12 months corrected age better predicted subsequent RM in extremely low gestational age infants (23-28 weeks of gestation). METHODS: Initial analysis was undertaken in a development cohort of 76 infants who underwent pulmonary function tests (PFTs) at 12 months corrected age. Parents completed infant respiratory diaries 2 weeks before the PFTs. Analysis was then undertaken in a validation cohort of 227 infants whose parents completed a 4-week respiratory diary when their infant was 12 months corrected age. BPD at 28 days (BPD28d) and 36 weeks post-menstrual age (BPD36w), RM1 (≥3 days and/or nights of cough, wheeze, and/or medicine use) and RM2 (≥4 days and/or nights of cough, wheeze, and/or respiratory medicine use) each week for 2 weeks at 12 months corrected age were assessed with regard to prediction of respiratory outcomes at 24 months documented by respiratory health questionnaires. RESULTS: BPD28d and BPD36w were not significantly associated with any respiratory outcome. Areas under the receiver operating characteristic curves were significantly better for either definition of RM than BPD28d or BPD36w for all outcomes. CONCLUSIONS: RM documented by parental completed diaries at 12 months corrected age better predicted respiratory outcome at 24 months corrected age than BPD regardless of diagnostic criteria.

United Kingdom Oscillation Study: long-term outcomes of a randomised trial of two modes of neonatal ventilation.

BACKGROUND: One in 200 infants in the UK is born extremely prematurely, i.e. before 29 weeks of gestation. Seventy-five per cent of such infants survive, but many have long-term respiratory and/or functional problems. OBJECTIVES: To compare respiratory and functional outcomes of school-age children born extremely prematurely who received either high-frequency oscillation (HFO) or conventional ventilation (CV) immediately after birth to test the hypothesis that the use of HFO would be associated with superior small airway function at school age without adverse effects. DESIGN: Follow-up of a randomised trial, the United Kingdom Oscillation Study, in which infants were randomised to receive HFO or CV within 1 hour of birth. SETTING: King's College Hospital NHS Foundation Trust, London, UK. PARTICIPANTS: Three hundred and nineteen children aged between 11 and 14 years were recruited (160 had received HFO); the planned sample size was 320. INTERVENTIONS: HFO versus CV. MAIN OUTCOME MEASURES: The results of comprehensive lung function assessments (primary outcome small airway function), echocardiographic examinations and respiratory, health-related quality of life and functional assessment questionnaires. RESULTS: Significant baseline differences in maternal and neonatal characteristics between the two groups favoured the CV group, who had a higher mean birthweight (56 g) and were born later (0.3 weeks), and a greater proportion of whom had received surfactant. There were no significant differences between the two groups in their characteristics when assessed at 11-14 years of age. The children who had received HFO had significantly superior small airway function; their forced expiratory flow at 75% vital capacity z-score was 0.23 higher than that of the CV group [95% confidence interval (CI) 0.02 to 0.45]. Thirty-seven per cent of the HFO group and 46% of the CV group had small airway function results that were below the tenth centile. There were significant differences between ventilation groups in favour of HFO for other lung function results as expressed by z-scores {forced expiratory volume at 1 minute (FEV1) [difference 0.35 (95% CI 0.09 to 0.60)], the ratio of FEV1 to forced vital capacity [0.58 (95% CI 0.16 to 0.99)], diffusing capacity of the lung for carbon monoxide [0.31 (95% CI 0.04 to 0.58)], maximum vital capacity [0.31 (95% CI 0.05 to 0.57)]} and expressed as % predicted {peak expiratory flow rate [5.85 (95% CI 2.21 to 9.49)] and respiratory resistance at 5 Hz [-7.13 Hz (95% CI -2.50 to -1.76 Hz)]}. There were no significant differences between ventilation groups with regard to the echocardiographic results, respiratory morbidity in the last 12 months, health problems, Health Utilities Index scores or Strengths and Difficulties Questionnaire (SDQ) scores. When SDQ scores were dichotomised, there was a significant finding for one subscale: a greater proportion of HFO children reported emotional symptoms. This finding was not replicated by parents' or teachers' reports. Two hundred and twenty-four teachers completed questionnaires regarding the children's educational attainment and provision. There were statistically significant differences in attainment in three subjects in favour of HFO: art and design, information technology, and design and technology. The HFO children had lower risk of receiving special education needs support [odds ratio 0.56 (95% CI 0.32 to 1.00)], but the difference was not significant. CONCLUSIONS: Follow-up at 11-14 years of age of extremely prematurely born infants entered into a randomised trial of HFO versus CV has demonstrated significant differences in lung function in favour of HFO. There was no evidence that this was offset by poorer functional outcomes; indeed, HFO children did better in some school subjects. It will be important to determine whether or not these differences are maintained after puberty as this is the last positive effect on lung function. TRIAL REGISTRATION: Current Controlled Trials ISRCTN98436149.